Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4222
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SYMBICORT (Aerosol)
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MEDICATION GUIDE: SYMBICORT' 80/4.5(budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg) Inhalation Aerosol SYMBICORT'160/4.5 (budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg) Inhalation Aerosol Read the Medication Guide that comes with SYMBICORT' before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. What is the most important information I should know about SYMBICORT? What is SYMBICORT? SYMBICORT combines an inhaled corticosteroid medicine, budesonide (the same medicine found in PULMICORT TURBUHALER), and a long-acting beta-agonist medicine (LABA), formoterol (the same medicine found in FORADIL AEROLIZER). SYMBICORT is used long-term, twice a day, everyday to control symptoms of asthma, and prevent symptoms such as wheezing in patients 12 years of age and older. SYMBICORT contains formoterol (the same medicine found in FORADIL AEROLIZER). Because LABA medicines such as formoterol may increase the chance of death from asthma problems, SYMBICORT is not for patients with asthma who: What should I tell my healthcare provider before using SYMBICORT? Tell your healthcare provider about all of your health conditions, including if you: Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. SYMBICORT and certain other medicines may interact with each other. This may cause serious side effects. Know all the medicines you take. Keep a list and show it to your healthcare provider and pharmacist each time you get a new medicine. How do I use SYMBICORT? See the step-by-step instructions for using SYMBICORT at the end of this Medication Guide. Do not use SYMBICORT unless your healthcare provider has taught you and you understand everything. Ask your healthcare provider or pharmacist if you have any questions. What are the possible side effects with SYMBICORT? SYMBICORT contains formoterol. In patients with asthma, LABA medicines such as formoterol may increase the chance of death from asthma problems. See���What is the most important information I should know about SYMBICORT?��� Other possible side effects with SYMBICORT include: Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the side effects with SYMBICORT. Ask your healthcare provider or pharmacist for more information. How do I store SYMBICORT? General Information about SYMBICORT Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide. Do not use SYMBICORT for a condition for which it was not prescribed. Do not give your SYMBICORT to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about SYMBICORT. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about SYMBICORT that was written for healthcare professionals. You can also contact the company that makes SYMBICORT (toll free) at 1-800-236-9933 or visit our website at www.symbicort-us.com. HOW TO USE SYMBICORT Follow the instructions below for using SYMBICORT. You will breathe-in (inhale) the medicine. If you have any questions, ask your doctor or pharmacist. PREPARING YOUR INHALER FOR USE Do not spray the medicine in your eyes during priming or use. WAYS TO HOLD THE INHALER FOR USE OR USING YOUR SYMBICORT INHALER 5. SHAKE THE INHALER WELL for 5 seconds. Remove the mouthpiece cover. Check the mouthpiece for foreign objects. 6. Breathe out fully (exhale). Raise the inhaler up to your mouth. Place the white mouthpiece fully into your mouth and close your lips around it. Make sure that the inhaler is upright and that the opening of the mouthpiece is pointing towards the back of your throat (see Figure 4). 7. While breathing in deeply and slowly through your mouth, press down firmly and fully on the grey top of the inhaler to release the medicine (see Figures 2 and 3). 8. Continue to breathe in and hold your breath for about 10 seconds, or for as long as is comfortable. Before breathing out, release your finger from the grey top and remove the inhaler from your mouth while keeping the inhaler upright. 9. Shake the inhaler again for 5 seconds and repeat steps 6 through 8. AFTER USING YOUR SYMBICORT INHALER 10. Replace the mouthpiece cover after use. 11. After you finish taking this medicine (2 puffs), rinse your mouth with water. Spit out the water. Do not swallow it. 12. Use the enclosed dose tracker card to track the number of puffs you have taken by marking off or punching through each of your morning and evening doses. OTHER IMPORTANT INFORMATION ABOUT YOUR SYMBICORT INHALER It is very important that you keep track of the number of inhalations (puffs) you have taken from your SYMBICORT inhaler. Discard SYMBICORT after you have used the number of inhalations on the product label and box. Your inhaler may not feel empty, but you will not get the right amount of medicine if you keep using it. SYMBICORT should also be discarded within 3 months after it is taken out of its foil pouch. HOW TO CLEAN YOUR SYMBICORT INHALER Clean the white mouthpiece of the inhaler every 7 days. To clean the mouthpiece: SYMBICORT and PULMICORT TURBUHALER are trademarks of the AstraZeneca group of companies. ADVAIR DISKUS, ADVAIR HFA, SEREVENT and DISKUS are trademarks of GlaxoSmithKline. FORADIL AEROLIZER is a trademark of Novartis Pharmaceuticals Corporation. ��AstraZeneca 2006 Manufactured for AstraZeneca LP, Wilmington, DE 19850 By: AstraZeneca Dunkerque Production, Dunkerque, France Product of France This Medication Guide has been approved by the U.S. Food and Drug Administration 31154���00 Rev. 07/06
