The safety of orally inhaled budesonide; formoterol for asthma was studied in patients 12 years or older in three 12-week controlled clinical trials. Studies included 277 and 124 patients receiving the two available strengths of budesonide; formoterol 80/4.5 mcg and 160/4.5 mcg, respectively. The most commonly reported adverse reactions (occurring at an incidence of 3% or more) in the two dosing groups are listed regardless of causality and at increased incidence vs. placebo: back pain (3.2%, 1.6%), headache (6.5%, 11.3%), influenza (3.2%, 2.4%), nasal congestion (2.5%, 3.2%), naso-pharyngitis (10.5%, 9.7%), vomiting (1.4%, 3.2%), pharyngo-laryngeal pain (6.1%, 8.9%), sinusitis (5.8%, 4.8%), stomach discomfort (1.1%, 6.5%), and upper respiratory tract infection (7.6%, 10.5%). The safety profile in pediatric patients 6 to 11 years old with asthma was similar to that of older patients. Reactions occurring in 3% or more included upper respiratory tract infection, pharyngitis, headache, and rhinitis. In clinical trials for COPD, 771 patients received budesonide; formoterol 160/4.5 mcg for an average duration of 255.2 days. The most commonly reported adverse reactions (occurring at an incidence of 3% or more) relative to placebo included naso-pharyngitis (7.3%), bronchitis (5.4%), sinusitis (3.5%), and viral respiratory tract infection (3.5%). Lung infections other than pneumonia (mostly bronchitis) occurred in 7.9% of patients receiving active drug. Other adverse reactions reported with budesonide; formoterol use include nausea, muscle cramps, tremor, dizziness, dysphonia, cough, and throat irritation.[32950]

Budesonide; formoterol, like other products containing inhaled beta-2 agonists, can produce life-threatening paradoxical bronchospasm. In the event of a paradoxical bronchospasm, discontinue budesonide; formoterol immediately and initiate an alternative therapy.[32950]

An increase in the need for rescue inhaler use and/or worsening wheezing may occur during therapy with budesonide; formoterol and are symptoms of a deterioration of the underlying respiratory condition, a potentially life-threatening condition. Advise patients not to exceed recommended doses of this medicine, but instead, seek immediate medical attention if such symptoms occur.[32950] When long-acting beta agonists (LABAs) such as formoterol are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.[62717] The use of a LABA as monotherapy to treat asthma, without inhaled corticosteroids [ICS], is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients.[37481] [41282] These findings are considered a class effect of LABA monotherapy. In most cases, serious acute respiratory events have occurred in patients with severe asthma and/or in patients in whom asthma has been acutely deteriorating, but such events have also occurred in patients with less severe asthma. These findings pertain only to patients who have asthma.[32950]

Immediate and delayed hypersensitivity reactions, including anaphylactoid reactions, angioedema, bronchospasm, urticaria, exanthema, dermatitis, and pruritus have been reported with budesonide; formoterol use.[32950]

Formoterol, like other beta2-agonists and sympathomimetic amines, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate (sinus tachycardia), systolic or diastolic blood pressure (hypertension), and/or symptoms or cardiac arrhythmias, such as supraventricular tachycardia (SVT) and extrasystoles (palpitations). Although such effects are uncommon after administration of formoterol at recommended doses, if such effects occur then budesonide; formoterol may need to be discontinued. Beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, QT prolongation, and ST segment depression; the clinical significance of these findings is unknown. Beta2-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. During long-term safety studies in adolescent and adult patients 12 years of age and older, treated for up to 1 year, no significant or unexpected chemistry, ECG, or Holter monitor assessments occurred. During postmarketing experience, angina pectoris, cardiac arrhythmias (e.g., atrial fibrillation, ventricular extrasystoles, and tachyarrhythmias), palpitations, QT interval prolonged on ECG, increased blood pressure, including hypertension, hypotension, and hypokalemia have been reported with formoterol; budesonide or other products containing formoterol.[32950]

