İHALE DÜNYASI
İHALE DÜNYASI
FORADIL (R) AEROLIZER (R) consists of a capsule dosage form containing a dry powder formulation of FORADIL (formoterol fumarate) intended for oral inhalation only with the AEROLIZER Inhaler. Each clear, hard gelatin capsule contains a dry powder blend of 12 mcg of formoterol fumarate and 25 mg of lactose (which contains trace levels of milk proteins) as a carrier. The active component of FORADIL is formoterol fumarate, a racemate. Formoterol fumarate is a selective beta 2 -adrenergic bronchodilator. Its chemical name is (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate; its structural formula is Formoterol fumarate has a molecular weight of 840.9, and its empirical formula is (C 19 H 24 N 2 O 4 ) 2 *C 4 H 4 O 4 * 2 H 2 O. Formoterol fumarate is a white to yellowish crystalline powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether. The AEROLIZER Inhaler is a plastic device used for inhaling FORADIL. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the AEROLIZER Inhaler delivered 10 mcg of formoterol fumarate from the mouthpiece. Peak inspiratory flow rates (PIFR) achievable through the AEROLIZER Inhaler were evaluated in 33 adult and adolescent patients and 32 pediatric patients with mild-to-moderate asthma. Mean PIFR was 117.82 L/min (range 34-188 L/min) for adult and adolescent patients, and 99.66 L/min (range 43-187 L/min) for pediatric patients. Approximately ninety percent of each population studied generated a PIFR through the device exceeding 60 L/min. To use the delivery system, a FORADIL capsule is placed in the well of the AEROLIZER Inhaler, and the capsule is pierced by pressing and releasing the buttons on the side of the device. The formoterol fumarate formulation is dispersed into the air stream when the patient inhales rapidly and deeply through the mouthpiece. formoterol fumarate structural formula
Asthma FORADIL AEROLIZER is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, in adults and children 5 years of age and older with reversible obstructive airways disease, including patients with symptoms of nocturnal asthma. Long-acting beta 2 -adrenergic agonists (LABA), such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death (see WARNINGS). Use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients (see WARNINGS). For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. Exercise-Induced Bronchospasm FORADIL AEROLIZER is also indicated for the acute prevention of exercise-induced bronchospasm (EIB) in adults and children 5 years of age and older, when administered on an occasional, as-needed basis. Use of FORADIL AEROLIZER as a single agent for the prevention of exercise-induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of FORADIL AEROLIZER for the prevention of exercise-induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. Chronic Obstructive Pulmonary Disease FORADIL AEROLIZER is indicated for the long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with Chronic Obstructive Pulmonary Disease including chronic bronchitis and emphysema. | Asthma FORADIL AEROLIZER is indicated for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, in adults and children 5 years of age and older with reversible obstructive airways disease, including patients with symptoms of nocturnal asthma. Long-acting beta 2 -adrenergic agonists (LABA), such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death (see WARNINGS). Use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients (see WARNINGS). For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. | Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients (see WARNINGS). For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. | Exercise-Induced Bronchospasm FORADIL AEROLIZER is also indicated for the acute prevention of exercise-induced bronchospasm (EIB) in adults and children 5 years of age and older, when administered on an occasional, as-needed basis. Use of FORADIL AEROLIZER as a single agent for the prevention of exercise-induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of FORADIL AEROLIZER for the prevention of exercise-induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. | Chronic Obstructive Pulmonary Disease FORADIL AEROLIZER is indicated for the long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with Chronic Obstructive Pulmonary Disease including chronic bronchitis and emphysema.
