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Symbicort

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Symbicort

CLINICAL PHARMACOLOGY

Mechanism of Action

SYMBICORT (budesonide and formoterol fumarate dihydrate)

SYMBICORT (budesonide and formoterol fumarate dihydrate) contains both budesonide and formoterol; therefore, the mechanisms of action described below for the individual components apply to SYMBICORT (budesonide and formoterol fumarate dihydrate) . These drugs represent two classes of medications (a synthetic corticosteroid and a long-acting selective beta2-adrenoceptor agonist) that have different effects on clinical, physiological, and inflammatory indices of Chronic Obstructive Pulmonary Disease (COPD) and asthma.

Budesonide

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay.

In glucocorticoid receptor affinity studies, the 22R form of budesonide was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.

Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non–allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in COPD and asthma.

Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of budesonide. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85%-95%), and the low potency of formed metabolites.

Formoterol

Formoterol fumarate is a long-acting selective beta2-adrenergic agonist (beta2-agonist) with a rapid onset of action.

Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. The in vitro binding selectivity to beta2- over beta1-adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta2-selectivity ratio than formoterol.

Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

Pharmacodynamics

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 SYMBICORT (budesonide and formoterol fumarate dihydrate) 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 postdose. For SYMBICORT (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, SYMBICORT (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 evaluated 2152 patients aged 12 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 SYMBICORT (budesonide and formoterol fumarate dihydrate) , compared with patients treated with formoterol dry inhalation powder 4.5 mcg, two 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 SYMBICORT (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 SYMBICORT (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 SYMBICORT (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 2 clinical 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 SYMBICORT (budesonide and formoterol fumarate dihydrate) , the individual components of SYMBICORT (budesonide and formoterol fumarate dihydrate) , and placebo. [see Clinical Studies].

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 SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 the monoproducts and placebo, all administered as two inhalations twice daily. Based on ECGs, 6 patients treated with SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5, 6 patients treated with formoterol 4.5, 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 SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5, formoterol 4.5, 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 SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5, formoterol or placebo taken as two inhalations twice daily. Based on ECG (Holter) monitoring, one patient on SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5, no patients on formoterol 4.5, 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 studies. The data indicated approximately 30% lower mean 24-hour urinary free cortisol values following chronic administration ( > 6 months) of SYMBICORT (budesonide and formoterol fumarate dihydrate) relative to placebo. SYMBICORT (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 SYMBICORT (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 SYMBICORT (budesonide and formoterol fumarate dihydrate) compared with inhaled budesonide administered at the same delivered dose via a dry powder inhaler [see CLINICAL PHARMACOLOGY, Pharmacokinetics, SYMBICORT (budesonide and formoterol fumarate dihydrate) ]. Therefore, the systemic effects (HPA axis and growth) of budesonide delivered from SYMBICORT (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, Pediatric Use].

HPA Axis Effects: The effects of inhaled budesonide administered via a dry powder inhaler on the hypothalamic-pituitary-adrenal (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 (6hour 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]. For SYMBICORT (budesonide and formoterol fumarate dihydrate) , these effects are detailed in the CLINICAL PHARMACOLOGY, Pharmacodynamics, SYMBICORT (budesonide and formoterol fumarate dihydrate) section.

Use of long-acting beta2-adrenergic agonist 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.

Pharmacokinetics

SYMBICORT (budesonide and formoterol fumarate dihydrate)
Absorption

Budesonide: Healthy Subjects: Orally inhaled budesonide is rapidly absorbed in the lungs and peak concentration is typically reached within 20 minutes. After oral administration of budesonide peak plasma concentration was achieved in about 1 to 2 hours and the absolute systemic availability was 6%-13% due to extensive first pass metabolism. In contrast, most of the budesonide delivered to the lungs was systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lung (as assessed by plasma concentration method and using a budesonide-containing dry powder inhaler) with an absolute systemic availability of 39% of the metered dose.