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SYMBICORT should be administered by the orally inhaled route in patients with asthma 12 years of age and older. SYMBICORT should not be used for transferring patients from systemic corticosteroid therapy. Long-acting beta-adrenergic agonists may increase the risk of asthma-related death (see WARNINGS). Therefore, when treating patients with asthma, SYMBICORT should only be used for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with two maintenance therapies. SYMBICORT is not indicated for patients whose asthma can be successfully managed by inhaled corticosteroids or other controller medications along with occasional use of inhaled short-actingbeta-agonists. SYMBICORT is available in 2 strengths, SYMBICORT 80/4.5 and SYMBICORT 160/4.5, containing 80 and 160 mcg of budesonide, respectively, and 4.5 mcg of formoterol fumarate dihydrate per inhalation. Each dose is administered as 2 inhalations twice daily (in the morning and the evening) by the orally inhaled route only. Rinsing the mouth after every dose is advised. For patients who are currently receiving medium to high doses of inhaled corticosteroid therapy, and whose disease severity clearly warrants treatment with two maintenance therapies, the recommended starting dose is SYMBICORT 160/4.5, 2 inhalations twice daily. For patients who are currently receiving low to medium doses of inhaled corticosteroid therapy, and whose disease severity clearly warrants treatment with two maintenance therapies, the recommended starting dose is SYMBICORT 80/4.5, 2 inhalations twice daily. For patients who are not currently receiving inhaled corticosteroid therapy, but whose disease severity clearly warrants initiation of treatment with two maintenance therapies, the recommended starting dose is SYMBICORT 80/4.5 or 160/4.5, 2 inhalations twice daily depending upon asthma severity. If a previously effective dosage regimen of SYMBICORT fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength of SYMBICORT with a higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids, should be considered. The maximum daily recommended dose is 640/18 mcg budesonide/formoterol (given as two inhalations of SYMBICORT 160/4.5 twice daily) for patients 12 years of age and older. Do not use more than twice daily or use a higher number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of SYMBICORT as this will result in adaily dose of formoterol in excess of the dose determined to be safe. For all patients, consideration should be given to titrating to the lowest effective strength after adequate asthma stability has been achieved. SYMBICORT is not approved for the treatment or prevention of exercise-induced bronchospasm. Patients who are receiving SYMBICORT twice daily should not use formoterol or other long-acting beta-agonists for prevention of exercise-induced bronchospasm, or for any other reason. If symptoms arise in the period between doses, an inhaled, short-acting beta-agonist should be taken for immediate relief. In clinical studies, significant improvement in FEVoccurred within 15 minutes of beginning treatment with SYMBICORT in most patients and improvement in asthma control (asthma symptoms, albuterol rescue use, PEF) occurred within one day. The maximum benefit may not be achieved for 2 weeks or longer after beginning treatment. Individual patients may experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately to the starting dose after 1-2 weeks of therapy with SYMBICORT 80/4.5, replacing the strength with SYMBICORT 160/4.5 may provide additional asthma control. SYMBICORT should be primed before using for the first time by releasing 2 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well before each spray and releasing 2 test sprays into the air away from the face.<br/>Geriatric Use: In studies where geriatric patients (65 years of age or older, see PRECAUTIONS, Geriatric Use) have been treated with SYMBICORT, efficacy and safety did not differ from that in younger patients. Based on available data for SYMBICORT and its active components, no dosage adjustment is recommended.
