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| Product NDC Code | 51862-580 | ||||
|---|---|---|---|---|---|
| Drug Name | Budesonide (enteric coated) |
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| Type | Brand | ||||
| Pharm Class | Corticosteroid Hormone Receptor Agonists [MoA], Corticosteroid [EPC] |
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| Route | ORAL | ||||
| Dosage Form | CAPSULE, DELAYED RELEASE PELLETS | ||||
| RxCUI drug identifier | 1244214 | ||||
| Application Number | ANDA206623 | ||||
| Labeler Name | Mayne Pharma Inc. | ||||
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| Check if available Online | Get Medication Prices online with Discount |
Overdosage of BUDESONIDE (ENTERIC COATED)
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism and adrenal axis suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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) ] Most common adverse reactions (≥5%) in adults are: headache, respiratory infection, nausea, back pain, dyspepsia, dizziness, abdominal pain, flatulence, vomiting, fatigue, pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Occurring in greater than or equal to 5% of the patients in any treated group. in 8-Week Treatment Clinical Trials Budesonide capsules (enteric coated) Prednisolone 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. Adverse Reaction 9 mg n=520 Number (%) Placebo n=107 Number (%) 40 mg n=145 Number (%) Comparator This drug is not approved for the treatment of Crohn's disease in the United States. 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 Budesonide capsules (enteric coated) Prednisolone 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. Signs/Symptom 9 mg n=427 Number (%) Placebo n=107 Number (%) 40 mg n=145 Number (%) Total 145 (34%) 29 (27%) 69 (48%) Acne 63 (15) 14 (13) 33 (23) Statistically significantly different from budesonide capsules (enteric coated) 9 mg. 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 including hair growth increased, local and hair growth increased, general. 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. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of budesonide capsules (enteric coated). 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
| Budesonide capsules (enteric coated) | Prednisolone | |||
|---|---|---|---|---|
| Adverse Reaction | 9 mg n=520 Number (%) | Placebo n=107 Number (%) | 40 mg n=145 Number (%) | Comparator |
| 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) |
| Budesonide capsules (enteric coated) | Prednisolone | ||
|---|---|---|---|
| Signs/Symptom | 9 mg n=427 Number (%) | Placebo n=107 Number (%) | 40 mg n=145 Number (%) |
| 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) |
| 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 |
BUDESONIDE (ENTERIC COATED) Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS 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 or 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) ].
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics Treatment with glucocorticoids, including budesonide capsules (enteric coated) 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 AUC 0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients. Adults Plasma cortisol suppression was compared following five days' administration of budesonide capsules (enteric coated) 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 (AUC 0-24 ) was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide capsules (enteric coated) 9 mg per day. Pediatrics The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n=8, aged 9 to 14 years) and adults (n=6) with active Crohn's disease following administration of budesonide capsules (enteric coated) 9 mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC 0-24 of cortisol was 64% (±18%) in pediatrics and 50% (±27%) in adults after budesonide capsules (enteric coated) treatment [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) and Use in Specific Populations (8.4) ] . 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 (14.1) ] . After 8 weeks of treatment with 9 mg once daily budesonide capsules (enteric coated) 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 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 (pre-challenge) 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. to ACTH Challenge Following Administration of budesonide capsules (enteric coated) or Prednisolone for 8 weeks Budesonide Prednisolone Peak plasma cortisol above 18 mcg/dL At baseline 91% (20/22) 91% (21/23) At week 8 25% (4/16) 0% (0/18) Normal response to ACTH challenge At baseline 73% (16/22) 78% (18/23) At week 8 6% (1/16) 0% (0/18) 12.3 Pharmacokinetics Absorption Following administration of budesonide capsules (enteric coated), the time to peak concentration varied in individual patients between 30 and 600 minutes. 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. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing. Following oral administration of 9 mg of budesonide capsules (enteric coated) 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, respectively. Following administration of 9 mg of budesonide capsules (enteric coated) 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 nmol∙hr/L, respectively. Concomitant administration of a high-fat meal delayed the time to the peak concentration of budesonide from budesonide capsules (enteric coated) by 2.3 hours but did not significantly affect the AUC in healthy subjects. Distribution The mean volume of distribution (V ss ) of budesonide varied between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85% to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. Elimination Budesonide had a plasma clearance, 0.9 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. Metabolism Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrate 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. Excretion Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-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 is detected in urine. Specific Populations Age: Pediatric Population (8 years and older) The pharmacokinetics of budesonide were investigated in pediatric patients aged 9 to 14 years (n=8) after oral administration of budesonide capsules (enteric coated) and intravenous administration of budesonide. Following administration of 9 mg budesonide capsules (enteric coated) 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 (V ss ) 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 (5.1) , Use in Specific Population (8.4) ] . Hepatic Impairment 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 C max values demonstrated similar increases [see Dosage and Administration (2.4) , Warnings and Precautions (5.1) ] . 