Budesonide Information
Budesonide () Description
Budesonide () , USP, the active ingredient of Budesonide () capsules (enteric coated), is a synthetic corticosteroid. It 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 molecular formula of Budesonide () is CHO and its molecular weight is 430.5 g/mole. Its structural formula is:
Budesonide () is a white or almost white crystalline powder that is freely soluble in methylene chloride, sparingly soluble in alcohol and practically insoluble in water. Its partition coefficient between octanol and water at pH 5 is 1.6 x 10 ionic strength 0.01.
Each capsule contains 3 mg of micronized Budesonide () with the following inactive ingredients: acetyltributyl citrate, colloidal silicon dioxide, crospovidone, dimethicone, ethylcellulose, FD&C Red No. 40, gelatin, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, polysorbate 80, sodium hydroxide, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate.
The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.
Budesonide () Clinical Pharmacology
Budesonide () has a high topical glucocorticosteroid (GCS) activity and a substantial first pass elimination. The formulation contains granules which are coated to protect dissolution in gastric juice, but which dissolve at pH > 5.5, i.e., normally when the granules reach the duodenum. Thereafter, a matrix of ethylcellulose with Budesonide () controls the release of the drug into the intestinal lumen in a time-dependent manner.
Budesonide () is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma levels of Budesonide () severalfold. Coadministration of ketoconazole results in an 8-fold increase in AUC of Budesonide () , compared to Budesonide () alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral Budesonide () . Conversely, induction of CYP3A4 can result in the lowering of Budesonide () plasma levels. Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of Budesonide () . Budesonide () does not affect the plasma levels of oral contraceptives (i.e., ethinyl estradiol).
Since the dissolution of the coating of Budesonide () capsules (enteric coated) is pH dependent (dissolves at pH > 5.5), the release properties and uptake of the compound may be altered after treatment with drugs that change the gastrointestinal pH. However, the gastric acid inhibitory drug omeprazole, 20 mg qd, does not affect the absorption or pharmacokinetics of Budesonide () capsules (enteric coated). When an uncoated oral formulation of Budesonide () is coadministered with a daily dose of cimetidine 1 g, a slight increase in the Budesonide () peak plasma concentration and rate of absorption occurs, resulting in significant cortisol suppression.
Budesonide () has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of Budesonide () to GCS receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.
Treatment with systemically active GCS is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. Markers, indirect and direct, of this are cortisol levels in plasma or urine and response to ACTH stimulation.
Plasma cortisol suppression was compared following 5 days’ administration of Budesonide () capsules (enteric coated) and prednisolone in a crossover study in healthy volunteers. The mean decrease in the integrated 0 to 24 hour plasma cortisol concentration was greater (78%) with prednisolone 20 mg/day compared to 45% with Budesonide () capsules (enteric coated) 9 mg/day.
The safety and 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 five randomized and double-blind studies. The study patients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. Of the 651 patients treated with Budesonide () capsules (enteric coated), 17 (2.6%) were ≥ 65 years of age and none were > 74 years of age. The Crohn’s Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these five studies. 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 wellbeing) 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 ≤ 150 assessed after 8 weeks of treatment, was the primary efficacy variable in these five comparative efficacy studies of Budesonide () capsules (enteric coated). Safety assessments in these studies included monitoring of adverse experiences. A checklist of potential symptoms of hypercorticism was used.
One study (Study 1) compared the safety and efficacy of Budesonide () capsules (enteric coated) 9 mg qd in the morning to a comparator. At baseline, the median CDAI was 272. Budesonide () capsules (enteric coated) 9 mg qd resulted in a significantly higher clinical improvement rate at Week 8 than the comparator (Table 1).
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 bid, 4.5 mg bid, or 7.5 mg bid) versus placebo. At baseline, the median CDAI was 290. The 3 mg per day dose level (data not shown) could not be differentiated from placebo. The 9 mg per day arm was statistically different from placebo (Table 1), while no additional benefit was seen when the daily Budesonide () capsules (enteric coated) dose was increased to 15 mg per day (data not shown). In Study 3, the median CDAI at baseline was 263. Neither 9 mg qd nor 4.5 mg bid Budesonide () capsules (enteric coated) dose levels was statistically different from placebo (Table 1).
Two clinical trials (Studies 4 and 5) compared Budesonide () capsules (enteric coated) with oral prednisolone (initial dose 40 mg per day). At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the Budesonide () capsules (enteric coated) 9 mg qd 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 1).
The proportion of patients with normal plasma cortisol values (≥ 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.
The efficacy and safety 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/day prolonged the time to relapse, defined as an increase in CDAI of at least 60 units to a total score > 150 or withdrawal due to disease deterioration. The median time to relapse in the pooled population of the four studies was 154 days for patients taking placebo, and 268 days for patients taking Budesonide () capsules (enteric coated) 6 mg/day. Budesonide () capsules (enteric coated) 6 mg/day reduced the proportion of patients with loss of symptom control relative to placebo in the pooled population for the four studies at 3 months (28% vs. 45% for placebo).