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SYMBICORT 80/4.5 and SYMBICORT 160/4.5 each contain micronized budesonide and micronized formoterol fumarate dihydrate for oral inhalation only. One active component of SYMBICORT is budesonide, 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. The other active component of SYMBICORT is formoterol fumarate dihydrate, a selective beta-agonist designated chemically as (R*,R*)-(��)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide, (E)-2-butendioate(2:1), dihydrate. The empirical formula of formoterol is CHNOand its molecular weight is 840.9. Its structural formula is: Formoterol fumarate dihydrate is a powder which is slightly soluble in water. Its octanol-water partition coefficient at pH 7.4 is 2.6. The pKa of formoterol fumarate dihydrate at 25��C is 7.9 for the phenolic group and 9.2 for the amino group. Each 10.2 g SYMBICORT 80/4.5 and SYMBICORT 160/4.5 canister is formulated as a hydrofluoroalkane (HFA 227; 1,1,1,2,3,3,3-heptafluoropropane)-propelled pressurized metered dose inhaler containing 120 actuations. After priming, each actuation meters either 91/5.1 mcg or 181/5.1 mcg from the valve and delivers either 80/4.5 mcg or 160/4.5 mcg (budesonide micronized/formoterol fumarate dihydrate micronized) from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. SYMBICORT also contains povidone K25 USP as a suspending agent and polyethylene glycol 1000 NF as a lubricant. SYMBICORT should be primed before using for the first time by releasing 2 test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds before each spray and releasing 2 test sprays into the air away from the face.
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Mechanism of Action:<br/>SYMBICORT: SYMBICORT contains both budesonide and formoterol; therefore, the mechanisms of action described below for the individual components apply to SYMBICORT. These drugs represent two classes of medications (a synthetic corticosteroid and a long-acting selective beta-adrenoceptor agonist) that have different effects on clinical, physiological, and inflammatory indices of asthma.<br/>Budesonide: 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. In glucocorticoid receptor affinity studies, the 22R form of budesonide was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., 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 of budesonide. 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.<br/>Formoterol: Formoterol fumarate is a long-acting selective beta-adrenergic agonist (beta-agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta-receptors than at beta-receptors. The in vitro binding selectivity to beta- over beta-adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta-selectivity ratio than formoterol. Although beta-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta-receptors are the predominant receptors in the heart, there are also beta-receptors in the human heart comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta-agonists may have cardiac effects. The pharmacologic effects of beta-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.<br/>Animal Pharmacology: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.<br/>Pharmacokinetics:<br/>SYMBICORT: In a single-dose study, higher than recommended doses of SYMBICORT (12 inhalations of SYMBICORT 160/4.5 mcg) were administered to patients with moderate asthma. Peak plasma concentrations for budesonide of 4.5 nmol/L occurred at 20 minutes following dosing and peak concentrations for formoterol of 136 pmol occurred at 10 minutes following dosing. Approximately 8% of thedelivered dose of formoterol was recovered in the urine as unchanged drug. This study also demonstrated that the total systemic exposure to budesonide from SYMBICORT was approximately 30% lower than from inhaled budesonide via a dry powder inhaler (DPI) at the same delivered dose. Following administration of SYMBICORT, the half-life of the budesonide component was 4.7 hours and for the formoterol component was 7.9 hours. In a repeat dose study, the highest recommended dose of SYMBICORT (160/4.5 mcg, 2 inhalations twice daily) was administered to patients with moderate asthma and healthy subjects for one week. Peak plasma concentrations of budesonide (1.2 nmol/L) and formoterol (28 pmol/L) occurred at 21 and 10 minutes, respectively, in asthma patients. Peak plasma concentrations for budesonide and formoterol were about 30 to 40% higher in healthy subjects compared to that in asthma patients. However, the total systemic exposure was comparable to that in asthma patients. Following administration of SYMBICORT (160/4.5 mcg, two or four inhalations twice daily) for five days in healthy subjects, plasma concentrations of budesonide and formoterol generally increased in proportion to dose. Additionally in this study, the accumulation index for the group that received two inhalations twice daily was 1.32 for budesonide and 1.77 for formoterol.