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Long-acting beta2-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. 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 beta2-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 beta2-adrenergic agonists.
Deterioration of Disease and Acute Episodes
FORADIL AEROLIZER should not be initiated in patients with significantly worsening, acutely deteriorating, or potentially life-threatening episodes of asthma or COPD. The use of FORADIL AEROLIZER in this setting is not appropriate [see INDICATIONS AND USAGE].
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 beta2-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.
FORADIL AEROLIZER should not be used to treat acute symptoms. FORADIL AEROLIZER has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. When prescribing FORADIL AEROLIZER, the physician should also provide the patient with an inhaled, short-acting beta2-agonist for treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use of FORADIL AEROLIZER. Patients should also be cautioned that increasing inhaled beta2-agonist use is a signal of deteriorating asthma [see Information for Patients and the accompanying Medication Guide.]
When beginning treatment with FORADIL AEROLIZER, patients who have been taking inhaled, short-acting beta2agonists 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 symptoms.
FORADIL AEROLIZER is not a substitute for corticosteroids
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. Corticosteroids should not be stopped or reduced at the time FORADIL AEROLIZER is initiated. Patients who already 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 PATIENT INFORMATION].
Excessive Use and Use with Other Long-Acting Beta2-Agonists
FORADIL AEROLIZER should not be used more often or at doses higher than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Patients using FORADIL AEROLIZER should not use an additional LABA (e.g. salmeterol xinafoate, arformoterol tartrate) for any reason. 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].
As with other inhaled beta2-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.
Cardiovascular and Central Nervous System Effects
Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs [see OVERDOSAGE].
Formoterol fumarate, like other beta2-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.
Immediate Hypersensitivity Reactions
FORADIL AEROLIZER contains lactose, which contains trace levels of milk proteins. Allergic reactions to products containing milk proteins may occur in patients with severe milk protein allergy.
Formoterol fumarate, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
Hypokalemia and Hyperglycemia
Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.
Clinically significant changes in blood glucose and/or serum potassium were infrequent during clinical studies with long-term administration of FORADIL AEROLIZER at the recommended dose.
Inappropriate route of administration
FORADIL capsules should ONLY be used with the AEROLIZER Inhaler and SHOULD NOT be swallowed. FORADIL capsules should always be stored in the blister, and only removed IMMEDIATELY before use.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide and Instructions for Use)
Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be given the following information:
Patients should be informed that long-acting beta2-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. 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.
Patients should be informed that FORADIL AEROLIZER should not be the only therapy for the treatment of asthma and must only be used as additional therapy when a long-term asthma control medication (e.g., inhaled corticosteroids) do not adequately control asthma symptoms. Patients should be informed that when FORADIL AEROLIZER is added to their treatment regimen they must continue to use their long-term asthma control medication.
Not for Acute Symptoms
FORADIL AEROLIZER is not indicated to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting, beta2-agonist (the health-care provider should prescribe the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen, if FORADIL AEROLIZER treatment becomes less effective, or if they need more inhalations of a short-acting beta2-agonist than usual. Patients should not inhale more than the contents of one capsule at any one time. The daily dosage of FORADIL AEROLIZER should not exceed one capsule twice daily (24 mcg total daily dose).
Required Concomitant Therapy
Patients with asthma should be advised that FORADIL AEROLIZER must always be used with a long-term asthma control medication such as an inhaled corticosteroid.
FORADIL AEROLIZER should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with FORADIL AEROLIZER.
Common Adverse Reactions
The active ingredient of FORADIL (formoterol fumarate) is a long-acting, bronchodilator used for the treatment of asthma, including nocturnal asthma, for the prevention of exercise-induced bronchospasm, and for the maintenance treatment of bronchoconstriction in patients with Chronic Obstructive Pulmonary Disease including chronic bronchitis and emphysema. FORADIL AEROLIZER provides bronchodilation for up to 12 hours. Patients should be advised not to increase the dose or frequency of FORADIL AEROLIZER without consulting the prescribing physician. Patients should be warned not to stop or reduce concomitant asthma therapy without medical advice.
For asthma and COPD, the usual dose is one FORADIL capsule inhaled through the AEROLIZER inhaler 2 times each day (morning and evening). The 2 doses should be about 12 hours apart. Patients should be advised not to use other LABA when using FORADIL AEROLIZER.
When FORADIL AEROLIZER is used for the prevention of EIB, the contents of one capsule should be taken at least 15 minutes prior to exercise. Additional doses of FORADIL AEROLIZER should not be used for 12 hours. Prevention of EIB has not been studied in patients who are receiving chronic FORADIL AEROLIZER administration twice daily and these patients should not use additional FORADIL AEROLIZER for prevention of EIB.
Instructions for Administration
It is important for patients to understand how to correctly administer FORADIL capsules using the AEROLIZER Inhaler and how FORADIL should be used in relation to other asthma medications they are taking (see the accompanying Medication Guide).
