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ENTOCORT EC (Capsule)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4278

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ENTOCORT EC (Capsule)
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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 ENTOCORT EC 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<150), ENTOCORT EC 6 mg is recommended 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 ENTOCORT EC 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 ENTOCORT EC with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating ENTOCORT EC treatment. Hepatic Insufficiency: Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Reducing the dose of ENTOCORT EC capsules should be considered in these patients. CYP3A4 inhibitors: If concomitant administration with ketoconazole, or any other CYP3A4 inhibitor, is indicated, patients should be closely monitored for increased signs and/or symptoms of hypercorticism. Reduction in the dose of ENTOCORT EC capsules should be considered. ENTOCORT EC capsules should be swallowed whole and not chewed or broken.
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Budesonide, the active ingredient of ENTOCORT EC capsules, is a synthetic corticosteroid. It is designated chemically as (RS)-11��, 16��, 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 CHOand 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 x 10ionic strength 0.01. Each capsule contains 3 mg of micronized budesonide with the following inactive ingredients: ethylcellulose, acetyltributyl citrate, methacrylic acid copolymer type C, triethyl citrate, antifoam M, polysorbate 80, talc, and sugar spheres. The capsule shells have the following inactive ingredients: gelatin, iron oxide, and titanium dioxide.
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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, ie, 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.<br/>Pharmacokinetics:<br/>Absorption: The absorption of ENTOCORT EC seems to be complete, although Cand Tare variable. Time to peak concentration varies in individual patients between 30 and 600 minutes. Following oral administration of 9 mg of budesonide in healthy subjects, a peak plasma concentration of approximately 5 nmol/L is observed and the area under the plasma concentration time curve is approximately 30 nmolhr/L. The systemic availability after a single dose is higher in patients with Crohn's disease compared to healthy volunteers, (21% vs 9%) but approaches that in healthy volunteers after repeated dosing.<br/>Distribution: The mean volume of distribution (V) of budesonide varies 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 is about 0.8.<br/>Metabolism: Following absorption, budesonide is subject to high first pass metabolism (80-90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6��-hydroxy budesonide and 16��-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min. Similarly, high plasma clearance values have been shown in patients with Crohn's disease. These high plasma clearance values approach the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life, t, after administration of intravenous doses ranges between 2.0 and 3.6 hours, and does not differ between healthy adults and patients with Crohn's disease.<br/>Excretion: Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6��-hydroxy budesonide and 16��-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine.<br/>Special Populations: No significant pharmacokinetic differences have been identified due to sex.<br/>Hepatic Insufficiency: In patients with liver cirrhosis, systemic availability of orally administered budesonide correlates with disease severity and is, on average, 2.5-fold higher compared with healthy controls. Patients with mild liver disease are minimally affected. Patients with severe liver dysfunction were not studied. Absorption parameters are not altered, and for the intravenous dose, no significant differences in CL or Vare observed.<br/>Renal Insufficiency: The pharmacokinetics of budesonide in patients with renal impairment has not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide (<1/100). Thus, patients with impaired renal function taking budesonide are not expected to have an increased risk of adverse effects.<br/>Drug-Drug Interactions: Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma levels of budesonide severalfold. Co-administration of ketoconazole results in an eight-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 (ie, ethinyl estradiol). Since the dissolution of the coating of ENTOCORT EC 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 ENTOCORT EC. When an uncoated oral formulation of budesonide is co-administered 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.<br/>Food Effects: A mean delay in time to peak concentration of 2.5 hours is observed with the intake of a high-fat meal, with no significant differences in AUC.
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ENTOCORT EC is contraindicated in patients with known hypersensitivity to budesonide.