<br/>Budesonide:<br/>Formoterol:<br/>Pharmacodynamics:<br/>SYMBICORT: In a single-dose cross-over study involving 201 patients with persistent asthma, single-dose treatments of 4.5, 9, and 18 mcg of formoterol in combination with 320 mcg of budesonide delivered via SYMBICORT were compared to budesonide 320 mcg alone. Dose-ordered improvements in FEVwere demonstrated when compared with budesonide. ECGs and blood samples for glucose and potassium were obtained post dose. For SYMBICORT, small mean increases in serum glucose and decreases in serum potassium (+0.44 mmol/L and -0.18 mmol/L at the highest dose, respectively) were observed with increasing doses of formoterol, compared to budesonide. In ECGs, SYMBICORT produced small dose-related mean increases in heart rate (approximately 3 bpm at the highest dose), and QTc intervals (3-6 msec) compared to budesonide alone. No subject had a QT or QTcvalue���500 msec. In the United States, five 12-week, active- and placebo- controlled studies evaluated 2152 patients aged 12 and older with asthma. Systemic pharmacodynamic effects of formoterol (heart/pulse rate, blood pressure, QTc interval, potassium, and glucose) were similar in patients treated with SYMBICORT compared with patients treated with formoterol dry inhalation powder 4.5 mcg, 2 inhalations twice daily. No patient had a QT or QTc value���500 msec during treatment. In 3 placebo-controlled studies in adolescents and adults with asthma aged 12 and older, a total of 1232 patients (553 patients in the SYMBICORT group) had evaluable continuous 24-hour electrocardiographic monitoring. Overall, there were no important differences in the occurrence of ventricular or supraventricular ectopy and no evidence of increased risk for clinically significant dysrhythmia in the SYMBICORT group compared to placebo. Overall, no clinically important effects on HPA axis, as measured by 24-hour urinary cortisol, were observed for SYMBICORT-treated adult or adolescent patients at doses up to 640/18 mcg/day compared to budesonide.<br/>Budesonide: 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. Inhaled budesonide has been shown to decrease airway reactivity to 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 inhaled budesonide, 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 systemic effects of inhaled corticosteroids are related to the systemic exposure to such drugs. Pharmacokinetic studies have demonstrated that in both adults and children with asthma the systemic exposure to budesonide is lower with SYMBICORT compared with inhaled budesonide administered at the same delivered dose via a dry powderinhaler (see CLINICAL PHARMACOLOGY, Pharmacokinetics, SYMBICORT). Therefore, the systemic effects (HPA axis and growth) of budesonide delivered from SYMBICORT would be expected to be no greater than what is reported for inhaled budesonide when administered at comparable doses via the dry powder inhaler (see PRECAUTIONS, Pediatric Use). The effects of inhaled budesonide administered via a dry powder inhaler 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 budesonide 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 to 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 of inhaled budesonide twice daily 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 budesonide 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 budesonide when administered at recommended doses. In patients who had previously been oral steroid-dependent, use of budesonide in recommended doses was associated with higher stimulated cortisol response compared to baseline following 1 year of therapy.<br/>Formoterol: While the pharmacodynamic effect is via stimulation of beta-adrenergic receptors; excessive activation of these receptors commonly leads to skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. Inhaled formoterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium (see PRECAUTIONS, General). For SYMBICORT, these effects are detailed in the CLINICAL PHARMACOLOGY, Pharmacodynamics, SYMBICORT section. Use of long-acting beta-adrenergic agonist drugs can result in tolerance to bronchoprotective and bronchodilatory effects. Rebound bronchial hyper-responsiveness after cessation of chronic long-acting beta-agonist therapy has not been observed.<br/>Clinical Studies: SYMBICORT has been studied in patients with asthma 12 years of age and older. In two clinical studies comparing SYMBICORT with the individual components, improvements in most efficacy endpoints were greater with SYMBICORT than with the use of either budesonide or formoterol alone. In addition, one clinical study showed similar results between SYMBICORT and the concurrent use of budesonide and formoterol at corresponding doses from separate inhalers. The safety and efficacy of SYMBICORT were demonstrated in two randomized, double-blind, placebo-controlled US clinical studies involving 1076 patients 12 years of age and older. Fixed SYMBICORT dosages of 160/9 mcg, and 320/9 mcg twice daily (each dose administered as 2 inhalations of the 80/4.5- and 160/4.5-mcg strengths, respectively) were compared with the monocomponents (budesonide and formoterol) and placebo to provide information about appropriate dosing to cover a range of asthma severity.<br/>Study 1: Clinical Study with SYMBICORT 160/4.5: This 12-week study evaluated 596 patients 12 years of age and older by comparing: SYMBICORT 160/4.5 mcg, the free combination of budesonide 160 mcg plus formoterol 4.5 mcg in separate inhalers, budesonide 160 mcg, formoterol 4.5 mcg, and placebo; each administered as 2 inhalations twice daily. The study included a 2-week run-in period with budesonide 80 mcg, 2 inhalations twice daily. Most patients had moderate to severe asthma and were using moderate to high doses of inhaled corticosteroids prior to study entry. Randomization was stratified by previous inhaled corticosteroid treatment (71.6% on moderate- and 28.4% on high-dose inhaled corticosteroid). Mean percent predicted FEVat baseline was 68.1% and was similar across treatment groups. The co-primary efficacy endpoints were 12-hour-average post-dose FEVat week 2, and pre-dose