Following administration of SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two or four inhalations twice daily) for 5 days in healthy subjects, plasma concentration of budesonide generally increased in proportion to dose. The accumulation index for the group that received two inhalations twice daily was 1.32 for budesonide.

Asthma Patients: In a single-dose study, higher than recommended doses of SYMBICORT (budesonide and formoterol fumarate dihydrate) (12 inhalations of SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg) were administered to patients with moderate asthma. Peak budesonide plasma concentration of 4.5 nmol/L occurred at 20 minutes following dosing. This study demonstrated that the total systemic exposure to budesonide from SYMBICORT (budesonide and formoterol fumarate dihydrate) was approximately 30% lower than from inhaled budesonide via a dry powder inhaler (DPI) at the same delivered dose. Following administration of SYMBICORT (budesonide and formoterol fumarate dihydrate) , the half-life of the budesonide component was 4.7 hours.

In a repeat dose study, the highest recommended dose of SYMBICORT (budesonide and formoterol fumarate dihydrate) (160/4.5 mcg, two inhalations twice daily) was administered to patients with moderate asthma and healthy subjects for 1 week. Peak budesonide plasma concentration of 1.2 nmol/L occurred at 21 minutes in asthma patients. Peak budesonide plasma concentration was 27% lower in asthma patients compared to that in healthy subjects. However, the total systemic exposure of budesonide was comparable to that in asthma patients.

Peak steady-state plasma concentrations of budesonide administered by DPI in adults with asthma averaged 0.6 and 1.6 nmol/L at doses of 180 mcg and 360 mcg twice daily, respectively. In asthmatic patients, budesonide showed a linear increase in AUC and Cmax with increasing dose after both single and repeated dosing of inhaled budesonide.

COPD Patients: In a single-dose study, 12 inhalations of SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 mcg (total dose 960/54 mcg) were administered to patients with COPD. Mean budesonide peak plasma concentration of 3.3 nmol/L occurred at 30 minutes following dosing. Budesonide systemic exposure was comparable between SYMBICORT (budesonide and formoterol fumarate dihydrate) pMDI and coadministration of budesonide via a metered-dose inhaler and formoterol via a dry powder inhaler (budesonide 960 mcg and formoterol 54 mcg). In the same study, an open-label group of moderate asthma patients also received the same higher dose of SYMBICORT (budesonide and formoterol fumarate dihydrate) . For budesonide, COPD patients exhibited 12% greater AUC and 10% lower Cmax compared to asthma patients.

In the 6 month pivotal clinical study, steady-state pharmacokinetic data of budesonide was obtained in a subset of COPD patients with treatment arms of SYMBICORT (budesonide and formoterol fumarate dihydrate) pMDI 160/4.5 mcg, SYMBICORT (budesonide and formoterol fumarate dihydrate) pMDI 80/4.5 mcg, budesonide 160 mcg, budesonide 160 mcg and formoterol 4.5 mcg given together, all administered as two inhalations twice daily. Budesonide systemic exposure (AUC and Cmax) increased proportionally with doses from 80 mcg to 160 mcg and was generally similar between the 3 treatment groups receiving the same dose of budesonide (SYMBICORT (budesonide and formoterol fumarate dihydrate) pMDI 160/4.5 mcg, budesonide 160 mcg, budesonide 160 mcg and formoterol 4.5 mcg administered together).

Formoterol

Inhaled formoterol is rapidly absorbed; peak plasma concentrations are typically reached at the first plasma sampling time, within 5-10 minutes after dosing. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol delivered is swallowed and then absorbed from the gastrointestinal tract.

Healthy Subjects: Following administration of SYMBICORT (budesonide and formoterol fumarate dihydrate) (160/4.5 mcg, two or four inhalations twice daily) for 5 days in healthy subjects, plasma concentration of formoterol generally increased in proportion to dose. The accumulation index for the group that received two inhalations twice daily was 1.77 for formoterol.