FORADIL capsules should be administered only by the oral inhalation route and only using the AEROLIZER Inhaler (see the accompanying Medication Guide). FORADIL capsules should not be ingested (i.e., swallowed) orally . FORADIL capsules should always be stored in the blister, and only removed IMMEDIATELY BEFORE USE. Treatment of Asthma Long-acting beta 2 -adrenergic agonists (LABA), such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death (see Warnings). Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma less than 18 years of age who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. For adults and children 5 years of age and older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule every 12 hours using the AEROLIZER Inhaler. The patient must not exhale into the device. The total daily dose of FORADIL should not exceed one capsule twice daily (24 mcg total daily dose). More frequent administration or administration of a larger number of inhalations is not recommended. If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be taken for immediate relief. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma. Under these circumstances, the therapeutic regimen should be re-evaluated. For Prevention of Exercise-Induced Bronchospasm (EIB) Use of FORADIL AEROLIZER as a single agent for the prevention of exercise-induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of FORADIL AEROLIZER for the prevention of exercise-induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. For adults and children 5 years of age or older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule at least 15 minutes before exercise administered on an occasional as needed basis. When used intermittently as needed for prevention, protection may last up to 12 hours. Additional doses of FORADIL AEROLIZER should not be used for 12 hours after the administration of this drug. Regular, twice-daily dosing has not been studied in preventing EIB. Patients who are receiving FORADIL AEROLIZER twice daily for treatment of their asthma should not use additional doses for prevention of EIB and may require a short-acting bronchodilator. For Maintenance Treatment of Chronic Obstructive Pulmonary Disease (COPD) The usual dosage is the inhalation of the contents of one 12 mcg FORADIL capsule every 12 hours using the AEROLIZER inhaler. A total daily dose of greater than 24 mcg is not recommended. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered. | Treatment of Asthma Long-acting beta 2 -adrenergic agonists (LABA), such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death (see Warnings). Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma less than 18 years of age who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. For adults and children 5 years of age and older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule every 12 hours using the AEROLIZER Inhaler. The patient must not exhale into the device. The total daily dose of FORADIL should not exceed one capsule twice daily (24 mcg total daily dose). More frequent administration or administration of a larger number of inhalations is not recommended. If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be taken for immediate relief. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma. Under these circumstances, the therapeutic regimen should be re-evaluated. | Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For patients with asthma less than 18 years of age who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. For adults and children 5 years of age and older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule every 12 hours using the AEROLIZER Inhaler. The patient must not exhale into the device. The total daily dose of FORADIL should not exceed one capsule twice daily (24 mcg total daily dose). More frequent administration or administration of a larger number of inhalations is not recommended. If symptoms arise between doses, an inhaled short-acting beta 2 -agonist should be taken for immediate relief. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of asthma. Under these circumstances, the therapeutic regimen should be re-evaluated. | For Prevention of Exercise-Induced Bronchospasm (EIB) Use of FORADIL AEROLIZER as a single agent for the prevention of exercise-induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of FORADIL AEROLIZER for the prevention of exercise-induced bronchospasm may be clinically indicated, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid. For adults and children 5 years of age or older, the usual dosage is the inhalation of the contents of one 12-mcg FORADIL capsule at least 15 minutes before exercise administered on an occasional as needed basis. When used intermittently as needed for prevention, protection may last up to 12 hours. Additional doses of FORADIL AEROLIZER should not be used for 12 hours after the administration of this drug. Regular, twice-daily dosing has not been studied in preventing EIB. Patients who are receiving FORADIL AEROLIZER twice daily for treatment of their asthma should not use additional doses for prevention of EIB and may require a short-acting bronchodilator. | For Maintenance Treatment of Chronic Obstructive Pulmonary Disease (COPD) The usual dosage is the inhalation of the contents of one 12 mcg FORADIL capsule every 12 hours using the AEROLIZER inhaler. A total daily dose of greater than 24 mcg is not recommended. If a previously effective dosage regimen fails to provide the usual response, medical advice should be sought immediately as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered.
Because of the risk of asthma-related death and hospitalization, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated (see Warnings - Asthma Related Death). FORADIL (formoterol fumarate) is contraindicated in patients with a history of hypersensitivity to formoterol fumarate or to any components of this product.
