Budesonide

BUDESONIDE- budesonide capsule, coated pellets
Northstar Rx LLC.

1 INDICATIONS AND USAGE

1.1 Treatment of Mild to Moderate Active Crohn’s Disease

Budesonide capsules (enteric coated) are indicated for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon in patients 8 years of age and older.

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

Budesonide capsules (enteric coated) are indicated for the maintenance of clinical remission of mild to moderate Crohn’s disease involving the ileum and/or the ascending colon for up to 3 months in adults.

2 DOSAGE AND ADMINISTRATION

2.1 Administration Instructions

  • Take budesonide capsules (enteric coated) once daily in the morning.
  • Swallow budesonide extended-release capsules (enteric coated) whole. Do not chew or crush.
  • Avoid consumption of grapefruit juice for the duration of budesonide capsules (enteric coated) therapy [see Drug Interactions (7.1)].

2.2 Treatment of Mild to Moderate Active Crohn’s Disease

The recommended dosage of budesonide capsules (enteric coated) is:

Adults

9 mg orally once daily for up to 8 weeks. Repeated 8 week courses of budesonide capsules (enteric coated)can be given for recurring episodes of active disease.

Pediatric patients 8 to 17 years who weigh more than 25 kg

9 mg orally once daily for up to 8 weeks, followed by 6 mg once daily for 2 weeks.

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

The recommended dosage in adults, following an 8 week course(s) of treatment for active disease and once the patient’s symptoms are controlled (CDAI less than 150), is budesonide capsules(enteric coated) 6 mg orally once daily for maintenance of clinical remission up to 3 months. If symptom control is still maintained at 3 months an attempt to taper to complete cessation is recommended. Continued treatment with budesonide capsules (enteric coated) 6 mg for more than 3 months has not been shown to provide substantial clinical benefit.

Patients with mild to moderate active Crohn’s disease involving the ileum and/or ascending colon have been switched from oral prednisolone to budesonide capsules (enteric coated) with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating budesonide capsules (enteric coated) treatment.

2.4 Dosage Adjustment in Adult Patients with Hepatic Impairment

Consider reducing the dosage of budesonide capsules (enteric coated) to 3 mg once daily for adult patients with moderate hepatic impairment (Child-Pugh Class B). Avoid use in patients with severe hepatic impairment (Child-Pugh Class C) [see Warnings and Precautions (5.1), Use in Specific Populations (8.6)].

3 DOSAGE FORMS AND STRENGTHS

Budesonide extended-release capsules (enteric coated), 3 mg are white to off-white, free flowing pellets, filled in size ’1′ hard gelatin capsules having opaque light-orange colored cap printed with “720″ in black ink and opaque white body.

4 CONTRAINDICATIONS

Budesonide extended-release capsules (enteric coated) are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide capsules (enteric coated). Serious hypersensitivity reactions, including anaphylaxis have occurred [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypercorticism and Adrenal Axis Suppression

When corticosteroids are used chronically, systemic effects such as hypercorticism and adrenal axis suppression may occur. Corticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic corticosteroid is recommended. Since budesonide capsules (enteric coated) contains a corticosteroid, general warnings concerning corticosteroids should be followed [see Warnings and Precautions (5.2), (5.3), (5.4)].

Pediatric patients with Crohn’s disease have a slightly higher systemic exposure of budesonide and increased cortisol suppression than adults with Crohn’s disease [see Use in Specific Populations (8.4), Clinical Pharmacology (12.2)]. Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider reducing the dosage in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

5.2 Symptoms of Steroid Withdrawal in Patients Transferred from Other Systemic Corticosteroids

Monitor patients who are transferred from corticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, such as budesonide capsules (enteric coated), since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic corticosteroids with budesonide capsules (enteric coated) may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

5.3 Increased Risk of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of corticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

5.4 Other Corticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in labeling:

  • Hypercorticism and adrenal axis suppression [see Warnings and Precautions (5.1)]
  • Symptoms of steroid withdrawal in those patients transferred from other systemic corticosteroids [see Warnings and Precautions (5.2)]
  • Increased risk of infection [see Warnings and Precautions (5.3)]
  • Other corticosteroid effects [see Warnings and Precautions (5.4)]

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 Reactions1 in 8-Week Treatment Clinical Trials

1 Occurring in greater than or equal to 5% of the patients in any treated group.

2 Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg per week; or 40 mg in week 1to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week.

3 This drug is not approved for the treatment of Crohn’s disease in the United States.

Adverse Reaction Budesonide 9 mg n=520 Number (%) Placebo n=107 Number (%) Prednisolone2 40 mg n=145 Number (%) Comparator3 n=88 Number (%)
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 ClinicalTrials

1 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.

2 Statistically significantly different from budesonide capsules (enteric coated) 9 mg.

3 including hair growth increased, local and hair growth increased, general.

Header$ Budesonide 9 mg n=427 Placebo n=107 Prednisolone1 40 mg n=145
Signs/Symptom Number (%) Number (%) Number (%)
Total 145 (34%) 29 (27%) 69 (48%)
Acne 63(15) 14(13) 33(23)2
Bruising Easily 63(15) 12(11) 13(9)
Moon Face 46(11) 4(4) 53(37)2
Swollen Ankles 32(7) 6(6) 13(9)
Hirsutism3 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) were 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 Studies
Header$ Budesonide 3 mg n=88 Budesonide 6 mg n=145 Placebo n=143
Signs/Symptom Number (%) Number (%) 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) 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, 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.

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