Asthma patients: In a single-dose study, higher than recommended doses of SYMBICORT (budesonide and formoterol fumarate dihydrate) (12 inhalations of SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg) were administered to patients with moderate asthma. Peak plasma concentration for formoterol of 136 pmol occurred at 10 minutes following dosing. Approximately 8% of the delivered dose of formoterol was recovered in the urine as unchanged drug.

In a repeat dose study, the highest recommended dose of SYMBICORT (budesonide and formoterol fumarate dihydrate) (160/4.5 mcg, two inhalations twice daily) was administered to patients with moderate asthma and healthy subjects for 1 week. Peak formoterol plasma concentration of 28 pmol/L occurred at 10 minutes in asthma patients. Peak formoterol plasma concentration was about 42% lower in asthma patients compared to that in healthy subjects. However, the total systemic exposure of formoterol was comparable to that in asthma patients.

COPD patients: Following single-dose administration of 12 inhalations of SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5, mean peak formoterol plasma concentration of 167 pmol/L was rapidly achieved at 15 minutes after dosing. Formoterol exposure was slightly greater (~16-18%) from SYMBICORT (budesonide and formoterol fumarate dihydrate) pMDI compared to coadministration of budesonide via a metered-dose inhaler and formoterol via a dry powder inhaler (total dose of budesonide 960 mcg and formoterol 54 mcg). In the same study, an open label group of moderate asthma patients received the same dose of SYMBICORT (budesonide and formoterol fumarate dihydrate) . COPD patients exhibited 12-15% greater AUC and Cmax for formoterol compared to asthma patients.

In the 6 month pivotal clinical study, steady-state pharmacokinetic data of formoterol was obtained in a subset of COPD patients with treatment arms of SYMBICORT (budesonide and formoterol fumarate dihydrate) pMDI 160/4.5 mcg, SYMBICORT (budesonide and formoterol fumarate dihydrate) pMDI 80/4.5. mcg, formoterol 4.5 mcg, budesonide 160 mcg and formoterol 4.5 mcg given together, all administered as two inhalations twice daily. The systemic exposure of formoterol as evidenced by AUC, was about 30% and 16% higher from SYMBICORT (budesonide and formoterol fumarate dihydrate) pMDI compared to formoterol alone treatment arm and coadministration of individual components of budesonide and formoterol treatment arm, respectively.

Distribution

Budesonide: The volume of distribution of budesonide was approximately 3 L/kg. It was 85%-90% bound to plasma proteins. Protein binding was constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended inhaled doses. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood plasma ratio of about 0.8.

Formoterol: Over the concentration range of 10-500 nmol/L, plasma protein binding for the RR and SS enantiomers of formoterol was 46% and 58%, respectively. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 54 mcg dose.

Metabolism

Budesonide: In vitro studies with human liver homogenates have shown that budesonide was rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites was less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns were detected. Negligible metabolic inactivation was observed in human lung and serum preparations.

Formoterol: The primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation. CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation.

Elimination

Budesonide: Budesonide was excreted in urine and feces in the form of metabolites. Approximately 60% of an intravenous radiolabeled dose was recovered in the urine.

No unchanged budesonide was detected in the urine. The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose.

Formoterol: The excretion of formoterol was studied in four healthy subjects following simultaneous administration of radiolabeled formoterol via the oral and IV routes. In that study, 62% of the radiolabeled formoterol was excreted in the urine while 24% was eliminated in the feces.

Special Populations

Geriatric

The pharmacokinetics of SYMBICORT (budesonide and formoterol fumarate dihydrate) in geriatric patients have not been specifically studied.

Pediatric

Plasma concentrations of budesonide were measured following administration of four inhalations of SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg in a single-dose study in pediatric patients with asthma, 6-11 years of age. Urine was collected for determination of formoterol excretion. Peak budesonide concentrations of 1.4 nmol/L occurred at 20 minutes post-dose. Approximately 3.5% of the delivered formoterol dose was recovered in the urine as unchanged formoterol. This study also demonstrated that the total systemic exposure to budesonide from SYMBICORT (budesonide and formoterol fumarate dihydrate) was approximately 30% lower than from inhaled budesonide via a dry powder inhaler that was also evaluated at the same delivered dose.

