Budesonide Capsule, Coated Pellets

Budesonide delayed-release capsules are corticosteroid indicated for: • Treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon, in patients 8 years and older. (1.1)

• 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. (1.2) 1.1 Treatment of Mild to Moderate Active Crohn’s Disease

Budesonide delayed-release capsules 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 delayed-release capsules 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.

Hypersensitivity to budesonide or any of the ingredients in budesonide delayed-release capsules. (4) Budesonide delayed-release capsules are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide delayed-release capsules. Serious hypersensitivity reactions, including anaphylaxis have occurred

[see Adverse Reactions (6.2)].

Most common adverse reactions (≥ 5%) in adults are: headache, respiratory infection, nausea, back pain, dyspepsia, dizziness, abdominal pain, flatulence, vomiting, fatigue and pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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)]

• Immunosuppression and increased risk of infection [see Warnings and Precautions (5.3)]

• Kaposi's sarcoma [see Warnings and Precautions (5.4)]

• Other corticosteroid effects

[see Warnings and Precautions (5.5)] 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 delayed-release capsules 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 delayed-release capsules 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

1in 8-Week Treatment Clinical Trials

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

2Prednisolone 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.

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

Adverse Reaction

Budesonide Delayed-Release Capsules

9 mg

n=520

Number (%)

Placebo

n=107

Number (%)

Prednisolone

2

40 mg

n=145

Number (%)

Comparator

3

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 Clinical Trials

1Prednisolone tapering scheme: either 40 mg in week 1 to 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.

2Statistically significantly different from budesonide delayed-release capsules 9 mg.

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

Budesonide Delayed-Release Capsules

9 mg

n=427

Placebo

n=107

Prednisolone

1

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)

Hirsutism

3

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 delayed-release capsules 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 delayed-release capsules 6 mg once daily.

The adverse reaction profile of budesonide delayed-release capsules 6 mg once daily in maintenance of Crohn's disease was similar to that of short-term treatment with budesonide delayed-release capsules 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 Delayed-Release Capsules

3 mg

n=88

Budesonide Delayed-release Capsules

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

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 delayed-release capsules 9 mg (total daily dose) in short-term treatment clinical studies and/or budesonide delayed-release capsules 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 delayed-release capsules (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 delayed-release capsules 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 delayed-release capsules, 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. 6.2 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of budesonide delayed-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Anaphylactic reactions

Nervous System Disorders: Benign intracranial hypertension

Psychiatric Disorders: Mood swings

• Hypercorticism and Adrenal Axis Suppression

: May occur with treatment; monitor for signs and symptoms; pediatrics and patients with hepatic impairment may be at increased risk. (2.4, 5.1, 8.4, 8.6)

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

: Taper slowly from corticosteroids with high systemic effects; monitor for withdrawal symptoms and unmasking of allergies (rhinitis, eczema). (5.2)

• Immunosuppression and Increased Risk of Infection

: Increased risk of viral, bacterial, fungal, protozoal and helminthic infections, including potentially fatal varicella and measles infection. Monitor patients for new or worsening infection and consider drug discontinuation. Avoid use in patients with fungal infections,

Strongyloides

infestation, cerebral malaria and ocular herpes simplex. Screen for hepatitis B infection. (5.3)

• Karposi's Sarcoma

: Reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. (5.4)

• Other Corticosteroid Effects

: Monitor patients with concomitant conditions where corticosteroids may have unwanted effects (e.g., hypertension, diabetes mellitus). (5.5) 5.1 Hypercorticism and Adrenal Axis Suppression

Systemic effects such as hypercorticism and adrenal axis suppression may occur with use of corticosteroids, including budesonide delayed-release capsules [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. 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)]. Monitor patients for signs and symptoms of hypercorticism and adrenal axis suppression during treatment with budesonide delayed-release capsules.

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)].

Corticosteroids, including budesonide delayed-release capsules, 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. 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 delayed-release capsules, 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 delayed-release capsules may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. 5.3 Immunosuppression and Increased Risk of Infection

Corticosteroids, including budesonide delayed-release capsules, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: • Reduce resistance to new infections

• Exacerbate existing infections

• Increase the risk of disseminated infections

• Increase the risk of reactivation or exacerbation of latent infections

• Mask some signs of infection

Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

Monitor patients for the development of infection and consider discontinuation of budesonide delayed-release capsules if the patient develops an infection while on treatment.

Tuberculosis

If budesonide delayed-release capsules is used in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged budesonide delayed-release capsules therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis.

Varicella Zoster and Measles Viral Infections

Varicella and measles can have a serious or even fatal course in non-immune pediatric and adult patients taking corticosteroids, including budesonide delayed-release capsules. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles: • If a budesonide delayed-release capsules-treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered.