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. 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 Ketoconazole 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 (7.1) ] . Grapefruit Juice In an open, randomized, cross-over study, 8 healthy subjects were given budesonide capsules (enteric coated) 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 (7.1) ] . Oral Contraceptives (CYP3A4 Substrates) 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 μg 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. Omeprazole 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 budesonide capsules (enteric coated) 9 mg as a single dose was investigated. Omeprazole 20 mg once daily did not affect the absorption or pharmacokinetics of budesonide. Cimetidine 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. Co-administration of cimetidine resulted in a 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.
| Budesonide | Prednisolone | |
|---|---|---|
| Peak plasma cortisol above 18 mcg/dL | ||
| At baseline | 91% (20/22) | 91% (21/23) |
| At week 8 | 25% (4/16) | 0% (0/18) |
| Normal response | ||
| At baseline | 73% (16/22) | 78% (18/23) |
| At week 8 | 6% (1/16) | 0% (0/18) |
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 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.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Treatment with glucocorticoids, including budesonide capsules (enteric coated) 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 AUC 0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients. Adults Plasma cortisol suppression was compared following five days' administration of budesonide capsules (enteric coated) 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 (AUC 0-24 ) was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide capsules (enteric coated) 9 mg per day. Pediatrics The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n=8, aged 9 to 14 years) and adults (n=6) with active Crohn's disease following administration of budesonide capsules (enteric coated) 9 mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC 0-24 of cortisol was 64% (±18%) in pediatrics and 50% (±27%) in adults after budesonide capsules (enteric coated) treatment [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) and Use in Specific Populations (8.4) ] . 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 (14.1) ] . After 8 weeks of treatment with 9 mg once daily budesonide capsules (enteric coated) 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 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 (pre-challenge) 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. to ACTH Challenge Following Administration of budesonide capsules (enteric coated) or Prednisolone for 8 weeks Budesonide Prednisolone Peak plasma cortisol above 18 mcg/dL At baseline 91% (20/22) 91% (21/23) At week 8 25% (4/16) 0% (0/18) Normal response to ACTH challenge At baseline 73% (16/22) 78% (18/23) At week 8 6% (1/16) 0% (0/18)
| Budesonide | Prednisolone | |
|---|---|---|
| Peak plasma cortisol above 18 mcg/dL | ||
| At baseline | 91% (20/22) | 91% (21/23) |
| At week 8 | 25% (4/16) | 0% (0/18) |
| Normal response | ||
| At baseline | 73% (16/22) | 78% (18/23) |
| At week 8 | 6% (1/16) | 0% (0/18) |
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Absorption Following administration of budesonide capsules (enteric coated), the time to peak concentration varied in individual patients between 30 and 600 minutes. 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. Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 to 15 mg. No accumulation of budesonide was observed following repeated dosing. Following oral administration of 9 mg of budesonide capsules (enteric coated) 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, respectively. Following administration of 9 mg of budesonide capsules (enteric coated) 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 nmol∙hr/L, respectively. Concomitant administration of a high-fat meal delayed the time to the peak concentration of budesonide from budesonide capsules (enteric coated) by 2.3 hours but did not significantly affect the AUC in healthy subjects. Distribution The mean volume of distribution (V ss ) of budesonide varied between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85% to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. Elimination Budesonide had a plasma clearance, 0.9 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. Metabolism Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrate 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. Excretion Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [ 3 H]-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 is detected in urine. Specific Populations Age: Pediatric Population (8 years and older) The pharmacokinetics of budesonide were investigated in pediatric patients aged 9 to 14 years (n=8) after oral administration of budesonide capsules (enteric coated) and intravenous administration of budesonide. Following administration of 9 mg budesonide capsules (enteric coated) 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 (V ss ) 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 (5.1) , Use in Specific Population (8.4) ] . Hepatic Impairment 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 C max values demonstrated similar increases [see Dosage and Administration (2.4) , Warnings and Precautions (5.1) ] . 