Long-acting beta 2 -adrenergic agonists (LABA), including formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalizations in pediatric and adolescent patients. Clinical trials with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo. (See WARNINGS) Experience in Pediatric, Adolescent and Adult Patients with Asthma Of the 5,824 patients in multiple-dose controlled clinical trials, 1,985 were treated with FORADIL AEROLIZER at the recommended dose of 12 mcg twice daily. The following table shows adverse events where the frequency was greater than or equal to 1% in the FORADIL twice daily group and where the rates in the FORADIL group exceeded placebo. Three adverse events showed dose ordering among tested doses of 6, 12 and 24 mcg administered twice daily; tremor, dizziness and dysphonia. NUMBER AND FREQUENCY OF ADVERSE EXPERIENCES IN PATIENTS 5 YEARS OF AGE AND OLDER FROM MULTIPLE-DOSE CONTROLLED CLINICAL TRIALS Adverse Event FORADIL AEROLIZER 12 mcg twice daily Placebo n (%) n (%) Total Patients 1985 (100) 969 (100) Infection viral 341 (17.2) 166 (17.1) Bronchitis 92 (4.6) 42 (4.3) Chest infection 54 (2.7) 4 (0.4) Dyspnea 42 (2.1) 16 (1.7) Chest pain 37 (1.9) 13 (1.3) Tremor 37 (1.9) 4 (0.4) Dizziness 31 (1.6) 15 (1.5) Insomnia 29 (1.5) 8 (0.8) Tonsillitis 23 (1.2) 7 (0.7) Rash 22 (1.1) 7 (0.7) Dysphonia 19 (1.0) 9 (0.9) In two 12-week controlled trials with combined enrollment of 1095 patients 12 years of age and older, FORADIL AEROLIZER 12 mcg twice daily was compared to FORADIL AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily, and placebo. Serious asthma exacerbations (acute worsening of asthma resulting in hospitalization) occurred more commonly with FORADIL AEROLIZER 24 mcg twice daily than with the recommended dose of FORADIL AEROLIZER 12 mcg twice daily, albuterol, or placebo. The results are shown in the following table. NUMBER AND FREQUENCY OF SERIOUS ASTHMA EXACERBATIONS IN PATIENTS 12 YEARS OF AGE AND OLDER FROM TWO 12-WEEK CONTROLLED CLINICAL TRIALS Foradil 12 mcg twice daily Foradil 24 mcg twice daily Albuterol 180 mcg four times daily Placebo Trial #1 Serious asthma exacerbations 0/136 (0) 4/135 (3.0%) 1 2/134 (1.5%) 0/136 (0) Trial #2 Serious asthma exacerbations 1/139 (0.7%) 5/136 (3.7%) 2 0/138 (0) 2/141 (1.4%) 1 1 patient required intubation 2 2 patients had respiratory arrest; 1 of the patients died In a 16-week, randomized, multi-center, double-blind, parallel-group trial, patients who received either 24 mcg twice daily or 12 mcg twice daily doses of FORADIL AEROLIZER experienced more serious asthma exacerbations than patients who received placebo (see CLINICAL TRIALS). The results are shown in the following table. NUMBER AND FREQUENCY OF SERIOUS ASTHMA EXACERBATIONS IN PATIENTS 12 YEARS OF AGE AND OLDER FROM A 16-WEEK TRIAL Foradil 12 mcg twice daily Foradil 24 mcg twice daily Placebo Serious asthma exacerbations 3/527 (0.6%) 2/527 (0.4%) 1/514 (0.2%) Experience in Children with Asthma The safety of FORADIL AEROLIZER 12 mcg twice daily compared to FORADIL AEROLIZER 24 mcg twice daily and placebo was investigated in one large, multicenter, randomized, double-blind, 52-week clinical trial in 518 children with asthma (ages 5-12 years) in need of daily bronchodilators and anti-inflammatory treatment. More children who received FORADIL AEROLIZER 24 mcg twice daily than children who received FORADIL AEROLIZER 12 mcg twice daily or placebo experienced serious asthma exacerbations, as shown in the next table. NUMBER AND FREQUENCY OF SERIOUS ASTHMA EXACERBATIONS IN PATIENTS 5-12 YEARS OF AGE FROM A 52-WEEK TRIAL Foradil 12 mcg twice daily Foradil 24 mcg twice daily Placebo Serious asthma exacerbations 8/171 (4.7%) 11/171 (6.4%) 0/176 (0) The numbers and percent of patients who reported adverse events were comparable in the 12 mcg twice daily and placebo groups. In general, the pattern of the adverse events observed in children differed from the usual pattern seen in adults. The adverse events that were more frequent in the formoterol group than in the placebo group reflected infection/inflammation (viral infection, rhinitis, tonsillitis, gastroenteritis) or abdominal complaints (abdominal pain, nausea, dyspepsia). Experience in Adult Patients with COPD Of the 1634 patients in two pivotal multiple-dose Chronic Obstructive Pulmonary Disease (COPD) controlled trials, 405 were treated with FORADIL AEROLIZER 12 mcg twice