FEVaveraged over the course of the study. The study also required that patients who satisfied a pre-defined asthma worsening criterion be withdrawn. The pre-defined asthma worsening criteria were: a clinically important decrease in FEVor peak expiratory flow (PEF), increase in rescue albuterol use, nighttime awakening due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. For the criterion of nighttime awakening due to asthma, patients were allowed to remain in the study at the discretion of the investigator if none of the other asthma worsening criteria were met. The percentage of patients withdrawing due to or meeting predefined criteriafor worsening asthma is shown in Table 1. *These criteria were assessed on a daily basis irrespective of the timing of the clinic visit, with the exception of FEVwhich was assessed at each clinic visit. Individual criteria are shown for patients meeting any predefined asthma event, regardless of withdrawal status. For the criterion of nighttime awakening due to asthma, patients were allowed to remain in the study at the discretion of the investigator if none of the other criteria were met. Mean percent change from baseline in FEVmeasured immediately prior to dosing (predose) over 12 weeks is displayed in Figure 1. Because this study used predefined withdrawal criteria for worsening asthma, which caused a differential withdrawal rate in the treatment groups, predose FEVresults at the last available study visit (end of treatment, EOT) are also provided. Patients receiving SYMBICORT 160/4.5 mcg had significantly greater mean improvements from baseline in predose FEVat the end of treatment (0.19 L, 9.4%) compared with budesonide 160 mcg (0.10 L, 4.9%), formoterol 4.5 mcg (-0.12 L, -4.8%), and placebo (-0.17 L, -6.9%). The effect of SYMBICORT 160/4.5 mcg 2 inhalations twice daily on selected secondary efficacy variables, including morning and evening PEF, albuterol rescue use, and asthma symptoms over 24 hours on a 0-3 scale is shown in Table 2. *Number of patients (N) varies slightly due to the number of patients for whom data were available for each variable. Results shown are based on last available data for each variable. The subjective impact of asthma on patients' health-related quality of life was evaluated through the use of the standardized Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a 7-point scale where 1 = maximum impairment and 7 = no impairment). Patients receiving SYMBICORT 160/4.5 had clinically meaningful improvement in overall asthma-specific quality of life, as defined by a mean difference between treatment groups of>0.5 points in change from baseline in overall AQLQ score (difference in AQLQ score of 0.70 [95% CI 0.47, 0.93] compared to placebo).<br/>Study 2: Clinical Study with SYMBICORT 80/4.5: This 12-week study was similar in design to Study 1, and included 480 patients 12 years of age and older. This study compared: SYMBICORT 80/4.5 mcg, budesonide 80 mcg, formoterol 4.5 mcg, and placebo; each administered as 2 inhalations twice daily. The study included a 2-week placebo run-in period. Most patients had mild to moderate asthma and were using low to moderate doses of inhaled corticosteroids prior to study entry. Mean percent predicted FEVat baseline was 71.3% and was similar across treatment groups. Efficacy variables and endpoints were identical to those in Study 1. The percentage of patients withdrawing due to or meeting predefined criteria for worsening asthma is shown in Table 3. The method of assessment and criteria used were identical to that in Study 1. *These criteria were assessed on a daily basis irrespective of the timing of the clinic visit, with the exception of FEVwhich was assessed at each clinic visit. Individual criteria are shown for patients meeting any predefined asthma event, regardless of withdrawal status. For the criterion of nighttime awakening due to asthma, patients were allowed to remain in the study at the discretion of the investigator if none of the other criteria were met. Mean percent change from baseline in predose FEVover 12 weeks is displayed in Figure 2. Efficacy results for other secondary endpoints, including quality of life, were similar to those observed in Study 1.<br/>Onset and Duration of Action and Progression of Improvement in Asthma Control: The onset of action and progression of improvement in asthma control were evaluated in the 2 pivotal clinical studies. The median time to onset of clinically significant bronchodilation (>15% improvement in FEV) was seen within 15 minutes. Maximum improvement in FEVoccurred within 3 hours, and clinically significant improvement was maintained over 12 hours. Figures 3 and 4 show the percent change from baseline in postdose FEVover 12 hours on the day of randomization and on the last day of treatment for Study 1. Reduction in asthma symptoms and in albuterol rescue use, as well as improvement in morning and evening PEF, occurred within 1 day of the first dose of SYMBICORT; improvement in these variables was maintained over the 12 weeks of therapy. Following the initial dose of SYMBICORT, FEVimproved markedly during the first 2 weeks of treatment, continued to show improvement at the Week 6 assessment, and was maintained through Week 12 for both studies. No diminution in the 12-hour bronchodilator effect was observed with either SYMBICORT 80/4.5 mcg or SYMBICORT 160/4.5 mcg as assessed by FEVfollowing 12 weeks of therapy or at the last available visit. FEVdata from Study 1 evaluating SYMBICORT 160/4.5 mcg is displayed in Figures 3 and 4.