Patients should be instructed that FORADIL capsules should only be administered via the AEROLIZER device and the AEROLIZER device should not be used for administering other medications. The contents of FORADIL capsules are for oral inhalation only and must not be swallowed.
Patients should be informed never to use FORADIL AEROLIZER with a spacer and never to exhale into the device.
Patients should avoid exposing the FORADIL capsules to moisture and should handle the capsules with dry hands. The AEROLIZER Inhaler should never be washed and should be kept dry. The patient should always use the new AEROLIZER Inhaler that comes with each refill.
Patients should be told that in rare cases, the gelatin capsule might break into small pieces. These pieces should be retained by the screen built into the AEROLIZER Inhaler. However, it remains possible that rarely, tiny pieces of gelatin might reach the mouth or throat after inhalation. The capsule is less likely to shatter when pierced if: storage conditions are strictly followed, capsules are removed from the blister immediately before use, and the capsules are only pierced once.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study, but not at dietary doses up to 5 mg/kg (AUC exposure approximately 450 times human exposure at the maximum recommended human dose [MRHD]). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at the low dose of 0.5 mg/kg was approximately 45 times human exposure at the MRHD). This finding was not observed in the drinking water study, nor was it seen in mice (see below).
In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 590 times human exposure at the MRHD) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up to 5 mg/kg in either males or females (AUC exposure approximately 60 times human exposure at the MRHD). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg and above (AUC exposure at the low dose of 2 mg/kg was approximately 25 times human exposure at the MRHD). Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs.
Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats.
Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 1,200 times the MRHD on a mcg/m2 basis).
Use In Specific Populations
Pregnancy Category C
Teratogenic Effects: There are no adequate and well-controlled studies of FORADIL AEROLIZER in pregnant women. Animal reproduction studies of formoterol fumarate in rats and rabbits revealed evidence of teratogenicity as well as other developmental toxic effects. Because there are no adequate and well-controlled studies in pregnant women, FORADIL AEROLIZER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Formoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. When given to rats throughout organogenesis, oral doses equal to or greater than 80 times the maximum recommended human dose (MRHD) for adults (on a mcg/m2 basis for maternal doses of 0.2 mg/kg and above) delayed ossification of the fetus and doses equal to or greater than 2,400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) decreased fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2,400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose equal to 80 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 0.2 mg/kg).
In another testing laboratory, formoterol fumarate was shown to be teratogenic in rats and rabbits. Umbilical hernia, a malformation, was observed in rat fetuses at oral doses equal to or greater than 1,200 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 3 mg/kg/day and above). Brachygnathia, a skeletal malformation, was observed for rat fetuses at an oral dose equal to 6,100 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 15 mg/kg/day). In another study in rats, no teratogenic effects were seen at inhalation doses up to 500 times the MRHD for adults (on a mcg/m2 basis for maternal doses up to 1.2 mg/kg/day). Subcapsular cysts on the liver were observed for rabbit fetuses at an oral dose equal to 49,000 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 60 mg/kg). No teratogenic effects were observed at oral doses up to 3,000 times the MRHD for adults (on a mcg/m2 basis for maternal doses up to 3.5 mg/kg).
Labor and Delivery
There are no adequate and well-controlled human studies that have investigated the effects of FORADIL AEROLIZER during labor and delivery.
Because beta-agonists may potentially interfere with uterine contractility, FORADIL AEROLIZER should be used during labor only if the potential benefit justifies the potential risk.
Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses equal to or greater than 2,400 times the MRHD for adults (on a mcg/m2 basis for maternal doses of 6 mg/kg and above) in rats receiving the drug for several days at the end of pregnancy. These effects were not produced at a dose 80 times the MRHD for adults (on a mcg/m2 basis for a maternal dose of 0.2 mg/kg).
In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if FORADIL AEROLIZER is administered to nursing women. There are no well-controlled human studies of the use of FORADIL AEROLIZER in nursing mothers.
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 used to ensure adherence with both drugs [see INDICATIONS AND USAGE and WARNINGS AND PRECAUTIONS].
A total of 776 children 5 years of age and older with asthma were studied in three multiple-dose controlled clinical trials. Of the 512 children who received formoterol, 508 were 5-12 years of age, and approximately one third were 5-8 years of age [see ADVERSE REACTIONS].
A total of 25 pediatric patients, 4-11 years of age, were studied in two well-controlled single-dose clinical trials.
Of the total number of patients who received FORADIL AEROLIZER in adolescent and adult chronic dosing asthma clinical trials, 318 were 65 years of age or older and 39 were 75 years of age and older. Of the 811 patients who received FORADIL AEROLIZER in two pivotal multiple-dose controlled clinical studies in patients with COPD, 395 (48.7%) were 65 years of age or older while 62 (7.6%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. A slightly higher frequency of chest infection was reported in the 39 asthma patients 75 years of age and older, although a causal relationship with FORADIL has not been established. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/2/2012
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