Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/967
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PULMICORT TURBUHALER (Powder, Metered)
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PULMICORT TURBUHALER should be administered by the orally inhaled route in asthmatic patients age 6 years and older. Individual patients will experience a variable onset and degree of symptom relief. Generally, PULMICORT TURBUHALER has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhaled administration of PULMICORT TURBUHALER can occur within 24 hours of initiation of treatment, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. The safety and efficacy of PULMICORT TURBUHALER when administered in excess of recommended doses have not been established. The recommended starting dose and the highest recommended dose of PULMICORT TURBUHALER, based on prior asthma therapy, are listed in the following table. *In patients with mild to moderate asthma who are well controlled on inhaled corticosteroids, dosing with PULMICORT TURBUHALER 200 mcg or 400 mcg once daily may be considered. PULMICORT TURBUHALER can be administered once daily either in the morning or in the evening. If the once-daily treatment with PULMICORT TURBUHALER does not provide adequate control of asthma symptoms, the total daily dose should be increased and/or administered as a divided dose. Patients Maintained on Chronic Oral Corticosteroids Initially, PULMICORT TURBUHALER should be used concurrently with the patient's usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid is started by reducing the daily or alternate daily dose. The next reduction is made after an interval of one or two weeks, depending on the response of the patient. Generally, these decrements should not exceed 2.5mg of prednisone or its equivalent. A slow rate of withdrawal is strongly recommended. During reduction of oral corticosteroids, patients should be carefully monitored for asthma instability, including objective measures of airway function, and for adrenal insufficiency (see WARNINGS). During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal, eg, joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with PULMICORT TURBUHALER but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should continue more slowly. During periods of stress or a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids. NOTE: In all patients it is desirable to titrate to the lowest effective dose once asthma stability is achieved. Directions for Use Illustrated Patient's Instructions for Use accompany each package of PULMICORT TURBUHALER. Patients should be instructed to prime PULMICORT TURBUHALER prior to its initial use, and instructed to inhale deeply and forcefully each time the unit is used. Rinsing the mouth after inhalation is also recommended.
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Budesonide, the active component of PULMICORT TURBUHALER 200 mcg, is a corticosteroid 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 in heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 7.4 is 1.6 x 10. PULMICORT TURBUHALER is an inhalation-driven multi-dose dry powder inhaler that contains only micronized budesonide. Each actuation of PULMICORT TURBUHALER provides 200 mcg budesonide per metered dose, which delivers approximately 160 mcg budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec). In vitro testing has shown that the dose delivery for PULMICORT TURBUHALER is substantially dependent on airflow through the device. Patient factors such as inspiratory flow rates will also affect the dose delivered to the lungs of patients in actual use (see Patient's Instructions for Use). In adult patients with asthma (mean FEV2.9 L [0.8 - 5.1 L]) mean peak inspiratory flow (PIF) through PULMICORT TURBUHALER was 78 (40-111) L/min. Similar results (mean PIF 82 [43-125] L/min) were obtained in asthmatic children (6 to 15 years, mean FEV2.1 L [0.9 - 5.4 L]). Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery.
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Mechanism of Action: Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. The activity of PULMICORT TURBUHALER is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert. The precise mechanism of corticosteroid actions on inflammation in asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses from PULMICORT TURBUHALER. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites (see below).<br/>Pharmacokinetics: Absorption: After oral administration of budesonide, peak plasma concentration was achieved in about 1 to 2 hours and the absolute systemic availability was 6-13%. In contrast, most of budesonide delivered to the lungs is systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lungs (as assessed by plasma concentration method) with an absolute systemic availability of 39% of the metered dose. Pharmacokinetics of budesonide do not differ significantly in healthy volunteers and asthmaticpatients. Peak plasma concentrations of budesonide occurred within 30 minutes of inhalation from PULMICORT TURBUHALER. In asthmatic patients, budesonide showed a linear increase in AUC and Cwith increasing dose after both a single dose and repeated dosing from PULMICORT TURBUHALER. Distribution: The volume of distribution of budesonide was approximately 3 L/kg. It was 85-90% bound to plasma proteins. Protein binding was constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of PULMICORT TURBUHALER. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8. Metabolism:In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16��-hydroxyprednisolone and 6��-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination: The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose. Budesonide was excreted in urine and feces in the form of metabolites. Approximately 60% of an intravenous radiolabelled dose was recovered in the urine. No unchanged budesonide was detected in the urine. Special Populations: No pharmacokinetic differences have been identified due to race, gender or advanced age. Pediatric: Following intravenous dosing in pediatric patients age 10-14 years, plasma half-life was shorter than in adults (1.5 hours vs. 2.0 hours in adults). In the same population following inhalation of budesonide via a pressurized metered-dose inhaler, absolute systemic availability was similar to that in adults. Hepatic Insufficiency: Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy subjects. Drug-Drug Interactions: Ketoconazole, a potent inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide. At recommended doses, cimetidine had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.<br/>Pharmacodynamics: To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered-dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally ingested budesonide despite comparable systemic levels. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract. Generally, PULMICORT TURBUHALER has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhalation of PULMICORT TURBUHALER can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1 to 2 weeks, or longer. PULMICORT TURBUHALER has been shown to decrease airway reactivity in various challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain. Pretreatment with PULMICORT TURBUHALER 1600 mcg daily (800 mcg twice daily) for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEVfollowing inhaled allergen challenge. The effects of PULMICORT TURBUHALER on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 905 adults and 404 pediatric patients with asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact with PULMICORT TURBUHALER treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13% respectively, had an abnormal stimulated cortisol response (peak cortisol<14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test) as compared with 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800 and 1600 mcg budesonide twice daily via PULMICORT TURBUHALER for 6 weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in a 35% reduction. In this study, no patient on PULMICORT TURBUHALER at doses of 400 and 800 mcg twice daily met the criterion for an abnormal stimulated cortisol response (peak cortisol<14.5 mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label, long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA axis (both basal and stimulated plasma cortisol) of PULMICORT TURBUHALER when administered at recommended doses. In patients who had previously been oral steroid-dependent, use of PULMICORT TURBUHALER in recommended doses was associated with higher stimulated cortisol response compared with baseline following 1 year of therapy. The administration of budesonide via PULMICORT TURBUHALER in doses up to 800 mcg/day (mean daily dose 445 mcg/day) or via a pressurized metered-dose inhaler in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric patients (age 3 to 11 years) for 2 to 6 years had no significant effect on statural growth compared with non-corticosteroid therapy in 62 matched control patients. However, the long-term effect of PULMICORT TURBUHALER on growth is not fully known.
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PULMICORT TURBUHALER is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity to budesonide contraindicates the use of PULMICORT TURBUHALER.
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PULMICORT TURBUHALER consists of a number of assembled plastic details, the main parts being the dosing mechanism, the storage unit for drug substance and the mouthpiece. The inhaler is protected by a white outer tubular cover screwed onto the inhaler. The body of the inhaler is white and the turning grip is brown. The following wording is printed on the grip in raised lettering,���Pulmicort���200 mcg���. The TURBUHALER inhaler cannot be refilled and should be discarded when empty. PULMICORT TURBUHALER is available as 200 mcg/dose, 200 doses (NDC 0186-0915-42) and has a target fill weight of 104 mg. When there are 20 doses remaining in PULMICORT TURBUHALER, a red mark will appear in the indicator window. If the unit is used beyond the point at which the red mark appears at the bottom of the window, the correct amount of medication may not be obtained. The unit should be discarded. Store with the cover tightened in a dry place at controlled room temperature 20-25��C (68-77��F) [see USP]. Keep out of the reach of children. All trademarks are the property of the AstraZeneca group of companies. AstraZeneca 2001, 2006 Manufactured for: AstraZeneca LP, Wilmington, DE 19850 By: AstraZeneca AB, S��dert��lje, Sweden 33020���00 Rev. 10/06
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The potential for acute toxic effects following overdose of PULMICORT TURBUHALER is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur (see PRECAUTIONS). PULMICORT TURBUHALER at twice the highest recommended dose (3200 mcg daily) administered for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH. The minimal inhalation lethal dose in mice was 100 mg/kg (approximately 320 times the maximum recommended daily inhalation dose in adults and approximately 380 times the maximum recommended daily inhalation dose in children on a mcg/mbasis). There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 430 times the maximum recommended daily inhalation dose in adults and approximately 510 times the maximum recommended daily inhalation dose in children on a mcg/mbasis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children on a mcg/mbasis) and less than 100 mg/kg in rats (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children based on a mcg/mbasis). Post-marketing experience showed that patients experiencing acute overdose of inhaled budesonide commonly remained asymptomatic. The use of excessive doses (up to 6400 mcg daily) for prolonged periods showed systemic corticosteroid effects such as hypercorticism.