daily. The numbers and percent of patients who reported adverse events were comparable in the 12 mcg twice daily and placebo groups. Adverse events (AE's) experienced were similar to those seen in asthmatic patients, but with a higher incidence of COPD-related AE's in both placebo and formoterol treated patients. The following table shows adverse events where the frequency was greater than or equal to 1% in the FORADIL AEROLIZER group and where the rates in the FORADIL AEROLIZER group exceeded placebo. The two clinical trials included doses of 12 mcg and 24 mcg, administered twice daily. Seven adverse events showed dose ordering among tested doses of 12 and 24 mcg administered twice daily; pharyngitis, fever, muscle cramps, increased sputum, dysphonia, myalgia, and tremor. NUMBER AND FREQUENCY OF ADVERSE EXPERIENCES IN ADULT COPD PATIENTS TREATED IN MULTIPLE-DOSE CONTROLLED CLINICAL TRIALS Adverse Event FORADIL AEROLIZER 12 mcg twice daily Placebo n (%) n (%) Total patients 405 (100) 420 (100) Upper respiratory tract infection 30 (7.4) 24 (5.7) Pain back 17 (4.2) 17 (4.0) Pharyngitis 14 (3.5) 10 (2.4) Pain chest 13 (3.2) 9 (2.1) Sinusitis 11 (2.7) 7 (1.7) Fever 9 (2.2) 6 (1.4) Cramps leg 7 (1.7) 2 (0.5) Cramps muscle 7 (1.7) 0 Anxiety 6 (1.5) 5 (1.2) Pruritus 6 (1.5) 4 (1.0) Sputum increased 6 (1.5) 5 (1.2) Mouth dry 5 (1.2) 4 (1.0) Overall, the frequency of all cardiovascular adverse events in the two pivotal studies was low and comparable to placebo (6.4% for FORADIL AEROLIZER 12 mcg twice daily, and 6.0% for placebo). There were no frequently-occurring specific cardiovascular adverse events for FORADIL AEROLIZER (frequency greater than or equal to 1% and greater than placebo). Other adverse reactions to FORADIL AEROLIZER are similar in nature to other selective beta 2 -adrenoceptor agonists; e.g., angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. Post Marketing Experience In extensive worldwide marketing experience with FORADIL, serious exacerbations of asthma, including some that have been fatal, have been reported. While most of these cases have been in patients with severe or acutely deteriorating asthma (see WARNINGS), a few have occurred in patients with less severe asthma. It is not possible to determine from these individual case reports whether FORADIL AEROLIZER contributed to the events. Rare reports of anaphylactic reactions, including severe hypotension and angioedema, have also been received in association with the use of formoterol fumarate inhalation powder. | Experience in Pediatric, Adolescent and Adult Patients with Asthma Of the 5,824 patients in multiple-dose controlled clinical trials, 1,985 were treated with FORADIL AEROLIZER at the recommended dose of 12 mcg twice daily. The following table shows adverse events where the frequency was greater than or equal to 1% in the FORADIL twice daily group and where the rates in the FORADIL group exceeded placebo. Three adverse events showed dose ordering among tested doses of 6, 12 and 24 mcg administered twice daily; tremor, dizziness and dysphonia. NUMBER AND FREQUENCY OF ADVERSE EXPERIENCES IN PATIENTS 5 YEARS OF AGE AND OLDER FROM MULTIPLE-DOSE CONTROLLED CLINICAL TRIALS Adverse Event FORADIL AEROLIZER 12 mcg twice daily Placebo n (%) n (%) Total Patients 1985 (100) 969 (100) Infection viral 341 (17.2) 166 (17.1) Bronchitis 92 (4.6) 42 (4.3) Chest infection 54 (2.7) 4 (0.4) Dyspnea 42 (2.1) 16 (1.7) Chest pain 37 (1.9) 13 (1.3) Tremor 37 (1.9) 4 (0.4) Dizziness 31 (1.6) 15 (1.5) Insomnia 29 (1.5) 8 (0.8) Tonsillitis 23 (1.2) 7 (0.7) Rash 22 (1.1) 7 (0.7) Dysphonia 19 (1.0) 9 (0.9) In two 12-week controlled trials with combined enrollment of 1095 patients 12 years of age and older, FORADIL AEROLIZER 12 mcg twice daily was compared to FORADIL AEROLIZER 24 mcg twice daily, albuterol 180 mcg four times daily, and placebo. Serious asthma exacerbations (acute worsening of asthma resulting in hospitalization) occurred more commonly with FORADIL AEROLIZER 24 mcg twice daily than with the recommended dose of FORADIL AEROLIZER 12 mcg twice daily, albuterol, or placebo. The results are shown in the following table. NUMBER AND FREQUENCY OF SERIOUS ASTHMA EXACERBATIONS IN PATIENTS 12 YEARS OF AGE AND OLDER FROM TWO 12-WEEK CONTROLLED CLINICAL TRIALS Foradil 12 mcg twice daily Foradil 24 mcg twice daily Albuterol 180 mcg four times daily Placebo Trial #1 Serious asthma exacerbations 0/136 (0) 4/135 (3.0%) 1 2/134 (1.5%) 0/136 (0) Trial #2 Serious asthma exacerbations 1/139 (0.7%) 5/136 (3.7%) 2 0/138 (0) 2/141 (1.4%) 1 1 patient required intubation 2 2 patients had respiratory arrest; 1 of the patients died In a 16-week, randomized, multi-center, double-blind, parallel-group trial, patients who received either 24 mcg twice daily or 12 mcg twice daily doses of FORADIL AEROLIZER experienced more serious asthma exacerbations than patients who received placebo (see CLINICAL TRIALS). The results are shown in the following table. NUMBER AND FREQUENCY OF SERIOUS ASTHMA EXACERBATIONS IN PATIENTS 12 YEARS OF AGE AND OLDER FROM A 16-WEEK TRIAL Foradil 12 mcg twice daily Foradil 24 mcg twice daily Placebo Serious asthma exacerbations 3/527 (0.6%) 2/527 (0.4%) 1/514 (0.2%) | Experience in Children with Asthma The safety of FORADIL AEROLIZER 12 mcg twice daily compared to FORADIL AEROLIZER 24 mcg twice daily and placebo was investigated in one large, multicenter, randomized, double-blind, 52-week clinical trial in 518 children with asthma (ages 5-12 years) in need of daily bronchodilators and anti-inflammatory treatment. More children who received FORADIL AEROLIZER 24 mcg twice daily than children who received FORADIL AEROLIZER 12 mcg twice daily or placebo experienced serious asthma exacerbations, as shown in the next table. NUMBER AND FREQUENCY OF SERIOUS ASTHMA EXACERBATIONS IN PATIENTS 5-12 YEARS OF AGE FROM A 52-WEEK TRIAL Foradil 12 mcg twice daily Foradil 24 mcg twice daily Placebo Serious asthma exacerbations 8/171 (4.7%) 11/171 (6.4%) 0/176 (0) The numbers and percent of patients who reported adverse events were comparable in the 12 mcg twice daily and placebo groups. In general, the pattern of the adverse events observed in children differed from the usual pattern seen in adults. The adverse events that were more frequent in the formoterol group than in the placebo group reflected infection/inflammation (viral infection, rhinitis, tonsillitis, gastroenteritis) or abdominal complaints (abdominal pain, nausea, dyspepsia). | Experience in Adult Patients with COPD Of the 1634 patients in two pivotal multiple-dose Chronic Obstructive Pulmonary Disease (COPD) controlled trials, 405 were treated with FORADIL AEROLIZER 12 mcg twice daily. The numbers and percent of patients who reported adverse events were comparable in the 12 mcg twice daily and placebo groups. Adverse events (AE's) experienced were similar to those seen in asthmatic patients, but with a higher incidence of COPD-related AE's in both placebo and formoterol treated patients. The following table shows adverse events where the frequency was greater than or equal to 1% in the FORADIL AEROLIZER group and where the rates in the FORADIL AEROLIZER group exceeded placebo. The two clinical trials included doses of 12 mcg and 24 mcg, administered twice daily. Seven adverse events showed dose ordering among tested doses of 12 and 24 mcg administered twice daily; pharyngitis, fever, muscle cramps, increased sputum, dysphonia, myalgia, and tremor. NUMBER AND FREQUENCY OF ADVERSE EXPERIENCES IN ADULT COPD PATIENTS TREATED IN MULTIPLE-DOSE CONTROLLED CLINICAL TRIALS Adverse Event FORADIL AEROLIZER 12 mcg twice daily Placebo n (%) n (%) Total patients 405 (100) 420 (100) Upper respiratory tract infection 30 (7.4) 24 (5.7) Pain back 17 (4.2) 17 (4.0) Pharyngitis 14 (3.5) 10 (2.4) Pain chest 13 (3.2) 9 (2.1) Sinusitis 11 (2.7) 7 (1.7) Fever 9 (2.2) 6 (1.4) Cramps leg 7 (1.7) 2 (0.5) Cramps muscle 7 (1.7) 0 Anxiety 6 (1.5) 5 (1.2) Pruritus 6 (1.5) 4 (1.0) Sputum increased 6 (1.5) 5 (1.2) Mouth dry 5 (1.2) 4 (1.0) Overall, the frequency of all cardiovascular adverse events in the two pivotal studies was low and comparable to placebo (6.4% for FORADIL AEROLIZER 12 mcg twice daily, and 6.0% for placebo). There were no frequently-occurring specific cardiovascular adverse events for FORADIL AEROLIZER (frequency greater than or equal to 1% and greater than placebo). Other adverse reactions to FORADIL AEROLIZER are similar in nature to other selective beta 2 -adrenoceptor agonists; e.g., angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. | Post Marketing Experience In extensive worldwide marketing experience with FORADIL, serious exacerbations of asthma, including some that have been fatal, have been reported. While most of these cases have been in patients with severe or acutely deteriorating asthma (see WARNINGS), a few have occurred in patients with less severe asthma. It is not possible to determine from these individual case reports whether FORADIL AEROLIZER contributed to the events. Rare reports of anaphylactic reactions, including severe hypotension and angioedema, have also been received in association with the use of formoterol fumarate inhalation powder.