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. 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 Ketoconazole 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 (7.1) ] . Grapefruit Juice In an open, randomized, cross-over study, 8 healthy subjects were given budesonide capsules (enteric coated) 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 (7.1) ] . Oral Contraceptives (CYP3A4 Substrates) 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 μg 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. Omeprazole 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 budesonide capsules (enteric coated) 9 mg as a single dose was investigated. Omeprazole 20 mg once daily did not affect the absorption or pharmacokinetics of budesonide. Cimetidine 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. Co-administration of cimetidine resulted in a 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Budesonide 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) ] . Hypersensitivity to any of the ingredients in budesonide capsules (enteric coated). ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Budesonide, the active ingredient in budesonide extended-release capsules (enteric coated), is a synthetic corticosteroid. Budesonide is designated chemically as (RS)-11β, 16α, 17,21- tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is: Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 5 is 1.6 × 10 3 ionic strength 0.01. Budesonide capsules (enteric coated) is formulated as hard gelatin capsules filled with enteric-coated granules that dissolve at pH greater than 5.5. Each capsule for oral administration contains 3 mg of micronized budesonide with the following inactive ingredients: acetyltributyl citrate, ethylcellulose, hypromellose, methacrylic acid copolymer (type C powder), polyethylene glycol, polysorbate 80, sodium lauryl sulfate, sugar spheres (sucrose and corn starch), talc, and triethyl citrate. The capsule shells have the following inactive ingredients gelatin, D&C red #28, D&C red #33, and titanium dioxide. In addition, the black ink S-1-8114/S-1-8115 contains, black iron oxide, D&C yellow #10 aluminum lake, FD&C blue#1 brilliant blue FCF aluminum lake, FD&C blue #2 indigo carmine aluminum lake, FD&C red #40 allura red AC aluminum lake, propylene glycol, and shellac. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Administration Instructions ( 2.1 ): Take once daily in the morning. Swallow whole. Do not chew or crush. 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 capsules (enteric coated). 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 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) ].
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Budesonide extended-release capsules (enteric coated): 3 mg hard gelatin capsules with a pink opaque cap and white opaque body printed with "m580" on the cap in black ink. Capsules: 3 mg ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Budesonide capsules (enteric coated) are a 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 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.
Spl product data elements
Usually a list of ingredients in a drug product.BUDESONIDE (ENTERIC COATED) Budesonide Budesonide Budesonide Acetyltributyl citrate Ethylcellulose (10 MPA.S) Hypromellose, Unspecified METHACRYLIC ACID AND ETHYL ACRYLATE COPOLYMER Polyethylene Glycol, Unspecified Polysorbate 80 Sodium Lauryl Sulfate SUCROSE STARCH, CORN TALC TRIETHYL CITRATE GELATIN, UNSPECIFIED D&C RED NO. 28 D&C RED NO. 33 TITANIUM DIOXIDE FERROSOFERRIC OXIDE D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 PROPYLENE GLYCOL SHELLAC pink opaque cap white opaque body m580
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with budesonide were conducted in rats and mice. 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 (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test and the mouse micronucleus test. In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with budesonide were conducted in rats and mice. 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 (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test and the mouse micronucleus test. In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 3 mg Capsule Bottle Label NDC 51862-580-01 Budesonide Capsules (Enteric Coated) 3 mg PHARMACIST: Dispense the accompanying Patient Information leaflet to each patient. Rx Only 100 Capsules mayne pharma PRINCIPAL DISPLAY PANEL - 3 mg Capsule Bottle Label
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.Distributed by: Mayne Pharma Greenville, NC 27834 61852 Revised – 10/2019
BUDESONIDE (ENTERIC COATED): Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise Patients to read the FDA-Approved patient labeling (Patient Information). Hypercorticism and Adrenal Axis Suppression Advise patients that budesonide capsules (enteric coated) may cause hypercorticism and adrenal axis suppression and to follow a taper schedule, as instructed by their healthcare provider if transferring to budesonide capsules (enteric coated) from systemic corticosteroids [see Warnings and Precautions (5.1) , (5.2) ] . Advise patients that 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. Increased Risk of Infection Advise patients to avoid exposure to people with chicken pox or measles and, if exposed, to consult their healthcare provider immediately. Inform patients that they are at increased risk of developing a variety of infections; including worsening of existing tuberculosis, fungal, bacterial, viral or parasitic infections or ocular herpes simplex and to contact their healthcare provider if they develop any symptoms of infection [see Warnings and Precautions (5.3) ] . Pregnancy Advise female patients that budesonide capsules (enteric coated) may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1) ] . Administration Advise patients to: 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 their budesonide capsules (enteric coated) therapy [see Drug Interactions (7.1) ] .