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SYMBICORT is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity to any of the ingredients in SYMBICORT contraindicates its use.
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SYMBICORT is available in two strengths: SYMBICORT 80/4.5 (NDC 0186-0372-20) and SYMBICORT 160/4.5 (NDC 0186-0370-20). Each strength is supplied as a pressurized aluminum canister with a shield component, with a red plastic actuator body with white mouthpiece and attached gray dust cap. Each canister contains 120 inhalations and has a net fill weight of 10.2 grams. Each canister is packaged in a foil overwrap pouch with desiccant sachet and placed into a carton. Each carton contains one canister and a Medication Guide. The SYMBICORT canister should only be used with the SYMBICORT actuator and the SYMBICORT actuator should not be used with any other inhalation drug product. The correct amount of medication in each inhalation cannot be ensured after the labeled number of inhalations from the canister have been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of inhalations have been used or within 3 months after removal from the foil pouch. Never immerse the canister into water to determine the amount remaining in the canister (���float test���). Store at controlled room temperature 20��C to 25��C (68��F to 77��F) [see USP]. Store the inhaler with the mouthpiece down. For best results, the canister should be at room temperature before use. Shake well for 5 seconds before using. Keep out of the reach of children. Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Do not store near heat or open flame. Exposure to temperatures over 120��F may cause bursting. Never throw container into fire or incinerator. SYMBICORT is a trademark of the AstraZeneca group of companies. ��AstraZeneca 2006. Manufactured for: AstraZeneca LP, Wilmington, DE 19850 By: AstraZeneca Dunkerque Production, Dunkerque, France Product of France 31152-00 Rev. 7/06
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WARNING: Long-acting beta-adrenergic agonists may increase the risk of asthma-related death. Therefore, when treating patients with asthma, SYMBICORT' should only be used for patients not adequately controlled on other asthma-controller medications (e.g., low-to-medium dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with two maintenance therapies. Data from a large placebo-controlled US study that compared the safety of another long-acting beta-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol may apply to formoterol (a long-acting beta-adrenergic agonist), one of the active ingredients in SYMBICORT (see WARNINGS).
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SYMBICORT: SYMBICORT contains both budesonide and formoterol; therefore, the risks associated with overdosage for the individual components described below apply to SYMBICORT. In pharmacokinetic studies, a total of 1920/54 mcg (12 actuations of SYMBICORT 160/4.5) was administered as a single dose to both healthy subjects and patients with asthma and was well tolerated. In a long-term active-controlled safety study, SYMBICORT 160/4.5 was well tolerated for up to 12 months at doses up to twice the highest recommended dailydose. Clinical signs in dogs that received a single inhalation dose of SYMBICORT (a combination of budesonide and formoterol) in a dry powder included tremor, mucosal redness, nasal catarrh, redness of intact skin, abdominal respiration, vomiting, and salivation; in the rat, the only clinical sign observed was increased respiratory rate in the first hour after dosing. No deaths occurred in rats given a combination of budesonide and formoterol at acute inhalation doses of 97 and 3 mg/kg, respectively (approximately 1200 and 1350 times the maximum recommended human daily inhalation dose on a mcg/mbasis). No deaths occurred in dogs given a combination of budesonide and formoterol at the acute inhalation doses of 732 and 22 mcg/kg, respectively (approximately 30 times the maximum recommended human daily inhalation dose of budesonide and formoterol on a mcg/mbasis).<br/>Budesonide: The potential for acute toxic effects following overdose of budesonide is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur (see PRECAUTIONS). Budesonide at five times the highest recommended dose (3200 mcg daily) administered to humans 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. In mice the minimal inhalation lethal dose was 100 mg/kg (approximately 600 times the maximum recommended human daily inhalation dose on a mcg/mbasis). In rats there were no deaths following the administration of an inhalation dose of 68 mg/kg (approximately 900 times the maximum recommended human daily inhalation dose on a mcg/mbasis). The minimal oral lethal dose in mice was 200 mg/kg (approximately 1300 times the maximum recommended human daily inhalation dose on a mcg/mbasis) and less than 100 mg/kg in rats (approximately 1300 times the maximum recommended human daily inhalation dose on a mcg/mbasis).<br/>Formoterol: An overdose of formoterol would likely lead to an exaggeration of effects that are typical for beta-agonists; therefore, the following adverse experiences may occur: angina, hypertension or hypotension, palpitations, tachycardia, arrhythmia, prolonged QTc-interval, headache, tremor, nervousness, muscle cramps, dry mouth, insomnia, fatigue, malaise, seizures, metabolic acidosis, hypokalemia, hyperglycemia, nausea and vomiting. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of formoterol. Formoterol was well tolerated at a delivered dose of 90 mcg/day over 3 hours in adult patients with acute bronchoconstriction and when given three times daily for a total dose of 54 mcg/day for 3 days to stable asthmatics. Treatment of formoterol overdosage consists of discontinuation of the medication together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of formoterol. Cardiac monitoring is recommended in cases of overdosage. No deaths were seen in mice given formoterol at an inhalation dose of 276 mg/kg (more than 62,200 times the maximum recommended human daily inhalation dose on a mcg/mbasis). In rats the minimum lethal inhalation dose was 40 mg/kg (approximately 18,000 times the maximum recommended human daily inhalation dose on a mcg/mbasis). No deaths were seen in mice that received an oral dose of 2000 mg/kg (more than 450,000 times the maximum recommended human daily inhalation dose on a mcg/mbasis). Maximum non-lethal oral doses were 252 mg/kg in young rats and 1500 mg/kg in adult rats (approximately 114,000 times and 675,000 times the maximum recommended human inhalation dose on a mcg/mbasis).