Gender/Race

Specific studies to examine the effects of gender and race on the pharmacokinetics of SYMBICORT (budesonide and formoterol fumarate dihydrate) have not been conducted. Population PK analysis of the SYMBICORT (budesonide and formoterol fumarate dihydrate) data indicates that gender does not affect the pharmacokinetics of budesonide and formoterol. No conclusions can be drawn on the effect of race due to the low number of non-Caucasians evaluated for PK.

Nursing Mothers

The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breastfeeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels ( < 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use in Specific Populations, Nursing Mothers].

Renal or Hepatic Insufficiency

There are no data regarding the specific use of SYMBICORT (budesonide and formoterol fumarate dihydrate) in patients with hepatic or renal impairment. Reduced liver function may affect the elimination of corticosteroids. Budesonide pharmacokinetics was affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous budesonide pharmacokinetics was, however, similar in cirrhotic patients and in healthy subjects. Specific data with formoterol is not available, but because formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver impairment.

Drug-Drug Interactions

A single-dose crossover study was conducted to compare the pharmacokinetics of eight inhalations of the following: budesonide, formoterol, and budesonide plus formoterol administered concurrently. The results of the study indicated that there was no evidence of a pharmacokinetic interaction between the two components of SYMBICORT (budesonide and formoterol fumarate dihydrate) .

Inhibitors of cytochrome P450 enzymes

Ketoconazole: Ketoconazole, a strong inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide.

Cimetidine: At recommended doses, cimetidine, a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

Specific drug-drug interaction studies with formoterol have not been performed.

Animal Toxicology and/or Pharmacology

Preclinical: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Reproductive Toxicology Studies: SYMBICORT (budesonide and formoterol fumarate dihydrate)

SYMBICORT (budesonide and formoterol fumarate dihydrate) has been shown to be teratogenic and embryocidal in rats when given at inhalation doses of 12/0.66 mcg/kg (budesonide/formoterol) and above (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis). Umbilical hernia, a malformation, was observed for fetuses at doses of 12/0.66 mcg/kg and above (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis). No teratogenic or embryocidal effects were detected at 2.5/0.14 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis).

Budesonide

As with other corticosteroids, budesonide has been shown to be teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weight, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg/day in rabbits (less than the maximum recommended human daily inhalation dose on a mcg/m2 basis) and 500 mcg/kg/day in rats (approximately 6 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 250 mcg/kg/day (approximately 3 times the maximum recommended human daily inhalation dose on a mcg/m2 basis).

Formoterol

Formoterol fumarate has been shown to be teratogenic, embryocidal, to increase pup loss at birth and during lactation, and to decrease pup weights in rats when given at oral doses of 3 mg/kg/day and above (approximately 1400 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). Umbilical hernia, a malformation, was observed in rat fetuses at oral doses of 3 mg/kg/day and above (approximately 1400 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). Brachygnathia, a skeletal malformation, was observed in rat fetuses at an oral dose of 15 mg/kg/day (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). Pregnancy was prolonged at an oral dose of 15 mg/kg/day (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). In another study in rats, no teratogenic effects were seen at inhalation doses up to 1.2 mg/kg/day (approximately 500 times the maximum recommended human daily inhalation dose on a mcg/m2 basis).

Formoterol fumarate has been shown to be teratogenic in rabbits when given at an oral dose of 60 mg/kg (approximately 54,000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). Subcapsular cysts on the liver were observed in rabbit fetuses at an oral dose of 60 mg/kg (approximately 54,000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis). No teratogenic effects were observed at oral doses up to 3.5 mg/kg (approximately 3200 times the maximum recommended human daily inhalation dose on a mcg/m2 basis).