Budesonide () Indications And Usage
Budesonide () capsules (enteric coated) are indicated for:
Budesonide () Contraindications
Budesonide () capsules (enteric coated) are contraindicated in patients with known hypersensitivity to Budesonide () .
Budesonide () Warnings
Glucocorticosteroids 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 glucocorticosteroid is recommended. Since Budesonide () capsules (enteric coated) are a glucocorticosteroid, general warnings concerning glucocorticoids should be followed.
Care is needed in patients who are transferred from glucocorticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of systemic steroid should be reduced cautiously.
Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package insert for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.
Budesonide () Precautions
Caution should be taken in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.
Replacement of systemic glucocorticosteroids with Budesonide () capsules (enteric coated) may unmask allergies, e.g., rhinitis and eczema, which were previously controlled by the systemic drug.
When Budesonide () capsules (enteric coated) are used chronically, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur.
Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral Budesonide () has been demonstrated in patients with liver cirrhosis.
Budesonide () capsules (enteric coated) should be swallowed whole and NOT CHEWED OR BROKEN.
Patients should be advised to avoid the consumption of grapefruit juice for the duration of their Budesonide () capsules (enteric coated) therapy.
Patients should be given the patient package insert for additional information.
Carcinogenicity studies with Budesonide () were conducted in rats and mice. In a 2-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 2-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 sex-linked recessive lethality test, the rat hepatocycte 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).
The disposition of Budesonide () when delivered by inhalation from a dry powder inhaler at doses of 200 mcg or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to Budesonide () in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over 8 hours post-dose revealed that the maximum Budesonide () concentration for the 400 mcg and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of Budesonide () from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide () plasma concentrations obtained from five infants at about 90 minutes after breast-feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (
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 study. The maximum Budesonide () plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral Budesonide () approximately 5 to 10 nmol/L which is up to 10 times higher than the 1 to 2 nmol/L for a 800 mcg daily dose of inhaled Budesonide () at steady-state in the above inhalation study.
Since there are no data from controlled trials on the use of Budesonide () capsules (enteric coated) by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from Budesonide () capsules (enteric coated), a decision should be made whether to discontinue nursing or to discontinue Budesonide () capsules (enteric coated), taking into account the clinical importance of Budesonide () capsules (enteric coated) to the mother.
Budesonide () , like other corticosteroids, is secreted in human milk. Data from Budesonide () delivered via dry powder inhaler indicates that the total daily oral dose of Budesonide () available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. 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.
Budesonide () Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of Budesonide () capsules (enteric coated) was evaluated in 651 patients in five short-term, active disease state studies. They ranged in age from 17 to 74 (mean 35), 40% were male and 97% were white, 2.6% were ≥ 65 years of age. Five hundred and twenty patients were treated with Budesonide () capsules (enteric coated) 9 mg (total daily dose). In general, Budesonide () capsules (enteric coated) were well tolerated in these trials. The most common adverse events reported were headache, respiratory infection, nausea, and symptoms of hypercorticism. Clinical studies have shown that the frequency of glucocorticosteroid-associated adverse events was substantially reduced with Budesonide () capsules (enteric coated) compared with prednisolone at therapeutically equivalent doses. Adverse events occurring in ≥ 5% of the patients are listed in Table 2:
The safety of Budesonide () capsules (enteric coated) was evaluated in 233 patients in four long-term clinical trials (52 weeks). A total of 145 patients were treated with Budesonide () capsules (enteric coated) 6 mg. A total of 8% of Budesonide () capsules (enteric coated) patients discontinued treatment due to adverse events compared with 10% in the placebo group. The adverse event profile in long-term treatment of Crohn’s disease was similar to that of short-term treatment with Budesonide () capsules (enteric coated) 9 mg in active Crohn’s disease.
In the long-term clinical trials, the following adverse events occurred in ≥ 5% of the 6 mg Budesonide () capsules (enteric coated) patients and are not listed in Table 2 or by body system below: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).
Adverse events, occurring in 520 patients treated with Budesonide () capsules (enteric coated) 9 mg (total daily dose) in short-term active disease state studies, with an incidence of
For the 145 patients treated with Budesonide () capsules (enteric coated) 6 mg (total daily dose) in long-term studies, the following adverse events that are not included in the list above occurred with an incidence 2% and greater than for placebo: abscess, amnesia, dizziness, fever, pharynx disorder, purpura, rhinitis, and urinary tract infection.
Budesonide () 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 ≥ 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, C-reactive protein increased, and adrenal insufficiency.
Budesonide () Overdosage
Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy.
If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal 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.