Spl patient package insert
Information necessary for patients to use the drug safely and effectively.PATIENT INFORMATION Budesonide (bue-des-oh-nide) extended-release Capsules (Enteric Coated) Rx Only Read this Patient Information before you start taking budesonide capsules (enteric coated) and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What are budesonide capsules (enteric coated)? Budesonide capsules (enteric coated) are a prescription corticosteroid medicine used to treat mild to moderate Crohn's disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon): in people 8 years of age and older with active Crohn's disease in adults to help keep symptoms from coming back for up to 3 months. It is not known if budesonide capsules (enteric coated) are safe and effective in children under 8 years of age, or in children 8 to 17 years of age who weigh 55 pounds (25 kg) or less, for the treatment of mild to moderate active Crohn's disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon). It is not known if budesonide capsules (enteric coated) is safe and effective in children to help keep symptoms of mild to moderate Crohn's disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon) from coming back. Who should not take budesonide capsules (enteric coated)? Do not take budesonide capsules (enteric coated) if: you are allergic to budesonide or any of the ingredients in budesonide capsules (enteric coated). See the end of this leaflet for a complete list of ingredients in budesonide capsules (enteric coated). What should I tell my healthcare provider before taking budesonide capsules (enteric coated)? Before you take budesonide capsules (enteric coated) tell your healthcare provider if you: have liver problems. are planning to have surgery. have chicken pox or measles or have recently been near anyone with chicken pox or measles. have an infection. have diabetes or glaucoma or have a family history of diabetes or glaucoma. have cataracts. have or had tuberculosis. have high blood pressure (hypertension). have decreased bone mineral density (osteoporosis). have stomach ulcers. have any other medical condition. are pregnant or plan to become pregnant. Budesonide capsules (enteric coated) may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take budesonide capsules (enteric coated) when you are pregnant. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during your treatment with budesonide capsules (enteric coated). are breastfeeding or plan to breastfeed. It is not known if budesonide capsules (enteric coated) passes into your breast milk or if it will affect your baby. Talk to your healthcare provider about the best way to feed your baby if you take budesonide capsules (enteric coated). Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide capsules (enteric coated) and other medicines may affect each other causing side effects. How should I take budesonide capsules (enteric coated)? Take budesonide capsules (enteric coated) exactly as your healthcare provider tells you. Your healthcare provider will tell you how many budesonide capsules (enteric coated) to take. Your healthcare provider may change your dose if needed. Take budesonide capsules (enteric coated) 1 time each day in the morning. Take budesonide capsules (enteric coated) whole. Do not chew or crush budesonide capsules (enteric coated) before swallowing. If you take too much budesonide capsules (enteric coated) call your healthcare provider right away or go to the nearest hospital emergency room. What should I avoid while taking budesonide capsules (enteric coated)? Do not drink grapefruit juice during your treatment with budesonide capsules (enteric coated). Drinking grapefruit juice can increase the level of budesonide capsules (enteric coated) in your blood. What are the possible side effects of budesonide capsules (enteric coated)? Budesonide capsules (enteric coated) may cause serious side effects, including: Effects of having too much corticosteroid medicine in your blood (hypercorticism). Long-time use of budesonide capsules (enteric coated) can cause you to have too much corticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: acne bruise easily rounding of your face (moon face) ankle swelling thicker or more hair on your body and face a fatty pad or hump between your shoulders (buffalo hump) pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms Adrenal suppression. When budesonide capsules (enteric coated) are taken for a long period of time (chronic use), adrenal suppression can happen. This is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and low blood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide capsules (enteric coated). Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide capsules (enteric coated) may cause your allergies to come back. These allergies may include a skin condition called eczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while taking budesonide capsules (enteric coated). Increased risk of infection. Budesonide capsules (enteric coated) weakens your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles, while taking budesonide capsules (enteric coated). Tell your healthcare provider right away if you come in contact with anyone who has chicken pox or measles. Tell your healthcare provider about any signs or symptoms of infection during treatment with budesonide capsules (enteric coated), including: fever pain aches chills feeling tired nausea and vomiting The most common side effects of budesonide capsules (enteric coated) in adults include: headache infection in your air passages (respiratory infection) nausea back pain indigestion dizziness stomach area (abdominal) pain gas vomiting tiredness pain The most common side effects of budesonide capsules (enteric coated) in children 8 to 17 years of age, who weigh more than 55 pounds (25 kg), are similar to the most common side effects in adults. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of budesonide capsules (enteric coated). For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Mayne Pharma at 1-844-825-8500. How should I store budesonide capsules (enteric coated)? Store budesonide capsules (enteric coated) at room temperature between 68°F to 77°F (20°C to 25°C). Keep budesonide capsules (enteric coated) in a tightly closed container. Keep budesonide capsules (enteric coated) and all medicines out of the reach of children. General information about the safe and effective use of budesonide capsules (enteric coated). Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide capsules (enteric coated) for a condition for which it was not prescribed. Do not give budesonide capsules (enteric coated) to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about budesonide capsules (enteric coated) that is written for health professionals. What are the ingredients in budesonide capsules (enteric coated)? Active ingredient: budesonide Inactive ingredients: acetyltributyl citrate, ethylcellulose, hypromellose, methacrylic acid copolymer (type C powder), polyethylene glycol, polysorbate 80, sodium lauryl sulfate, sugar spheres (sucrose and corn starch), talc, and triethyl citrate. The capsule shell has the following inactive ingredients gelatin, D&C red #28, D&C red #33, and titanium dioxide. In addition, the black ink S-1-8114/S-1-8115 contains, black iron oxide, D&C yellow #10 aluminum lake, FD&C blue#1 brilliant blue FCF aluminum lake, FD&C blue #2 indigo carmine aluminum lake, FD&C red #40 allura red AC aluminum lake, propylene glycol, and shellac. Distributed by: Mayne Pharma Greenville, NC 27834 For more information contact Mayne Pharma at 1-844-825-8500. This Patient Information has been approved by the U.S. Food and Drug Administration. Rev 10/2019
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Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Treatment of Mild to Moderate Active Crohn's Disease Adults The efficacy of budesonide capsules (enteric coated) 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 budesonide capsules (enteric coated). 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 capsules (enteric coated) 9 mg daily in the morning to a comparator. At baseline, the median CDAI was 272. Budesonide capsules (enteric coated) 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 Clinical Budesonide Capsules (enteric coated) Budesonide Capsules (enteric coated) Placebo Prednisolone Study 9 mg Daily 4.5 mg Twice Daily Comparator This drug is not approved for the treatment of Crohn's disease in the United States 1 62/91 (69%) p=0.0004 compared to comparator. 37/83 (45%) 2 31/61 (51%) p=0.001 compared to placebo. 13/64 (20%) 3 38/79 (48%) 41/78 (53%) 13/40 (33%) 4 35/58 (60%) 25/60 (42%) 35/58 (60%) 5 45/86 (52%) 56/85 (65%) 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 capsules (enteric coated) (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 capsules (enteric coated) 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 capsules (enteric coated) 9 mg once daily, budesonide capsules (enteric coated) 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 capsules (enteric coated) dose levels were statistically different from placebo (Table 5). The recommended dosage of budesonide capsules (enteric coated) 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 (2.1) ] . Two clinical trials (Studies 4 and 5) compared budesonide capsules (enteric coated) with oral prednisolone (initial dose 40 mg per day). Study 4 was a 3-armed parallel group study. The groups were treated with budesonide capsules (enteric coated) 9 mg once daily, budesonide capsules (enteric coated) 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for 8 weeks, followed by a 4-week double blind taper phase. At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the budesonide capsules (enteric coated) 9 mg daily and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in the budesonide capsules (enteric coated) 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 capsules (enteric coated) groups in both trials (60 to 66%) than in the prednisolone groups (26 to 28%) at Week 8. Pediatrics (8 to 17 Years of Age) The effectiveness of budesonide capsules (enteric coated), 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 capsules (enteric coated) 9 mg once daily, with prednisolone, administered at tapering doses starting from 1 mg/kg. Twenty-two (22) patients were treated with budesonide capsules (enteric coated) and 24 patients were treated with prednisolone. After 8 weeks of treatment, 55% (95% CI: 32%, 77%) of patients treated with budesonide capsules (enteric coated) 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 capsules (enteric coated) 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 capsules (enteric coated) and 1.64 at baseline to 0.38 after 8 weeks of treatment with prednisolone. Use of budesonide capsules (enteric coated) in this age group is supported by evidence from adequate and well- controlled studies of budesonide capsules (enteric coated) in adults, and by safety and pharmacokinetic studies performed in pediatric patients. 