Clinical Studies

Asthma

SYMBICORT (budesonide and formoterol fumarate dihydrate) has been studied in patients with asthma 12 years of age and older. In two clinical studies comparing SYMBICORT (budesonide and formoterol fumarate dihydrate) with the individual components, improvements in most efficacy end points were greater with SYMBICORT (budesonide and formoterol fumarate dihydrate) than with the use of either budesonide or formoterol alone. In addition, one clinical study showed similar results between SYMBICORT (budesonide and formoterol fumarate dihydrate) and the concurrent use of budesonide and formoterol at corresponding doses from separate inhalers.

The safety and efficacy of SYMBICORT (budesonide and formoterol fumarate dihydrate) were demonstrated in two randomized, double-blind, placebo-controlled US clinical studies involving 1076 patients 12 years of age and older. Fixed SYMBICORT (budesonide and formoterol fumarate dihydrate) dosages of 160/9 mcg, and 320/9 mcg twice daily (each dose administered as two inhalations of the 80/4.5 and 160/4.5 mcg strengths, respectively) were compared with the monocomponents (budesonide and formoterol) and placebo to provide information about appropriate dosing to cover a range of asthma severity.

Study 1: Clinical Study with SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5

This 12-week study evaluated 596 patients 12 years of age and older by comparing SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, the free combination of budesonide 160 mcg plus formoterol 4.5 mcg in separate inhalers, budesonide 160 mcg, formoterol 4.5 mcg, and placebo; each administered as two inhalations twice daily. The study included a 2-week run-in period with budesonide 80 mcg, two inhalations twice daily. Most patients had moderate to severe asthma and were using moderate to high doses of inhaled corticosteroids prior to study entry. Randomization was stratified by previous inhaled corticosteroid treatment (71.6% on moderate- and 28.4% on high-dose inhaled corticosteroid). Mean percent predicted FEV1 at baseline was 68.1% and was similar across treatment groups. The coprimary efficacy end points were 12-hour-average postdose

FEV1 at week 2, and predose FEV1 averaged over the course of the study. The study also required that patients who satisfied a predefined asthma worsening criterion be withdrawn. The predefined asthma-worsening criteria were a clinically important decrease in FEV1 or peak expiratory flow (PEF), increase in rescue albuterol use, nighttime awakening due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. For the criterion of nighttime awakening due to asthma, patients were allowed to remain in the study at the discretion of the investigator if none of the other asthma-worsening criteria were met. The percentage of patients withdrawing due to or meeting predefined criteria for worsening asthma is shown in Table 3.

Table 3: The number and percentage of patients withdrawing due to or meeting predefined criteria for worsening asthma (Study 1)

  SYMBICORT (budesonide and formoterol fumarate dihydrate)
160/4.5 mcg
n=124
Budesonide
160 mcg plus
Formoterol
4.5 mcg
n=115
Budesonide
160 mcg
n=109
Formoterol
4.5 mcg
n=123
Placebo
n=125
Patients withdrawn due to predefined asthma event* 13 (10.5) 13 (11.3) 22 (20.2) 44 (35.8) 62 (49.6)
Patients with a predefined asthma event* 37 (29.8) 24 (20.9) 48 (44.0) 68 (55.3) 84 (67.2)
Decrease in FEV1 4 (3.2) 8 (7.0) 7 (6.4) 15 (12.2) 14 (11.2)
Rescue medication use 2 (1.6) 0 3 (2.8) 3 (2.4) 7 (5.6)
Decrease in AM PEF 2 (1.6) 5 (4.3) 5 (4.6) 17 (13.8) 15 (12.0)
Nighttime awakenings 24 (19.4) 11 (9.6) 29 (26.6) 32 (26.0) 49 (39.2)
Clinical exacerbation 7 (5.6) 6 (5.2) 5 (4.6) 17 (3.8) 16 (12.8)
*These criteria were assessed on a daily basis irrespective of the timing of the clinic visit, with the exception of FEV1, which was assessed at each clinic visit.
Individual criteria are shown for patients meeting any predefined asthma event, regardless of withdrawal status.
For the criterion of nighttime awakening due to asthma, patients were allowed to remain in the study at the discretion of the investigator if none of the other criteria were met.