Budesonide () Dosage And Administration
The recommended adult dosage for the treatment of mild to moderate active Crohn's disease involving the ileum and/or the ascending colon is 9 mg taken once daily in the morning for up to 8 weeks. Repeated 8-week courses of Budesonide () capsules (enteric coated) can be given for recurring episodes of active disease.
Following an 8-week course(s) of treatment for active disease and once the patient’s symptoms are controlled (CDAI
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.
Budesonide () How Supplied
Budesonide () Capsules (enteric coated) are available as 3 mg capsules.
The 3 mg capsule is a red opaque cap/red opaque body, hard-shell gelatin capsule filled with white to off-white enteric-coated pellets with no markings. The capsule is axially printed with over in black ink on both the cap and body. They are available as follows:
NDC 0378-7155-01bottles of 100 capsules
NDC 0378-7155-05bottles of 500 capsules
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
Budesonide () References
1. Fält A, Bengtsson T, Kennedy B, . Exposure of infants to Budesonide () through breast milk of asthmatic mothers. 2007, 120(4). 798-802.
Budesonide () Patient Information Leaflet Budesonide Capsules (enteric Coated)
Read this information carefully before you begin treatment. Read the information you get whenever you get more medicine. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Budesonide () capsules (enteric coated), ask your health care provider (provider). Only your provider can determine if Budesonide () capsules (enteric coated) are right for you.
Budesonide () capsules (enteric coated) are a medicine to treat mild to moderate Crohn’s disease in many people. However, it does not work for everyone who takes it. Budesonide () capsules (enteric coated) are a corticosteroid, which means it works mainly in one area of the body. The medicine in Budesonide () capsules (enteric coated) is released in the intestine. Therefore, it controls the symptoms of Crohn’s disease even though 90% of the drug does not go into the bloodstream. Because of this, it causes fewer severe side effects than other corticosteroids. (See the end of this Patient Information for information about Crohn’s disease.)
To help your provider decide if Budesonide () capsules (enteric coated) are right for you, tell your provider:
Take Budesonide () capsules (enteric coated) in the morning. Swallow each Budesonide () capsule (enteric coated) whole. . Your provider will tell you how long to take Budesonide () capsules (enteric coated).
Patients who take medicines that suppress the immune system, such as Budesonide () capsules (enteric coated), are more likely to get infections. Avoid people with infections. Also, if you never had chicken pox or measles, be careful to avoid people with these conditions. These conditions can be more serious if you get them while taking Budesonide () capsules (enteric coated).
While you are taking Budesonide () capsules (enteric coated), do not drink grapefruit juice regularly. Grapefruit juice can increase the amount of Budesonide () in your blood. Other juices, like orange juice or apple juice, do not have this effect.
The most common side effects of Budesonide () capsules (enteric coated) are headache, infection in your air passages (respiratory infection), nausea, and symptoms of hypercorticism (too much steroids in your body).
These symptoms include an increase in the size of the face and neck, acne, and bruising. Most symptoms of too much steroids in your body occur less often with Budesonide () capsules (enteric coated) than with other steroids.
Call your provider right away if you notice itching, skin rash, fever, swelling of your face and neck, or trouble breathing while you are taking Budesonide () capsules (enteric coated). These may be signs that you are allergic to the medicine and you may need emergency medical help.
Switching from a systemic medicine, like prednisone, to a nonsystemic medicine, such as Budesonide () capsules (enteric coated), can cause allergies controlled by the systemic medicine to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside the nose).
These are not all the possible side effects of Budesonide () capsules (enteric coated). Ask your provider or pharmacist for a complete listing of all possible side effects of Budesonide () capsules (enteric coated).
Crohn’s disease is an inflammatory bowel disease. The inflammation caused by Crohn’s disease is usually found in a part of the small intestine called the ileum and in the large intestine (colon). It may also occur in any part of the gastrointestinal tract (digestive system) from the mouth to the anus (rectum). The cause of Crohn’s disease is not yet known.
There are many symptoms of Crohn’s disease. These include diarrhea, crampy abdominal (stomach area) pain, fever, and sometimes bleeding from the rectum. Appetite loss followed by weight loss may occur. There may also be redness and soreness of the eyes, joint pain, and sores on the skin. These symptoms may range from mild to severe.
There is no cure yet for Crohn’s disease. However, it is possible for the disease to quiet down (go into remission). During these periods of remission, there may be times when the symptoms get worse. In general, people with Crohn’s disease are able to lead productive lives.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. 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. Keep Budesonide () capsules (enteric coated) and all medicines out of the reach of children.
This leaflet summarizes the most important information about Budesonide () capsules (enteric coated). If you would like more information, talk with your provider. You can ask your pharmacist or provider for information about Budesonide () capsules (enteric coated) that is written for health professionals. You can also call 1-877-446-3679 (1-877-4-INFO-RX) for more information.
Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.
DECEMBER 2010BUDE:R1ppt
Budesonide ()
