Budesonide And Formoterol Fumarate Dihydrate

Similarly, no significant or unexpected patterns of abnormalities were observed for up to 1 year in safety measures including chemistry, hematology, ECG, Holter monitor, and HPA-axis assessments. Pediatric Patients 6 to Less than 12 Years of Age The safety data for pediatric patients aged 6 to less than 12 years is based on 1 trial of 12 weeks treatment duration.

5 (n=92) or budesonide pMDI 80 mcg (n=92), 2 inhalations twice daily. 5 twice daily in studies of similar design. 5 with a frequency of ≥3% and more frequently than patients treated only with budesonide pMDI 80 mcg included upper respiratory tract infection, pharyngitis, headache, and rhinitis.

5 in 1783 patients. 5 was studied in two placebo-controlled lung function studies (6 and 12 months in duration), and two active-controlled exacerbation studies (6 and 12 months in duration) in patients with COPD. 5, two inhalations twice daily.

Of these patients 651 were treated for 6 months and 366 were treated for 12 months. The budesonide and formoterol fumarate dihydrate group was composed of mostly Caucasian (93%) patients with a mean age of 63 years, and a mean percent predicted FEV 1 at baseline of 33%.

5 mcg or placebo (MDI and DPI) twice daily. Table 3 includes all adverse events that occurred at an incidence of ≥3% in the budesonide and formoterol fumarate dihydrate group and more commonly than in the placebo group. In considering these data, the increased average duration of patient exposure to budesonide and formoterol fumarate dihydrate should be taken into account, as incidences are not adjusted for an imbalance of treatment duration.

Table 3 Adverse reactions occurring at an incidence of ≥ 3% and more commonly than placebo in the Budesonide and Formoterol Fumarate Dihydrate group: pooled data from two double-blind, placebo-controlled clinical COPD trials Treatment All treatments were administered as 2 inhalations twice daily.

9% vs. 1%, respectively). There were no clinically important or unexpected patterns of abnormalities observed for up to 1 year in chemistry, hematology, ECG, ECG (Holter) monitoring, HPA-axis, bone mineral density and ophthalmology assessments.

5, two inhalations twice daily were consistent with the lung function studies. 3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of budesonide and formoterol fumarate dihydrate.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with budesonide and formoterol fumarate dihydrate.

Cardiac disorders: angina pectoris, tachycardia, atrial and ventricular tachyarrhythmias, atrial fibrillation, extrasystoles, palpitations Endocrine disorders: hypercorticism, growth velocity reduction in pediatric patients Eye disorders: cataract, glaucoma, increased intraocular pressure Gastrointestinal disorders: oropharyngeal candidiasis, nausea Immune system disorders: immediate and delayed hypersensitivity reactions, such as anaphylactic reaction, angioedema, bronchospasm, urticaria, exanthema, dermatitis, pruritus Metabolic and nutrition disorders: hyperglycemia, hypokalemia Musculoskeletal, connective tissue, and bone disorders: muscle cramps Nervous system disorders: tremor, dizziness Psychiatric disorders: behavior disturbances, sleep disturbances, nervousness, agitation, depression, restlessness Respiratory, thoracic, and mediastinal disorders: dysphonia, cough, throat irritation Skin and subcutaneous tissue disorders: skin bruising Vascular disorders: hypotension, hypertension

13) • Effects on growth: Monitor growth of pediatric patients. 14 ) • Glaucoma and cataracts: Close monitoring is warranted. 15 ) • Metabolic effects: Be alert to eosinophilic conditions, hypokalemia, and hyperglycemia. 18 ) • Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.

1 Serious Asthma-Related Events – Hospitalizations, Intubations and Death Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART) ].

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. These findings are considered a class effect of LABA.

When LABA 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 to ICS alone (see Serious Asthma-Related Events with ICS/LABA ).

Serious Asthma-Related Events with ICS/LABA Four large, 26-week, randomized, blinded, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared to ICS alone in patients with asthma.

1) ] ; one trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder; and one trial compared mometasone furoate/formoterol to mometasone furoate. The fourth trial included pediatric patients 4 to 11 years of age and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder.

The primary safety endpoint for all four trials was serious asthma-related events (hospitalizations, intubations and death). A blinded adjudication committee determined whether events were asthma-related. 7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone.

A meta-analysis of the three adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

Table 1. Meta-analysis of Serious Asthma-Related Events in Patients with Asthma Aged 12 Years and Older ICS/LABA (N = 17,537) Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis. ICS (N = 17,552) ICS/LABA vs ICS Hazard ratio (95% CI) Estimated using a Cox proportional hazards model of time to first event with baseline hazards stratified by each of the 3 trials.

Serious asthma-related event Number of patients with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Patients can have one or more events, but only the first event was counted for analysis.

A single, blinded, independent adjudication committee determined whether events were asthma-related. 44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 ICS = Inhaled Corticosteroid, LABA = Long-acting Beta2-adrenergic Agonist The pediatric safety trial included 6208 pediatric patients 4 to 11 years of age who received ICS/LABA (fluticasone propionate /salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder).