Mean percent change from baseline in FEV1 measured immediately prior to dosing (predose) over 12 weeks is displayed in Figure 1. Because this study used predefined withdrawal criteria for worsening asthma, which caused a differential withdrawal rate in the treatment groups, predose FEV1 results at the last available study visit (end of treatment, EOT) are also provided. Patients receiving SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg had significantly greater mean improvements from baseline in predose FEV1 at the end of treatment (0.19 L, 9.4%), compared with budesonide 160 mcg (0.10 L, 4.9%), formoterol 4.5 mcg (-0.12 L, -4.8%), and placebo (-0.17 L, -6.9%).

Figure 1 - Mean Percent Change From Baseline in Predose FEV1 Over 12 Weeks (Study 1)

Mean Percent Change From Baseline in Predose FEV1 Over 12 Weeks (Study 1) - Illustration

The effect of SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg two inhalations twice daily on selected secondary efficacy variables, including morning and evening PEF, albuterol rescue use, and asthma symptoms over 24 hours on a 0-3 scale is shown in Table 4.

Table 4: Mean values for selected secondary efficacy variables (Study 1)

Efficacy Variable SYMBICORT (budesonide and formoterol fumarate dihydrate)
160/4.5 mcg
(n*=124)
Budesonide
160 mcg plus
Formoterol
4.5 mcg
(n*=115)
Budesonide
160 mcg
(n*=109)
Formoterol
4.5 mcg
(n*=123)
Placebo
(n*=125)
AM PEF (L/min)
  Baseline 341 338 342 339 355
  Change from Baseline 35 28 9 -9 -18
PM PEF (L/min)
  Baseline 351 348 357 354 369
  Change from Baseline 34 26 7 -7 -18
Albuterol rescue use
  Baseline 2.1 2.3 2.7 2.5 2.4
  Change from Baseline -1.0 -1.5 -0.8 -0.3 0.8
Average symptom score/day (0-3 scale)
  Baseline 0.99 1.03 1.04 1.04 1.08
  Change from Baseline -0.28 -0.32 -0.14 -0.05 0.10
*Number of patients (n) varies slightly due to the number of patients for whom data were available for each variable. Results shown are based on last available data for each variable.

The subjective impact of asthma on patients' health-related quality of life was evaluated through the use of the standardized Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a 7-point scale where 1 = maximum impairment and 7 = no impairment). Patients receiving SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 had clinically meaningful improvement in overall asthma-specific quality of life, as defined by a mean difference between treatment groups of > 0.5 points in change from baseline in overall AQLQ score (difference in AQLQ score of 0.70 [95% CI 0.47, 0.93], compared to placebo).

Study 2: Clinical Study with SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5

This 12-week study was similar in design to Study 1, and included 480 patients 12 years of age and older. This study compared SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 mcg, budesonide 80 mcg, formoterol 4.5 mcg, and placebo; each administered as two inhalations twice daily. The study included a 2-week placebo run-in period. Most patients had mild to moderate asthma and were using low to moderate doses of inhaled corticosteroids prior to study entry. Mean percent predicted FEV1 at baseline was 71.3% and was similar across treatment groups. Efficacy variables and end points were identical to those in Study 1.

The percentage of patients withdrawing due to or meeting predefined criteria for worsening asthma is shown in Table 5. The method of assessment and criteria used were identical to that in Study 1.