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ENTOCORT EC 3 mg capsules are hard gelatin capsules with an opaque light grey body and an opaque pink cap, coded with ENTOCORT EC 3 mg on the capsule. They are supplied as follows: NDC 65483-702-10Bottles of 100<br/>Storage:: Store at 25��C (77��F); excursions permitted to 15-30��C (59-86��F) [See USP Controlled Room Temperature]. Keep container tightly closed. ENTOCORT is a trademark of the AstraZeneca group of companies. PROMETHEUS is a trademark of Prometheus Laboratories Inc. ��AstraZeneca 2005 Manufactured by: AstraZeneca AB S-151 85 Sodertalje, Sweden Distributed by: Prometheus Laboratories Inc. Sand Diego, CA 92121 Product of Sweden EN004B05 30029-02 Rev 04/05<br/>PATIENT INFORMATION: 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 ENTOCORT EC (EN-toe-cort EE CEE), ask your health care provider (provider). Only your provider can determine if ENTOCORT EC is right for you. What is ENTOCORT EC? ENTOCORT EC is a medicine to treat mild to moderate Crohn's Disease in many people. However, it does not work for everyone who takes it. ENTOCORT EC is a nonsystemic corticosteroid, which means it works mainly in one area of the body. The medicine in ENTOCORT EC 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.) Who should not take ENTOCORT EC? Do not take ENTOCORT EC if: To help your provider decide if ENTOCORT EC is right for you, tell your provider: How should I take ENTOCORT EC? Take ENTOCORT EC in the morning. Swallow each ENTOCORT EC capsule whole. Do not open, chew, or crush ENTOCORT EC capsules. Your provider will tell you how long to take ENTOCORT EC. What should I avoid while taking ENTOCORT EC? Patients who take medicines that suppress the immune system, such as ENTOCORT EC, 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 ENTOCORT EC. While you are taking ENTOCORT EC, do not drink grapefruit juice regularly. Grapefruit juice can increase the amount of ENTOCORT EC in your blood. Other juices, like orange juice or apple juice, do not have this effect. What are the side effects of ENTOCORT EC? The most common side effects of ENTOCORT EC 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 ENTOCORT EC 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 ENTOCORT EC. 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 ENTOCORT EC, 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). Call your provider if These are not all the possible side effects of ENTOCORT EC. Ask your provider or pharmacist for a complete listing of all possible side effects of ENTOCORT EC. What is Crohn's disease? 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. General advice about prescription medicines Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ENTOCORT EC for a condition for which it was not prescribed. Do not give ENTOCORT EC to other people, even if they have the same symptoms you have. It may harm them. Keep ENTOCORT EC and all medicines out of the reach of children. This leaflet summarizes the most important information about ENTOCORT EC. If you would like more information, talk with your provider. You can ask your pharmacist or provider for information about ENTOCORT EC that is written for health professionals. You can also visit the ENTOCORT EC Web site at (www.EntocortEC.com) or call the information center at AstraZeneca toll-free (1-800-237-8898). ENTOCORT is a trademark of the AstraZeneca group of companies. PROMETHEUS is a trademark of Prometheus Laboratories Inc. ��AstraZeneca 2005 Manufactured by: AstraZeneca AB S-151 85 Sodertalje, Sweden Distributed by: Prometheus Laboratories Inc. San Diego, CA 92121 Product of Sweden EN004B05 30029-02 Rev 04/05
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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.
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Budesonide
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ENTOCORT EC (Capsule)
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The safety of ENTOCORT EC was evaluated in 651 patients. 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 ENTOCORT EC 9 mg (total daily dose). In general, ENTOCORT EC was 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 ENTOCORT EC capsules compared with prednisolone at therapeutically equivalent doses. Adverse events occurring in���5% of the patients are listed in Table 2: The safety of ENTOCORT EC was evaluated in 233 patients in four long-term clinical trials (52 weeks). A total of 145 patients were treated with ENTOCORT EC 6 mg. A total of 8% of ENTOCORT EC 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 ENTOCORT EC 9 mg in active Crohn's disease. In the long-term clinical trials, the following adverse events occurred in���5% of the 6 mg ENTOCORT EC 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 ENTOCORT EC 9 mg (total daily dose), with an incidence<5% and greater than placebo (n=107), are listed below by body system: Body as a Whole: asthenia, C-Reactive protein increased, chest pain, dependent edema, face edema, flu-like disorder, malaise; Cardiovascular:hypertension; Central and Peripheral Nervous System: hyperkinesia, paresthesia, tremor, vertigo; Gastrointestinal: anus disorder, Crohn's disease aggravated, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder; Hearing and Vestibular: Ear infection-not otherwise specified; Heart Rate and Rhythm: palpitation, tachycardia; Metabolic and Nutritional: hypokalemia, weight increase; Musculoskeletal: arthritis aggravated, cramps, myalgia; Psychiatric: agitation, appetite increased, confusion, insomnia, nervousness, sleep disorder, somnolence; Resistance Mechanism:moniliasis; Reproductive, Female: intermenstrual bleeding, menstrual disorder; Respiratory: bronchitis, dyspnea; Skin and Appendages: acne, alopecia, dermatitis, eczema, skin disorder, sweating increased; Urinary: dysuria, micturition frequency, nocturia; Vascular: flushing; Vision: eye abnormality, vision abnormal; White Blood Cell: leukocytosis For the 145 patients treated with ENTOCORT EC 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<5% but>2% and greater than for placebo: abscess, amnesia, dizziness, fever, pharynx disorder, purpura, rhinitis, and urinary tract infection.<br/>Glucocorticosteroid Adverse Reactions: Table 3 displays the frequency and incidence of symptoms of hypercorticism by active questioning of patients in clinical trials. In addition to the symptoms in Table 3, three cases of benign intracranial hypertension have been reported in patients treated with budesonide from post-marketing surveillance. A cause and effect relationship has not been established. Table 4 displays the frequency and incidence of symptoms of hypercorticism by active questioning of patients in long-term clinical trials. The incidence of symptoms of hypercorticism as described above in long-term clinical trials was similar to that seen in the short-term clinical trials. A randomized, open, parallel-group multicenter safety study specifically compared the effect of ENTOCORT EC (<9 mg/day) and prednisolone (<40 mg/day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with ENTOCORT EC than with prednisolone in steroid-na��ve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of treatment-emergent symptoms of hypercorticism was significantly higher with prednisolone treatment.
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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 ENTOCORT EC is 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.
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ENTOCORT EC is indicated for
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ENTOCORT EC