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Budesonide
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SYMBICORT (Aerosol)
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Long-acting beta-adrenergic agonists may increase the risk of asthma-related death (See Boxed WARNING, WARNINGS, and PRECAUTIONS sections). The incidence of common adverse events in the table below is based upon three 12-week, double-blind, placebo-controlled US clinical studies in which 401 adult and adolescent patients (148 males and 253 females) age 12 years and older were treated twice daily with 2 inhalations of SYMBICORT 80/4.5 or SYMBICORT 160/4.5, budesonide HFA metered dose inhaler (MDI) 80 or 160 mcg, formoterol dry powder inhaler (DPI) 4.5 mcg, or placebos (MDI and DPI). *All treatments were administered as two inhalations twice daily. The table above includes all events (whether or not considered drug-related by the investigators) that occurred at an incidence of���3% in any one SYMBICORT group and that were more common than in the placebo group with twice-daily dosing. In considering these data, the increased average duration of exposure for SYMBICORT patients should be taken into account, as incidences are not adjusted for unequal treatment duration. The following additional adverse events occurred in patients���12 years of age in the active- and placebo-controlled clinical studies among 2344 patients treated with SYMBICORT twice daily with an incidence of���1% to<3% regardless of relationship to treatment, and are listed in decreasing order of incidence: asthma, nausea, dysphonia, pyrexia, sinus headache, diarrhea, pharyngitis, tremor, lower respiratory tract infection, muscle spasms, urinary tract infection, rhinitis, arthralgia, myalgia, dyspepsia, gastroenteritis viral, abdominal pain upper, dizziness, sinus congestion, rhinitis allergic, pain in extremity, palpitations, bronchitis acute, tension headache, migraine, post procedural pain. Additionally, the incidence of cough, bronchitis, and viral upper respiratory tract infection was���3% (but each<4%) in this population but did not meet criteria for inclusion in the above table, as these data are not derived from placebo-controlled trials for subjects���12 years old. The following adverse events occurred in this same population (patients���12 years of age) with an incidence<1%, and are listed because they have previously been reported during treatment with any formulation of inhaled SYMBICORT, budesonide and/or formoterol, regardless of the indication: immediate and delayed hypersensitivity reactions, e.g., rash, pruritus, urticaria, angioedema; cardiac events, e.g., tachycardia, coronary ischemia, atrial and ventricular tachyarrhythmias; variations in blood pressure, e.g., hypotension, hypertension, hypertensive crisis; hypokalemia; hyperglycemia; taste disturbance; psychiatric symptoms, e.g., irritability, anxiety, restlessness, nervousness, agitation, depression; skin bruising. Long-Term Safety: Long-term safety studies in adolescent and adult patients 12 years of age and older, treated for up to one year at doses up to 1280/36 mcg/day (640/18 mcg twice daily), revealed neither clinically important changes in the incidence nor new types of adverse events emerging after longer periods of treatment. Similarly, no significant or unexpected patterns of abnormalities were observed for up to one year in safety measures including chemistry, hematology, ECG, Holter monitor, and HPA-axis assessments. Adverse Event Reports From Other Sources: Other relevant rare adverse events reported in the published literature, clinical trials or from worldwide marketing experience with any formulation of inhaled SYMBICORT, budesonide and/or formoterol, regardless of the indication include: immediate hypersensitivity reactions, such as anaphylactic reaction and bronchospasm; symptoms of hypocorticism and hypercorticism; glaucoma, cataracts, psychiatric symptoms, including aggressive reactions, behavioral disturbances, psychosis.