Orally inhaled budesonide; formoterol has a relatively low risk of hypothalamic-pituitary-adrenal (HPA) suppression when used at recommended doses. Pharmacologic doses of budesonide administered for prolonged periods may, however, result in adrenocortical insufficiency.[32950] Adrenal suppression and increased intracranial pressure have been reported with the use and/or withdrawal of orally inhaled steroids in pediatric patients.[51792] Local immunosuppression associated with inhaled budesonide use may be manifested as an overgrowth of fungus in the nose, mouth, and throat. Oral candidiasis (thrush) is a well-known adverse reaction of oral inhalation steroid therapy and occurred in 1.4% to 6% of adult patients receiving inhaled budesonide; formoterol during clinical trials.[32950]

Growth inhibition has been observed in some children following therapy with orally inhaled corticosteroids including budesonide. Growth inhibition has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients. With orally inhaled corticosteroids, the mean reduction in growth velocity is approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to the dose and duration of exposure. In general, the benefits of regular inhaled corticosteroid (ICS) use outweigh the potential risk of relatively small and non-cumulative growth suppression in children with asthma; however, growth should be monitored.[57670] Further study is needed to determine the long-term effects of growth velocity reduction in children, including the impact on final adult height. To minimize the effects of inhaled corticosteroids, each patient should be titrated to the lowest effective dose.[32950]

Corticosteroids, even orally inhaled doses like budesonide, can induce cataracts and have the potential to induce or worsen ocular hypertension (glaucoma). Although rarely reported during treatment with budesonide; formoterol, patients are encouraged to keep up with routine ophthalmological exams.[32950]

Behavior disturbances, sleep disturbances, agitation, depression, nervousness, restlessness, and skin bruising (ecchymosis) have been reported with postmarketing use of budesonide; formoterol.[32950]

Prolonged use (e.g., more than 1 year) of high doses of inhaled corticosteroids, like budesonide, especially when used in combination with frequent courses of systemic corticosteroids, may be associated with reduced bone mineral density (BMD), which may increase the risk of osteopenia or osteoporosis. The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown.[32950]

Clinically significant changes in blood glucose were seen infrequently during clinical studies with budesonide; formoterol at recommended doses. Hyperglycemia has been reported postmarketing.[32950] [65232]

Hypersensitivity to any of the ingredients in budesonide; formoterol contraindicates its use. Although true corticosteroid hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to budesonide should not receive any form of budesonide. It is possible, though also rare, that such patients will display cross-hypersensitivity to other corticosteroids. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid.[27616] Immediate hypersensitivity reactions may also occur after the administration of budesonide; formoterol, as demonstrated by rare cases of urticaria, angioedema, rash, and bronchospasm.

Budesonide; formoterol use is contraindicated as a primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required. Do not initiate during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Long-acting beta-2 agonists (LABAs), when used alone, have been associated with increased risk of severe asthma exacerbation and asthma-related death; this is considered a class effect. When a LABA is used in fixed-dose combination with an inhaled corticosteroid (ICS), data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone. Available data do not suggest an increased risk of death with the use of LABAs in patients with COPD.[32950] [41230] [62717] Budesonide; formoterol should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD; this product has not been studied in patients with these acutely deteriorating conditions. Do not use budesonide; formoterol for the relief of acute symptoms (i.e., as rescue therapy for the treatment of acute bronchospasm). Acute symptoms should be treated with an inhaled, short-acting beta-agonist (SABA).[32950] When initiating treatment with budesonide; formoterol, patients who have been taking oral or inhaled SABAs on a regular basis should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. Prescribe an inhaled SABA, such as albuterol, for rescue treatment of an acute asthma or COPD attack and inform patients that increased use of an inhaled SABA is a signal of deteriorating disease. Loss of symptom control with budesonide; formoterol is also a marker of deterioration of disease; in this setting, a re-evaluation of the patient and the asthma or COPD treatment regimen should be undertaken at once, giving special consideration to the possible need for replacing the current strength of budesonide; formoterol with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use budesonide; formoterol more often than recommended, at higher doses than recommended, or in conjunction with other LABAs as this would be considered duplicative therapy and may lead to additive untoward effects. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma.[32950]

Discontinue the regular use of short acting beta-2 agonists (i.e., four times daily) upon budesonide; formoterol initiation; however, short acting beta-2 agonists can be continued for symptomatic relief of acute asthma symptoms, often referred to as rescue inhalers. Furthermore, patients should not use budesonide; formoterol in conjunction with other long acting beta-2 agonists or other inhaled corticosteroid therapy as this would be considered duplicative therapy and may lead to additive untoward effects.