• If a budesonide delayed-release capsules-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated.

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including budesonide delayed-release capsules. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with budesonide delayed-release capsules. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections

Corticosteroids, including budesonide delayed-release capsules, may exacerbate systemic fungal infections; therefore, avoid budesonide delayed-release capsules use in the presence of such infections. For patients on chronic budesonide delayed-release capsules therapy who develop systemic fungal infections, budesonide delayed-release capsules withdrawal or dosage reduction is recommended.

Amebiasis

Corticosteroids, including budesonide delayed-release capsules, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating budesonide delayed-release capsules in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation

Avoid budesonide delayed-release capsules in patients with known or suspected

Strongyloides

(threadworm) infection. Corticosteroid-induced immunosuppression may lead to

Strongyloides

superinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Cerebral Malaria

Avoid corticosteroids, including budesonide delayed-release capsules, in patients with cerebral malaria.

Ocular Herpes Simplex

Avoid corticosteroids, including budesonide delayed-release capsules, in patients with active ocular herpes simplex. 5.4 Kaposi’s Sarcoma

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi's sarcoma. 5.5 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.

Administration Instructions (2.1) • Take once daily in the morning. • Swallow whole. Do not chew or crush. • For patients unable to swallow an intact capsule, open the capsules and empty the granules onto one tablespoonful of applesauce. Mix and consume the entire contents within 30 minutes. Do not chew or crush. Follow with 8 ounces of water. • Avoid consumption of grapefruit juice for the duration of therapy. Recommended Dosage Mild to moderate active Crohn's disease (2.2) • Adults: 9 mg once daily for up to 8 weeks; repeat 8 week treatment courses for recurring episodes of active disease. • Pediatrics 8 to 17 years who weigh more than 25 kg: 9 mg once daily for up to 8 weeks, followed by 6 mg once daily in the morning for 2 weeks. Maintenance of clinical remission of mild to moderate Crohn's disease (2.3) • Adults: 6 mg once daily for up to 3 months; taper to complete cessation after 3 months. Continued treatment for more than 3 months has not been shown to provide substantial clinical benefit. • When switching from oral prednisolone, begin tapering prednisolone concomitantly with initiating budesonide delayed-release capsules. Hepatic Impairment • Consider reducing the dosage to 3 mg once daily in adult patients with moderate hepatic impairment (Child-Pugh Class B). (2.4, 5.1, 8.6) 2.1 Administration Instructions • Take budesonide delayed-release capsules once daily in the morning. • Swallow budesonide delayed-release capsules whole. Do not chew or crush. • For patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows: • Place one tablespoonful of applesauce into a clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. • Open the capsule(s). • Carefully empty all the granules inside the capsule(s) on the applesauce. • Mix the granules with the applesauce. • Consume the entire contents within 30 minutes of mixing. Do not chew or crush the granules. Do not save the applesauce and granules for future use. • Follow the applesauce and granules immediately with a glass (8 ounces) of cool water to ensure complete swallowing of the granules. • Avoid consumption of grapefruit juice for the duration of budesonide delayed-release capsules therapy [see Drug Interactions (7.1)]. 2.2 Treatment of Mild to Moderate Active Crohn’s Disease The recommended dosage of budesonide delayed-release capsules is: Adults 9 mg orally once daily for up to 8 weeks. Repeated 8 week courses of budesonide delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating budesonide delayed-release capsules treatment. 2.4 Dosage Adjustment in Adult Patients with Hepatic Impairment Consider reducing the dosage of budesonide delayed-release capsules 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)].

Consider reducing the dosage of budesonide delayed-release capsules 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)] .

Delayed-Release Capsules: 3 mg (3) Budesonide Delayed-Release Capsules, 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.

CYP3A4 Inhibitors (e.g., ketoconazole, grapefruit juice)

: Can increase systemic budesonide concentrations: avoid use. (2.1, 7.1) 7.1 CYP3A4 Inhibitors

Budesonide is a substrate for CYP3A4. Avoid use with CYP3A4 inhibitors. Concomitant oral administration of a strong CYP3A4 inhibitor (ketoconazole) caused an eight-fold increase of the systemic exposure to oral budesonide. Inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine) can increase systemic budesonide concentrations [see Clinical Pharmacology (12.3)].

Grapefruit Juice

Avoid ingestion of grapefruit juice with budesonide. Intake of grapefruit juice which inhibits CYP3A4 activity with budesonide can increase the systemic exposure for budesonide [see Clinical Pharmacology (12.3)].