Asthma

Cardiovascular effects: In a single-dose cross-over study involving 201 patients with persistent asthma, single-dose treatments of 4.5, 9, and 18 mcg of formoterol in combination with 320 mcg of budesonide delivered via BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL were compared to budesonide 320 mcg alone. Dose-ordered improvements in FEV1 were demonstrated when compared with budesonide. ECGs and blood samples for glucose and potassium were obtained post-dose. For budesonide and formoterol fumarate dihydrate, small mean increases in serum glucose and decreases in serum potassium (+0.44 mmol/L and -0.18 mmol/L at the highest dose, respectively) were observed with increasing doses of formoterol, compared to budesonide. In ECGs, budesonide and formoterol fumarate dihydrate produced small dose-related mean increases in heart rate (approximately 3 bpm at the highest dose), and QTc intervals (3-6 msec) compared to budesonide alone. No subject had a QT or QTc value ≥500 msec.

In the United States, five 12-week, active- and placebo-controlled studies and one 6-month active-controlled study evaluated 2976 patients aged 6 years and older with asthma. Systemic pharmacodynamic effects of formoterol (heart/pulse rate, blood pressure, QTc interval, potassium, and glucose) were similar in patients treated with budesonide and formoterol fumarate dihydrate, compared with patients treated with formoterol dry inhalation powder 4.5 mcg, 2 inhalations twice daily. No patient had a QT or QTc value ≥500 msec during treatment. 

In three placebo-controlled studies in adolescents and adults with asthma, aged 12 years and older, a total of 1232 patients (553 patients in the budesonide and formoterol fumarate dihydrate group) had evaluable continuous 24-hour electrocardiographic monitoring. Overall, there were no important differences in the occurrence of ventricular or supraventricular ectopy and no evidence of increased risk for clinically significant dysrhythmia in the budesonide and formoterol fumarate dihydrate group compared to placebo. 

HPA-axis effects: Overall, no clinically important effects on HPA-axis, as measured by 24-hour urinary cortisol, were observed for budesonide and formoterol fumarate dihydrate treated adult or adolescent patients at doses up to 640/18 mcg/day compared to budesonide.

Chronic Obstructive Pulmonary Disease

Cardiovascular effects: In two COPD lung function studies, 6 months and 12 months in duration including 3668 COPD patients, no clinically important differences were seen in pulse rate, blood pressure, potassium, and glucose between budesonide and formoterol fumarate dihydrate, the individual components of BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL, and placebo [see Clinical Studies (14.2)].

ECGs recorded at multiple clinic visits on treatment in both studies showed no clinically important differences for heart rate, PR interval, QRS duration, heart rate, signs of cardiac ischemia or arrhythmias between budesonide and formoterol fumarate dihydrate 160/4.5 the monoproducts and placebo, all administered as 2 inhalations twice daily. Based on ECGs, 6 patients treated with budesonide and formoterol fumarate dihydrate 160/4.5, 6 patients treated with formoterol 4.5 mcg, and 6 patients in the placebo group experienced atrial fibrillation or flutter that was not present at baseline. There were no cases of nonsustained ventricular tachycardia in the budesonide and formoterol fumarate dihydrate 160/4.5, formoterol 4.5 mcg, or placebo groups.

In the 12-month study, 520 patients had evaluable continuous 24-hour ECG (Holter) monitoring prior to the first dose and after approximately 1 and 4 months on treatment. No clinically important differences in ventricular or supraventricular arrhythmias, ventricular or supraventricular ectopic beats, or heart rate were observed among the groups treated with budesonide and formoterol fumarate dihydrate 160/4.5, formoterol or placebo taken as 2 inhalations twice daily. Based on ECG (Holter) monitoring, one patient on budesonide and formoterol fumarate dihydrate 160/4.5, no patients on formoterol 4.5 mcg, and three patients in the placebo group experienced atrial fibrillation or flutter that was not present at baseline.

HPA-axis effects: Twenty-four hour urinary cortisol measurements were collected in a pooled subset (n=616) of patients from two COPD lung function studies. The data indicated approximately 30% lower mean 24-hour urinary free cortisol values following chronic administration (> 6 months) of budesonide and formoterol fumarate dihydrate, relative to placebo. Budesonide and formoterol fumarate dihydrate appeared to exhibit comparable cortisol suppression to budesonide 160 mcg alone or coadministration of budesonide 160 mcg and formoterol 4.5 mcg. For patients treated with budesonide and formoterol fumarate dihydrate, or placebo for up to 12 months, the percentage of patients who shifted from normal to low for this measure were generally comparable.

Other Budesonide Products

To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally ingested budesonide, despite comparable systemic levels. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract. 

Inhaled budesonide has been shown to decrease airway reactivity to various challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain. 

Pretreatment with inhaled budesonide, 1600 mcg daily (800 mcg twice daily) for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV1 following inhaled allergen challenge. 

The systemic effects of inhaled corticosteroids are related to the systemic exposure to such drugs. Pharmacokinetic studies have demonstrated that in both adults and children with asthma the systemic exposure to budesonide is lower with budesonide and formoterol fumarate dihydrate, compared with inhaled budesonide administered at the same delivered dose via a dry powder inhaler [see Clinical Pharmacology (12.3)]. Therefore, the systemic effects (HPA-axis and growth) of budesonide delivered from budesonide and formoterol fumarate dihydrate, would be expected to be no greater than what is reported for inhaled budesonide when administered at comparable doses via the dry powder inhaler [see Use in Specific Populations (8.4)].

HPA-axis effects: The effects of inhaled budesonide administered via a dry powder inhaler on the HPA-axis were studied in 905 adults and 404 pediatric patients with asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact with budesonide treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13%, respectively, had an abnormal stimulated cortisol response (peak cortisol <14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test) as compared to 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800, and 1600 mcg of inhaled budesonide twice daily for 6 weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10-mg prednisone resulted in a 35% reduction. In this study, no patient on budesonide at doses of 400 and 800 mcg twice daily met the criterion for an abnormal stimulated-cortisol response (peak cortisol <14.5 mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label, long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA-axis (both basal- and stimulated-plasma cortisol) of budesonide when administered at recommended doses. In patients who had previously been oral-steroid-dependent, use of budesonide in recommended doses was associated with higher stimulated-cortisol response compared to baseline following 1 year of therapy. 

Other Formoterol Products

While the pharmacodynamic effect is via stimulation of beta-adrenergic receptors, excessive activation of these receptors commonly leads to skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. Inhaled formoterol, like other beta2-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium [see Warnings and Precautions (5)]. For budesonide and formoterol fumarate dihydrate, these effects are detailed in the Clinical Pharmacology, Pharmacodynamics, BUDESONIDE AND FORMOTEROL FUMARATE DIHYDRATE INHALATION AEROSOL (12.2) section. 

Use of LABA drugs can result in tolerance to bronchoprotective and bronchodilatory effects. 

Rebound bronchial hyperresponsiveness after cessation of chronic long-acting beta-agonist therapy has not been observed.