Formoterol, like other beta2-agonists and sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency (coronary artery disease), cardiac arrhythmias, and hypertension. Formoterol can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, budesonide; formoterol inhalation may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, QT prolongation, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Beta-adrenergic agonist therapies like formoterol 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.[32950]

Budesonide; formoterol should be used with caution in patients with diabetes mellitus. Inhalation of high doses of beta-2 agonists may cause transient, but clinically relevant, hyperglycemia in some patients. Corticosteroids are also associated with increases in blood glucose in some patients. Such increases in blood glucose are most relevant for patients with diabetes mellitus.[32950]

Budesonide; formoterol should be used cautiously in patients with hyperthyroidism (thyrotoxicosis), seizure disorder, pheochromocytoma, or other unusual responsiveness to sympathomimetic amines.[32950]

Budesonide; formoterol should be administered with extreme caution to patients being treated with MAOI therapy (see Drug Interactions).

Budesonide; formoterol should be used cautiously in patients with glaucoma or other visual disturbance or with a family history of glaucoma. Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids, including budesonide. Patients receiving corticosteroids chronically should be periodically assessed for cataract formation.

Although the risk of developing hypothalamic-pituitary-adrenal (HPA) suppression is very low with inhaled budesonide; formoterol, patients should, nevertheless, be monitored for this possibility. Particular care is needed for patients who are transferred from systemic to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic to less systemically absorbed inhaled corticosteroids. Patients previously maintained on doses equivalent to 20 mg/day or more of prednisone may be at increased risk. After withdrawal from systemic corticosteroids, a number of months are required for recovery of HPA-axis function.[32950]

Although inhaled budesonide; formoterol is absorbed systemically to a lesser extent than other corticosteroids, significant amounts can be absorbed when large doses are administered. This can increase the risk for infection. In general, inhaled corticosteroid therapy used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal infection, bacterial infection, viral infection, or a parasitic infection, especially those not adequately controlled by anti-infective agents. Inhaled corticosteroids should be used cautiously, if at all, in patients with an active herpes infection (including ocular herpes simplex). If a patient on immunosuppressant doses of corticosteroids is exposed to chickenpox, therapy with varicella-zoster immune globulin or pooled intramuscular immunoglobulin may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin may be indicated. Budesonide oral inhalation has been associated with the development of localized infection with Candida albicans in the nose, mouth, and pharynx. If this develops, discontinuation of inhaled budesonide is warranted, and appropriate local therapy should be instituted. Patients who are on long-term budesonide inhalation therapy should receive a periodic evaluation for Candida infection or other adverse effects.[32950]

Long-term use of orally inhaled corticosteroids, such as budesonide, may affect normal bone metabolism resulting in a loss of bone mineral density or osteopenia. Use budesonide; formoterol with caution in patients with risk factors for decreased bone mineral content, including tobacco use, advanced age, sedentary lifestyle, poor nutrition, family history of osteoporosis, or chronic use of drugs that decrease bone mass.[32950]

Formal pharmacokinetic studies using budesonide; formoterol inhalation have not been conducted in patients with hepatic impairment. However, since budesonide and formoterol are predominantly cleared by hepatic metabolism, impairment of liver function may lead to increased exposure of budesonide and formoterol. Therefore, patients with severe hepatic disease should be closely monitored.[32950]

The safety and efficacy of budesonide; formoterol have not been established in neonates, infants, or children younger than 6 years. For pediatric patients with persistent asthma, limit use to those who have asthma that is not adequately controlled with a long-term asthma control medication, such as an inhaled corticosteroid. When long-acting beta-agonists (LABAs) are used in fixed-dose combination with inhaled corticosteroids (ICS), data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.[32950] Available data from clinical trials suggest that asthma treatment with LABA monotherapy, without an inhaled corticosteroid, increases the risk of asthma-related hospitalization and death in children and adolescents.[37481] [41230] Pediatric patients may be more susceptible to developing systemic toxicity from corticosteroids. Growth inhibition has been observed in some children following therapy with corticosteroids, including inhaled budesonide therapy.[32950] Adrenal suppression and increased intracranial pressure have been reported with the use and/or withdrawal of orally inhaled corticosteroid formulations in young patients.[51792] To minimize the effects of orally inhaled corticosteroids, each patient should be titrated to the lowest effective dose. The growth of pediatric patients should be monitored regularly.[32950]