7%) patients randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. 27). S. trial that compared 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.

34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy. Formoterol Monotherapy Studies Clinical studies with formoterol used as monotherapy suggested a higher incidence of serious asthma exacerbation in patients who received formoterol than in those who received placebo.

The sizes of these studies were not adequate to precisely quantify the difference in serious asthma exacerbations between treatment groups. 2 Deterioration of Disease and Acute Episodes Budesonide and formoterol fumarate dihydrate should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD.

Budesonide and formoterol fumarate dihydrate has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of budesonide and formoterol fumarate dihydrate in this setting is not appropriate. Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma.

In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of budesonide and formoterol fumarate dihydrate with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids.

Patients should not use more than 2 inhalations twice daily (morning and evening) of budesonide and formoterol fumarate dihydrate. , as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta 2 -agonist, not budesonide and formoterol fumarate dihydrate, should be used to relieve acute symptoms such as shortness of breath.

, 4 times a day) should be instructed to discontinue the regular use of these drugs. 3 Excessive Use of Budesonide and Formoterol Fumarate Dihydrate and Use with Other Long-Acting Beta 2 -Agonists As with other inhaled drugs containing beta 2 -adrenergic agents, budesonide and formoterol fumarate dihydrate should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABA, as an overdose may result.

Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. , salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma or COPD.

4 Local Effects In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with budesonide and formoterol fumarate dihydrate. , oral antifungal) therapy while treatment with budesonide and formoterol fumarate dihydrate continues, but at times therapy with budesonide and formoterol fumarate dihydrate may need to be interrupted.

Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5 Pneumonia and Other Lower Respiratory Tract Infections Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap.

Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids. 3%). 3%). 2%). 0%). 6 Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals.

Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.

How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information).

If chicken pox develops, treatment with antiviral agents may be considered. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.

, beta 2 -agonists, leukotriene receptor antagonists, cromones). 0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%), compared to patients treated with noncorticosteroid asthma therapy (90%).

No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

7 Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids.

After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.

Although budesonide and formoterol fumarate dihydrate may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress, a severe asthma attack or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.

These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe asthma attack, or a severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to budesonide and formoterol fumarate dihydrate.

5 mg on a weekly basis during therapy with budesonide and formoterol fumarate dihydrate. Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [PEF]), beta-agonist use, and asthma or COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. , rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

, joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 8 Hypercorticism and Adrenal Suppression Budesonide, a component of budesonide and formoterol fumarate dihydrate, will often help control asthma and COPD symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.

Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of budesonide and formoterol fumarate dihydrate in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with budesonide and formoterol fumarate dihydrate should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time.

If such effects occur, the dosage of budesonide and formoterol fumarate dihydrate should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms. 3) ]. 10 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled medications, budesonide and formoterol fumarate dihydrate can produce paradoxical bronchospasm, which may be life threatening.

If paradoxical bronchospasm occurs following dosing with budesonide and formoterol fumarate dihydrate, it should be treated immediately with an inhaled, short-acting bronchodilator, BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL should be discontinued immediately, and alternative therapy should be instituted.

11 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of budesonide and formoterol fumarate dihydrate, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm.

12 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 [see Overdosage (10) ] .

Therefore, budesonide and formoterol fumarate dihydrate, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Formoterol, a component of budesonide and formoterol fumarate dihydrate, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of formoterol 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. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating budesonide and formoterol fumarate dihydrate and periodically thereafter.

If significant reductions in BMD are seen and budesonide and formoterol fumarate dihydrate is still considered medically important for that patient's COPD therapy, use of medication to treat or prevent osteoporosis should be strongly considered.

5 mcg, or placebo on BMD was evaluated in a subset of 326 patients (females and males 41 to 88 years of age) with COPD in the 12-month lung function study. BMD evaluations of the hip and lumbar spine regions were conducted at baseline and 52 weeks using dual energy x-ray absorptiometry (DEXA) scans.

01 g/cm 2 ). ANCOVA results for total spine and total hip BMD based on the end of treatment time point showed that all geometric LS Mean ratios for the pairwise treatment group comparisons were close to 1, indicating that overall, BMD for total hip and total spine regions for the 12-month time point were stable over the entire treatment period.

14 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. , via stadiometry). 4) ] . 15 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of inhaled corticosteroids, including budesonide, a component of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL.

Therefore, close monitoring is warranted in patients with a change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts. 5 mcg, or placebo on development of cataracts or glaucoma were evaluated in a subset of 461 patients with COPD in the 12-month lung function study.

Ophthalmic examinations were conducted at baseline, 24 weeks, and 52 weeks. 7) during the randomized treatment period. 2%) in the placebo group. 16 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions.

Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids.

Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established.

17 Coexisting Conditions Budesonide and formoterol fumarate dihydrate, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines.

Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 2) ]. The decrease in serum potassium is usually transient, not requiring supplementation.

Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with budesonide and formoterol fumarate dihydrate at recommended doses.