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Long-acting beta-adrenergic agonists may increase the risk of asthma-related death. Therefore, when treating patients with asthma, SYMBICORT should only be used for patients not adequately controlled on other asthma-controller medications (e.g., low-to-medium dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with two maintenance therapies. SYMBICORT Should Not Be Initiated In Patients During Rapidly Deteriorating Or Potentially Life-Threatening Episodes Of Asthma. Do Not Use SYMBICORT to Treat Acute Symptoms. SYMBICORT should not be used to treat acute symptoms of asthma. An inhaled, short-acting beta-agonist (e.g., albuterol), should be used to relieve acute asthma symptoms. Therefore, when prescribing SYMBICORT, the physician must also provide the patient with an inhaled, short-acting beta-agonist for treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use of SYMBICORT. When beginning treatment with SYMBICORT, patients who have been taking oral or inhaled, short-acting beta-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. For patients on SYMBICORT, short-acting, inhaled beta-agonists should only be used for symptomatic relief of acute asthma symptoms (see PRECAUTIONS, Information for Patients). Watch for Increasing Use of Inhaled, Short-Acting Beta-Agonists, Which Is a Marker of Deteriorating Asthma. Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient's inhaled, short-acting beta-agonist becomes less effective, the patient needs more inhalations than usual, or the patient develops a significant decrease in lung function, these may be markers of destabilization of asthma. In this setting, the patient requires immediate re-evaluation and reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of SYMBICORT with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than two actuations twice daily (morning and evening) of SYMBICORT. SYMBICORT Should Not be Used For Transferring Patients from Systemic Corticosteroid Therapy. Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids. Deaths due to adrenal insufficiency have occurred in asthmatic patients duringand after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months may be required for recovery of 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 inhaled corticosteroid therapy 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 corticosteroids during periods of stress or a severe asthma attack. Do Not Use an Inhaled, Long-Acting Beta-Agonist in Conjunction With SYMBICORT. Patients who are receiving SYMBICORT twice daily should not use additional formoterol or other long-acting inhaled beta-agonists (e.g., salmeterol) for prevention of exercise-induced bronchospasm (EIB) or the maintenance treatment of asthma. Additional benefit would not be gained from using supplemental formoterol or salmeterol for prevention of EIB since SYMBICORT already contains an inhaled, long-acting beta-agonist. Do Not Exceed Recommended Dosage. SYMBICORT should not be used more often or at higher doses than recommended. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. In addition, data from clinical studies with formoterol dry powder inhaler suggest that the use of doses higher than recommended (24 mcg twice daily) is associated with an increased risk of serious asthma exacerbations. In a 52-week active-controlled safety study evaluating SYMBICORT 160/4.5, patients treated with twice the highest recommended dose of SYMBICORT demonstrated a similar safety profile to that of patients treated with the highest recommended dose. Paradoxical Bronchospasm. As with other inhaled asthma medications, SYMBICORT may produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SYMBICORT, treatment with SYMBICORT should be discontinued immediately and alternate therapy should be instituted. Immediate Hypersensitivity Reactions. Immediate hypersensitivity reactions, such as urticaria, angioedema, rash, and bronchospasm may occur after administration of SYMBICORT. Cardiovascular Disorders. SYMBICORT, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Formoterol, a component of SYMBICORT, may produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of SYMBICORT at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Discontinuation of Systemic Corticosteroids. Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, and arthritis. Immunosuppression. Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. It is unknown how the dose, route, and duration of corticosteroid administration affect the risk ofdeveloping a disseminated infection. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient on immunosuppressant doses of corticosteroids is exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intramuscular immunoglobulin (IG), 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. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension (see PRECAUTIONS, Drug Interactions).
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SYMBICORT is indicated for the long-term maintenance treatment of asthma in patients 12 years of age and older. Long-acting beta-adrenergic agonists may increase the risk of asthma-related death (see WARNINGS). Therefore, when treating patients with asthma, SYMBICORT should only be used for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with two maintenance therapies. SYMBICORT is not indicated in patients whose asthma can be successfully managed by inhaled corticosteroids along with occasional use of inhaled, short-acting beta-agonists. SYMBICORT is NOT indicated for the relief of acute bronchospasm.
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SYMBICORT
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