There are no adequate and well-controlled studies of budesonide; formoterol during human pregnancy; however, studies of pregnant women taking inhaled budesonide alone have not shown increases in the risk of abnormalities when given during pregnancy. In animal studies, formoterol fumarate has only shown adverse effects when administered systemically at high systemic exposures greatly exceeding the maximum recommended human daily inhalational dose (MRHDID). No teratogenic, embryocidal, or developmental effects were seen in rats that received formoterol inhalation doses up to 375 times the MRHDID. Women with asthma who become pregnant while stabilized on budesonide; formoterol therapy should discuss their asthma management with a qualified health care professional.[32950] A review of Swedish registries indicated that in over 2,000 births there was no increased risk for congenital malformations during early pregnancy with budesonide inhalation powder or solution.[32950] It is known that improved maternal and perinatal outcomes are achieved with optimal control of asthma during pregnancy.[45934] Large studies of women with asthma have confirmed the lack of relationship between the use of inhaled beta-2 agonists and adverse maternal or fetal outcomes; however, less data are available for long-acting beta agonists (LABAs) such as formoterol vs. short-acting beta agonists (SABAs).[45934] However, most inhaled beta-2 agonists, as well as inhaled budesonide, are considered acceptable for use during pregnancy because of the low bioavailability and maternal serum levels after use.[45934] [49764] [63021] According to the 2004 guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group, long-acting beta-2 agonists (LABAs), in combination with inhaled corticosteroids (ICS), are one of the preferred treatment options for the long-term control of moderate asthma during pregnancy and lactation; use of medium dose ICS is also a preferred option. Although a preferred LABA is not recommended, the guideline states that more experience is available with salmeterol. Due to the availability of safety information during pregnancy, budesonide is preferred over other ICS.[45934] Infants born to mothers taking substantial corticosteroid doses during pregnancy should be monitored for signs of hypoadrenalism.[32950] There are no well-controlled human studies that have investigated the effects of budesonide; formoterol on preterm labor or labor at term. Because of the potential for beta-2 agonist interference with uterine contractility, use of budesonide; formoterol should be restricted to those patients in whom the benefits clearly outweigh the risks.[32950]

There are no well-controlled human studies that have investigated the effects of budesonide; formoterol during breast-feeding. Formoterol was excreted in milk in reproductive studies in rats; however, it is unknown whether formoterol is excreted in human milk. Glucocorticoids, such as budesonide, are excreted into human breast milk. Data from a small number (n = 8) of lactating women showed an estimated oral daily dose of budesonide available to the nursing infants which was approximately 0.3% to 1% of the dose inhaled by the mothers. Budesonide plasma concentrations obtained in five of the infants at about 140 minutes after drug administration to the mother and 90 minutes after breast-feeding were below quantifiable levels.[32950] The amount of inhaled budesonide excreted in breast-milk is minute, and infant exposure is negligible. While not measured, the amount of formoterol absorbed into the maternal bloodstream and excreted into breast-milk after inhalation is expected to be very low; therefore, it is unlikely that nursing infants would be exposed to clinically significant amounts of formoterol via breast milk. Most inhaled bronchodilators are considered acceptable for use during the postpartum period and breast-feeding because of the low bioavailability and maternal serum levels after use.[45934] [63021] The 2004 guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group consider a combination of inhaled corticosteroids with long-acting inhaled beta-2 agonists (LABAs) a preferred treatment option for moderate asthma in pregnancy and lactation.[45934] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Similar to other inhaled beta-agonists, budesonide; formoterol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, it should be treated immediately with a short-acting, inhaled bronchodilator, and budesonide; formoterol should be discontinued immediately and alternative therapy instituted.[32950]