ASTHMA RELATED DEATH Long-acting beta 2 -adrenergic agonists, such as formoterol, the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be considered to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta 2 -adrenergic agonists, including formoterol. No study adequate to determine whether the rate of asthma-related death is increased with FORADIL AEROLIZER has been conducted. Clinical studies with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo (See ADVERSE REACTIONS). The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. The studies described above enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by long-acting beta 2 -adrenergic agonists. FORADIL AEROLIZER should not be initiated in patients with significantly worsening or acutely deteriorating asthma, which may be a life-threatening condition. The use of FORADIL AEROLIZER in this setting is inappropriate. FORADIL AEROLIZER should not be used in conjunction with an inhaled, long-acting beta 2 -agonist. FORADIL AEROLIZER should not be used with other medications containing long-acting beta 2 -agonists. FORADIL AEROLIZER is not a substitute for inhaled or oral corticosteroids. Corticosteroids should not be stopped or reduced at the time FORADIL AEROLIZER is initiated. When beginning treatment with FORADIL AEROLIZER, patients who have been taking inhaled, short-acting beta 2 -agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute asthma symptoms . See PRECAUTIONS, Information for Patients and the accompanying Medication Guide. Paradoxical Bronchospasm As with other inhaled beta 2 -agonists, formoterol can produce paradoxical bronchospasm, that may be life-threatening. If paradoxical bronchospasm occurs, FORADIL AEROLIZER should be discontinued immediately and alternative therapy instituted. Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. It is important to watch for signs of worsening asthma, such as increasing use of inhaled, short-acting beta 2 -adrenergic agonists or a significant decrease in peak expiratory flow (PEF) or lung function. Such findings require immediate evaluation. Patients should be advised to seek immediate attention should their condition deteriorate. Increasing the daily dosage of FORADIL AEROLIZER beyond the recommended dose in this situation is not appropriate. FORADIL AEROLIZER should not be used more frequently than twice daily (morning and evening) at the recommended dose. Use of Anti-inflammatory Agents There are no data demonstrating that FORADIL has any clinical anti-inflammatory effect and therefore it cannot be expected to take the place of corticosteroids. Patients who require oral or inhaled corticosteroids for treatment of asthma should be continued on this type of treatment even if they feel better as a result of initiating FORADIL AEROLIZER. Any change in corticosteroid dosage, in particular a reduction, should be made ONLY after clinical evaluation (see PRECAUTIONS, Information for Patients). Cardiovascular Effects Formoterol fumarate, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of FORADIL AEROLIZER at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce 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. Therefore, formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension (see PRECAUTIONS, General). Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of FORADIL AEROLIZER, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm. Do Not Exceed Recommended Dose 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 trials with FORADIL AEROLIZER suggest that the use of doses higher than recommended is associated with an increased risk of serious asthma exacerbations (see ADVERSE REACTIONS). | Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be considered to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended. A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta 2 -adrenergic agonists, including formoterol. No study adequate to determine whether the rate of asthma-related death is increased with FORADIL AEROLIZER has been conducted. Clinical