Table 5: The number and percentage of patients withdrawing due to or meeting predefined criteria for worsening asthma (Study 2)

  SYMBICORT (budesonide and formoterol fumarate dihydrate)
80/4.5 mcg
(n=123)
Budesonide
80 mcg
(n=121)
Formoterol
4.5 mcg
(n=114)
Placebo
(n=122)
Patients withdrawn due to predefined asthma event* 9 (7.3) 8 (6.6) 21 (18.4) 40 (32.8)
Patients with a predefined asthma event* 23 (18.7) 26 (21.5) 48 (42.1) 69 (56.6)
Decrease in FEV1 3 (2.4) 3 (2.5) 11 (9.6) 9 (7.4)
Rescue medication use 1 (0.8) 3 (2.5) 1 (0.9) 3 (2.5)
Decrease in AM PEF 3 (2.4) 1 (0.8) 8 (7.0) 14 (11.5)
Nighttime awakening 17 (13.8) 20 (16.5) 31 (27.2) 52 (42.6)
Clinical exacerbation 1 (0.8) 3 (2.5) 5 (4.4) 20 (16.4)
*These criteria were assessed on a daily basis irrespective of the timing of the clinic visit, with the exception of FEV1, which was assessed at each clinic visit.
Individual criteria are shown for patients meeting any predefined asthma event, regardless of withdrawal status.
For the criterion of nighttime awakening due to asthma, patients were allowed to remain in the study at the discretion of the investigator if none of the other criteria were met.

Mean percent change from baseline in predose FEV1 over 12 weeks is displayed in Figure 2.

Figure 2 - Mean Percent Change From Baseline in Predose FEV1 Over 12 Weeks (Study 2)

Mean Percent Change From Baseline in Predose FEV1 Over 12 Weeks (Study 2) - Illustration

Efficacy results for other secondary end points, including quality of life, were similar to those observed in Study 1.

Onset and Duration of Action and Progression of Improvement in Asthma Control

The onset of action and progression of improvement in asthma control were evaluated in the two pivotal clinical studies. The median time to onset of clinically significant bronchodilation ( > 15% improvement in FEV1) was seen within 15 minutes. Maximum improvement in FEV1 occurred within 3 hours, and clinically significant improvement was maintained over 12 hours. Figures 3 and 4 show the percent change from baseline in postdose FEV1 over 12 hours on the day of randomization and on the last day of treatment for Study 1.

Reduction in asthma symptoms and in albuterol rescue use, as well as improvement in morning and evening PEF, occurred within 1 day of the first dose of SYMBICORT (budesonide and formoterol fumarate dihydrate) ; improvement in these variables was maintained over the 12 weeks of therapy.

Following the initial dose of SYMBICORT (budesonide and formoterol fumarate dihydrate) , FEV1 improved markedly during the first 2 weeks of treatment, continued to show improvement at the Week 6 assessment, and was maintained through Week 12 for both studies.

No diminution in the 12-hour bronchodilator effect was observed with either SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 mcg or SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, as assessed by FEV1, following 12 weeks of therapy or at the last available visit.

FEV1 data from Study 1 evaluating SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg is displayed in Figures 3 and 4.

Figure 3 - Mean Percent Change From Baseline in FEV1 on Day of Randomization (Study 1)

Mean Percent Change From Baseline in FEV1 on Day of Randomization (Study 1) - Illustration

Figure 4 - Mean Percent Change From Baseline in FEV1 At End of Treatment (Study 1)

Mean Percent Change From Baseline in FEV1 At End of Treatment (Study 1) - Illustration

Chronic Obstructive Pulmonary Disease (COPD)

The efficacy of SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 and SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 in the maintenance treatment of airflow obstruction in COPD patients was evaluated in two randomized, double-blind, placebo-controlled multinational studies, conducted over 6 months (Study 1) and 12 months (Study 2), in a total of 3668 patients (2416 males and 1252 females). The majority of patients (93%) were Caucasian. All patients were required to be at least 40 years of age, with a FEV1 of less than or equal to 50% predicted, a clinical diagnosis of COPD with symptoms for at least 2 years, and a smoking history of at least 10 pack years, prior to entering the trial. The mean prebronchodilator FEV1 at baseline of the patients enrolled in the study was 34% predicted. Forty-eight percent of the patients enrolled were on inhaled corticosteroids and 52.7% of patients were on short-acting anticholinergic bronchodilators during run-in. On randomization, inhaled corticosteroids were discontinued, and ipratropium bromide was allowed at a stable dose for those patients previously treated with short-acting anticholinergic bronchodilators. The co-primary efficacy variables in both studies were the change from baseline in average pre-dose and 1-hour post-dose FEV1 over the treatment period. The results of both studies 1 and 2 are described below.