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Budesonide
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PULMICORT TURBUHALER (Powder, Metered)
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The following adverse reactions were reported in patients treated with PULMICORT TURBUHALER. The incidence of common adverse events is based upon double-blind, placebo-controlled US clinical trials in which 1116 adult and pediatric patients age 6-70 years (472 females and 644 males) were treated with PULMICORT TURBUHALER (200 to 800 mcg twice daily for 12 to 20 weeks) or placebo. The following table shows the incidence of adverse events in patients previously receiving bronchodilators and/or inhaled corticosteroids in US controlled clinical trials. This population included 232 male and 62 female pediatric patients (age 6 to 17 years) and 332 male and 331 female adult patients (age 18 years and greater). The table above includes all events (whether considered drug-related or non-drug-related by the investigators) that occurred at a rate of���3% in any one PULMICORT TURBUHALER group and were more common than in the placebo group. In considering these data, the increased average duration of exposure for PULMICORT TURBUHALER patients should be taken into account. The following other adverse events occurred in these clinical trials using PULMICORT TURBUHALER with an incidence of 1 to 3% and were more common on PULMICORT TURBUHALER than on placebo. Body As A Whole: neck pain Cardiovascular: syncope Digestive: abdominal pain, dry mouth, vomiting Metabolic and Nutritional: weight gain Musculoskeletal: fracture, myalgia Nervous: hypertonia, migraine Platelet, Bleeding and Clotting: ecchymosis Psychiatric: insomnia Resistance Mechanisms: infection Special Senses: taste perversion In a 20-week trial in adult asthmatics who previously required oral corticosteroids, the effects of PULMICORT TURBUHALER 400 mcg twice daily (N=53) and 800 mcg twice daily (N=53) were compared with placebo (N=53) on the frequency of reported adverse events. Adverse events, whether considered drug-related or non-drug-related by the investigators, reported in more than five patients in the PULMICORT TURBUHALER group and which occurred more frequently with PULMICORT TURBUHALER than placebo are shown below (% PULMICORT TURBUHALER and % placebo). In considering these data, the increased average duration of exposure for PULMICORT TURBUHALER patients (78 days for PULMICORT TURBUHALER vs. 41 days for placebo) should be taken into account. Body As A Whole:asthenia (9% and 2%) headache (12% and 2%) pain (10% and 2%) Digestive:dyspepsia (8% and 0%) nausea (6% and 0%) oral candidiasis (10% and 0%) Musculoskeletal:arthralgia (6% and 0%) Respiratory:cough increased (6% and 2%) respiratory infection (32% and 13%) rhinitis (6% and 2%) sinusitis (16% and 11%) Patients Receiving PULMICORT TURBUHALER Once Daily The adverse event profile of once-daily administration of PULMICORT TURBUHALER 200 mcg and 400 mcg, and placebo, was evaluated in 309 adult asthmatic patients in an 18-week study. The study population included both patients previously treated with inhaled corticosteroids, and patients not previously receiving corticosteroid therapy. There was no clinically relevant difference in the pattern of adverse events following once-daily administration of PULMICORT TURBUHALER when compared with twice-daily dosing. Pediatric Studies In a 12-week placebo-controlled trial in 404 pediatric patients 6 to 18 years of age previously maintained on inhaled corticosteroids, the frequency of adverse events for each age category (6 to 12 years, 13 to 18 years) was comparable for PULMICORT TURBUHALER (at 100, 200 and 400 mcg twice daily) and placebo. There were no clinically relevant differences in the pattern or severity of adverse events in children compared with those reported in adults. Adverse Event Reports From Other Sources Rare adverse events reported in the published literature or from worldwide marketing experience with any formulation of inhaled budesonide include: immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema and bronchospasm; symptoms of hypocorticism and hypercorticism; glaucoma, cataracts; psychiatric symptoms including depression, aggressive reactions, irritability, anxiety and psychosis.
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Particular care is needed for patients who are transferred from systemically active corticosteroids to PULMICORT TURBUHALER because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although PULMICORT TURBUHALER may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroidsduring periods of stress or a severe asthma attack. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to PULMICORT TURBUHALER. Lung function (FEVor AM PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to PULMICORT TURBUHALER may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, eg, rhinitis, conjunctivitis, arthritis, eosinophilic conditions and eczema (see DOSAGE AND ADMINISTRATION). 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 pediatric patients or adults on immunosuppressant doses of corticosteroids. In pediatric or adult patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered. PULMICORT TURBUHALER is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma. As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with PULMICORT TURBUHALER, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with PULMICORT TURBUHALER should be discontinued and alternate therapy instituted. Patients should be instructed to contact their physician immediately when episodes of asthma not responsive to their usual doses of bronchodilators occur during treatment with PULMICORT TURBUHALER. During such episodes, patients may require therapy with oral corticosteroids.
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PULMICORT TURBUHALER is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients six years of age or older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of those patients may be able to reduce or eliminate their requirement for oral corticosteroids over time. PULMICORT TURBUHALER is NOT indicated for the relief of acute bronchospasm.
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PULMICORT TURBUHALER
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