studies with FORADIL AEROLIZER suggested a higher incidence of serious asthma exacerbations in patients who received FORADIL AEROLIZER than in those who received placebo (See ADVERSE REACTIONS). The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. The studies described above enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by long-acting beta 2 -adrenergic agonists. FORADIL AEROLIZER should not be initiated in patients with significantly worsening or acutely deteriorating asthma, which may be a life-threatening condition. The use of FORADIL AEROLIZER in this setting is inappropriate. FORADIL AEROLIZER should not be used in conjunction with an inhaled, long-acting beta 2 -agonist. FORADIL AEROLIZER should not be used with other medications containing long-acting beta 2 -agonists. FORADIL AEROLIZER is not a substitute for inhaled or oral corticosteroids. Corticosteroids should not be stopped or reduced at the time FORADIL AEROLIZER is initiated. When beginning treatment with FORADIL AEROLIZER, patients who have been taking inhaled, short-acting beta 2 -agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute asthma symptoms . See PRECAUTIONS, Information for Patients and the accompanying Medication Guide. | Paradoxical Bronchospasm As with other inhaled beta 2 -agonists, formoterol can produce paradoxical bronchospasm, that may be life-threatening. If paradoxical bronchospasm occurs, FORADIL AEROLIZER should be discontinued immediately and alternative therapy instituted. | Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. It is important to watch for signs of worsening asthma, such as increasing use of inhaled, short-acting beta 2 -adrenergic agonists or a significant decrease in peak expiratory flow (PEF) or lung function. Such findings require immediate evaluation. Patients should be advised to seek immediate attention should their condition deteriorate. Increasing the daily dosage of FORADIL AEROLIZER beyond the recommended dose in this situation is not appropriate. FORADIL AEROLIZER should not be used more frequently than twice daily (morning and evening) at the recommended dose. | Use of Anti-inflammatory Agents There are no data demonstrating that FORADIL has any clinical anti-inflammatory effect and therefore it cannot be expected to take the place of corticosteroids. Patients who require oral or inhaled corticosteroids for treatment of asthma should be continued on this type of treatment even if they feel better as a result of initiating FORADIL AEROLIZER. Any change in corticosteroid dosage, in particular a reduction, should be made ONLY after clinical evaluation (see PRECAUTIONS, Information for Patients). | Cardiovascular Effects Formoterol fumarate, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of FORADIL AEROLIZER at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce 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. Therefore, formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension (see PRECAUTIONS, General). | Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of FORADIL AEROLIZER, as demonstrated by cases of anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm. | Do Not Exceed Recommended Dose 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 trials with FORADIL AEROLIZER suggest that the use of doses higher than recommended is associated with an increased risk of serious asthma exacerbations (see ADVERSE REACTIONS). --- BOXED WARNING: WARNING: ASTHMA RELATED DEATH Long-acting beta 2 -adrenergic agonists (LABA), such as formoterol the active ingredient in FORADIL AEROLIZER, increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including formoterol (see WARNINGS). Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Because of this risk, use of FORADIL AEROLIZER for the treatment of asthma without a concomitant long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use FORADIL AEROLIZER only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue FORADIL AEROLIZER) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use FORADIL AEROLIZER for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Pediatric and Adolescent Patients Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and LABA should ordinarily be considered to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g. inhaled corticosteroid) and LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and LABA is recommended.