Study 1

This was a 6-month, placebo-controlled study of 1704 COPD patients (mean % predicted FEV1 at baseline ranging from 33.5% -34.7%) conducted to demonstrate the efficacy and safety of SYMBICORT (budesonide and formoterol fumarate dihydrate) in the treatment of airflow obstruction in COPD. The patients were randomized to one of the following treatment groups: SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 (n=277), SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 (n=281), budesonide 160 mcg + formoterol 4.5 mcg (n=287), budesonide 160 mcg (n=275), formoterol 4.5 mcg (n=284), or placebo (n=300). Patients receiving SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two inhalations twice daily, had significantly greater mean improvements from baseline in pre-dose FEV1 averaged over the treatment period [0.08 L, 10.7%] compared with formoterol 4.5 mcg [0.04 L, 6.9%] and placebo [0.01 L, 2.2%] (See Figure 5). Patients receiving SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 mcg, two inhalations twice daily, did not have significantly greater improvement from baseline in the pre-dose FEV1 averaged over the treatment period compared with formoterol 4.5 mcg.

Figure 5: Mean Percent Change From Baseline in Pre-dose FEV1 Over 6 months (Study 1)

Mean Percent Change From Baseline in Pre-dose FEV1 Over 6 months (Study 1) - Illustration

Patients receiving SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two inhalations twice daily, had significantly greater mean improvements from baseline in 1-hour post-dose FEV1 averaged over the treatment period [0.20 L, 22.6%], compared with budesonide 160 mcg [0.03 L, 4.9%] and placebo [0.03 L, 4.1%] (See Figure 6)

Figure 6: Mean Percent Change From Baseline in 1hour Post-dose FEV1 Over 6 months (Study 1)

Mean Percent Change From Baseline in 1hour Post-dose FEV1 Over 6 months (Study 1) - Illustration

Study 2

This was a 12-month, placebo-controlled study of 1964 COPD patients (mean % predicted FEV1 at baseline ranging from 33.7% -35.5%) conducted to demonstrate the efficacy and safety of SYMBICORT (budesonide and formoterol fumarate dihydrate) in the treatment of airflow obstruction in COPD. The patients were randomized to one of the following treatment groups: SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 (n=494), SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 (n=494), formoterol 4.5 mcg (n=495), or placebo (n=48l). Patients receiving SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two inhalations twice daily, had significantly greater improvements from baseline in mean pre-dose FEV1 averaged over the treatment period [0.10 L, 10.8%] compared with formoterol 4.5 mcg [0.06 L, 7.2%] and placebo [0.01 L, 2.8%]. Patients receiving SYMBICORT (budesonide and formoterol fumarate dihydrate) 80/4.5 mcg, two inhalations twice daily, did not have significantly greater improvements from baseline in the mean pre-dose FEV1 averaged over the treatment period compared to formoterol. Patients receiving SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two inhalations twice daily, also had significantly greater mean improvements from baseline in 1-hour post-dose FEV1 averaged over the treatment period [0.21 L, 24.0%] compared with placebo [0.02 L, 5.2%].

Serial FEV1 measures over 12 hours were obtained in a subset of patients in Study 1 (n=99) and Study 2 (n=121). The median time to onset of bronchodilation, defined as an FEV1 increase of 15% or greater from baseline, occurred at 5 minutes post-dose. Maximum improvement (calculated as the average change from baseline at each timepoint) in FEV1 occurred at approximately 2 hours post-dose.

In both Studies 1 and 2, improvements in secondary endpoints of morning and evening peak expiratory flow and reduction in rescue medication use were supportive of the efficacy of SYMBICORT (budesonide and formoterol fumarate dihydrate) 160/4.5.

Last reviewed on RxList: 6/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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