14.2 Maintenance of Clinical Remission of Mild to Moderate Crohn's Disease Adults The efficacy of budesonide capsules (enteric coated) 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 capsules (enteric coated) 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 capsules (enteric coated) 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 capsules (enteric coated) 6 mg per day. Budesonide capsules (enteric coated) 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% vs. 45% for placebo).
| Clinical | Budesonide Capsules (enteric coated) | Budesonide Capsules (enteric coated) | Placebo | Prednisolone | |
|---|---|---|---|---|---|
| Study | 9 mg Daily | 4.5 mg Twice Daily | Comparator | ||
| 1 | 62/91 (69%) | 37/83 (45%) | |||
| 2 | 31/61 (51%) | 13/64 (20%) | |||
| 3 | 38/79 (48%) | 41/78 (53%) | 13/40 (33%) | ||
| 4 | 35/58 (60%) | 25/60 (42%) | 35/58 (60%) | ||
| 5 | 45/86 (52%) | 56/85 (65%) | |||
References
This field may contain references when prescription drug labeling must summarize or otherwise relay on a recommendation by an authoritative scientific body, or on a standardized methodology, scale, or technique, because the information is important to prescribing decisions.15 REFERENCES 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.
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Clinical studies of budesonide capsules (enteric coated) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 651 patients treated with budesonide capsules (enteric coated) in clinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years of age. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and effectiveness of budesonide capsules (enteric coated) have been established in pediatric patients 8 to 17 years of age who weigh more than 25 kg for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. Use of budesonide capsules (enteric coated) in this age group is supported by evidence from adequate and well controlled studies of budesonide capsules (enteric coated) in adults, with additional data from 2 clinical studies in 149 pediatric patients treated up to 8 weeks and one pharmacokinetic study in 8 pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . The observed safety profile of budesonide capsules (enteric coated) in pediatric patients is consistent with its known safety profile in adults and no new safety concerns were identified [see Adverse Reactions (6.1) ] . Systemic corticosteroids, including budesonide capsules (enteric coated), may cause a reduction of growth velocity in pediatric patients. Pediatric patients with Crohn's disease have a 17% higher mean systemic exposure and cortisol suppression than adults with Crohn's disease [see Warning and Precautions (5.1) and Clinical Pharmacology (12.2) ] . The safety and effectiveness of budesonide capsules (enteric coated) have not been established in pediatric patients less than 8 years of age for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. The safety and effectiveness of budesonide capsules (enteric coated) have not been established in pediatric patients for the maintenance of clinical remission of mild to moderate Crohn's disease. An open-label study to evaluate the safety and tolerability of budesonide capsules (enteric coated) as maintenance treatment in pediatric patients aged 5 to 17 years was conducted, and did not establish the safety and efficacy of maintenance of clinical remission.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations [see Clinical Considerations ]. In animal reproduction studies with pregnant rats and rabbits, administration of subcutaneous budesonide during organogenesis at doses approximately 0.5 times or 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have a background of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Some published epidemiological studies show an association of adverse pregnancy outcomes in women with Crohn's disease, including preterm birth and low birth weight infants, during periods of increased disease activity (including increased stool frequency and abdominal pain). Pregnant women with Crohn's disease should be counseled regarding the importance of controlling disease. Fetal/Neonatal adverse reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1) ]. Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In a peri-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation along with delayed sexual maturation at exposures 0.2 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations [see Clinical Considerations ]. In animal reproduction studies with pregnant rats and rabbits, administration of subcutaneous budesonide during organogenesis at doses approximately 0.5 times or 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have a background of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Some published epidemiological studies show an association of adverse pregnancy outcomes in women with Crohn's disease, including preterm birth and low birth weight infants, during periods of increased disease activity (including increased stool frequency and abdominal pain). Pregnant women with Crohn's disease should be counseled regarding the importance of controlling disease. Fetal/Neonatal adverse reactions Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1) ]. Data Animal Data Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In a peri-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation along with delayed sexual maturation at exposures 0.2 times the MRHD (on a mg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity. 8.2 Lactation Risk Summary Lactation studies have not been conducted with oral budesonide, including budesonide capsules (enteric coated), and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide [ see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for budesonide capsules (enteric coated) and any potential adverse effects on the breastfed infant from budesonide capsules (enteric coated), or from the underlying maternal condition. Data One published study reports that budesonide is present in human milk following maternal inhalation of budesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of budesonide capsules (enteric coated) is higher (up to 9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single-and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5 to 10nmol/L which is up to 10 times higher than the1 to 2 nmol/L for a 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of budesonide capsules (enteric coated), budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. 8.4 Pediatric Use The safety and effectiveness of budesonide capsules (enteric coated) have been established in pediatric patients 8 to 17 years of age who weigh more than 25 kg for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. Use of budesonide capsules (enteric coated) in this age group is supported by evidence from adequate and well controlled studies of budesonide capsules (enteric coated) in adults, with additional data from 2 clinical studies in 149 pediatric patients treated up to 8 weeks and one pharmacokinetic study in 8 pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ] . The observed safety profile of budesonide capsules (enteric coated) in pediatric patients is consistent with its known safety profile in adults and no new safety concerns were identified [see Adverse Reactions (6.1) ] . Systemic corticosteroids, including budesonide capsules (enteric coated), may cause a reduction of growth velocity in pediatric patients. Pediatric patients with Crohn's disease have a 17% higher mean systemic exposure and cortisol suppression than adults with Crohn's disease [see Warning and Precautions (5.1) and Clinical Pharmacology (12.2) ] . The safety and effectiveness of budesonide capsules (enteric coated) have not been established in pediatric patients less than 8 years of age for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon. The safety and effectiveness of budesonide capsules (enteric coated) have not been established in pediatric patients for the maintenance of clinical remission of mild to moderate Crohn's disease. An open-label study to evaluate the safety and tolerability of budesonide capsules (enteric coated) as maintenance treatment in pediatric patients aged 5 to 17 years was conducted, and did not establish the safety and efficacy of maintenance of clinical remission. 8.5 Geriatric Use Clinical studies of budesonide capsules (enteric coated) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 651 patients treated with budesonide capsules (enteric coated) in clinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years of age. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment 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 to budesonide [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider dosage reduction in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4) ] . No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING Budesonide extended-release capsules (enteric coated) are size #1 hard gelatin capsules with a pink opaque cap and a white opaque body printed with "m580" on the cap in black ink containing 3 mg of budesonide, USP. Capsules are supplied as follows: NDC 51862-580-01 Bottles of 100 Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep container tightly closed.
| NDC 51862-580-01 | Bottles of 100 |
Storage and handling
Information about safe storage and handling of the drug product.Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep container tightly closed.
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API