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Pharmacotherapeutic group: Adrenergics and other drugs for obstructive airway diseases. ATC code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) contains budesonide and formoterol, which have different modes of action and show additive effects in terms of reduction of asthma and COPD exacerbations. The specific properties of budesonide and formoterol allow the combination to be used as maintenance treatment of asthma. The respective mechanisms of action of both drugs are discussed as follows.
Budesonide: Budesonide is a glucocorticosteroid which when inhaled has a rapid (within hours) and dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer asthma exacerbations. Inhaled budesonide has less severe adverse effects than systemic corticosteroids. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.
Formoterol: Formoterol is a selective beta2-adrenergic agonist that when inhaled results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose dependent, with an onset of effect within 1-3 minutes after inhalation. The duration of effect is at least 12 hours after a single dose.
Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER): Clinical Efficacy in Asthma: Therapeutic equivalence between Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) and Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) was demonstrated in three clinical efficacy and safety studies including asthmatic patients from 6 to 79 years of age and one long-term safety study in adolescents and adults with asthma. The safety profile of Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) has been shown to be as safe and well tolerated as Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER). As a result of demonstrating therapeutic equivalence, the clinical efficacy of Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) in asthma described as follows is based on studies conducted with Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER).
It has been shown in a separate study that Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) can be used safely with a named spacer device in children.
Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER): Clinical Efficacy for Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) maintenance therapy in Asthma: Clinical studies with Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced exacerbations. The effect on lung function of Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER) given as maintenance dose only was equal to that of budesonide and formoterol administered in separate inhalers in adults and exceeded that of budesonide alone in adults and children. All treatment arms used a short acting β-agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
In a 12-week paediatric study 85 children aged 6-11 years were treated with a maintenance dose of Budesonide + Formoterol fumarate dihydrate (Symbicort) (2 inhalations of 80/4.5 micrograms/inhalation twice daily), and a short-acting beta2-agonist as needed. Lung function was improved and the treatment was well tolerated compared to the corresponding dose of budesonide Turbuhaler.
Clinical Efficacy in COPD: Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER): In one 12-month study and one 6-month study in patients with COPD, Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) 160/4.5 was superior to placebo, budesonide and formoterol for post-dose FEV1 and predose FEV1. In the 12-month study, Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) was also superior to placebo and formoterol for both the number of, and the time to first severe COPD exacerbation (a worsening of COPD requiring oral steroid use of hospitalization.) Thus, the contribution of both budesonide and formoterol to the effect of Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) was demonstrated. Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) 160/4.5 also significantly reduced breathlessness, daily rescue medication use, night-time awakenings and improved health-related quality of life compared with placebo in both studies. Serial FEV1 measures over 12 hours were obtained in subsets of patients in both studies. The median time to onset of bronchodilation (>15% improvement in FEV1) was seen within 5 minutes at the end of treatment in patients receiving Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) 160/4.5. Maximal improvement in FEV1 occurred at approximately 2 hours post-dose and post-dose bronchodilator effect was generally maintained over 12 hours. The treatment was well tolerated.
Pharmacokinetics: Absorption: Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER): There was no evidence of pharmacokinetic interactions between budesonide and formoterol when given together.
In studies where Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) was administered to healthy subjects and patients with moderate asthma, peak plasma concentrations for budesonide occurred approximately 30 minutes and for formoterol 10 minutes after dosing. Peak plasma concentrations were 30-40% higher in healthy subjects compared to asthma patients. However, the total systemic exposure was comparable to that in asthma patients.
In repeat dose studies plasma concentrations of budesonide and formoterol generally increased in proportion to dose.
Collectively, in pharmacokinetic studies conducted in adults with asthma, systemic exposure to budesonide and formoterol administered via Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) was lower than when given via the monoproduct Budesonide (Budecort TURBUHALER). Collectively, the pharmacokinetic data from clinical efficacy and safety studies indicate that Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) delivers a comparable amount of budesonide to the systemic circulation, and thus the lung, as do budesonide pMDI and Budesonide (BUDECORT TURBUHALER). The results of the systemic exposure for formoterol were generally similar when administered via Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER).
Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER): The systemic bioavailability of budesonide and formoterol was comparable for the two treatments Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) and Budesonide + Formoterol fumarate dihydrate (SYMBICORT TURBUHALER).
Distribution and Biotransformation: Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. Volume of distribution is about 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol is inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates). Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6 beta-hydroxy-budesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. There are no indications of any metabolic interactions or any displacement reactions between formoterol and budesonide.
Elimination: The major part of a dose of formoterol is eliminated by metabolism in the liver followed by renal excretion. After inhalation of formoterol via Turbuhaler, 8% to 13% of the delivered dose of formoterol is excreted unmetabolised in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min) and the terminal elimination half-life averages 17 hours.
Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are excreted in urine as such or in conjugated form. Only negligible amounts of unchanged budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.
Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance, which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. The pharmacokinetics of formoterol in children has not been studied.
The pharmacokinetics of budesonide or formoterol in elderly and in patients with renal failure is unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.
Toxicology: Preclinical safety data: The toxicity observed in animal studies with budesonide and formoterol was similar whether budesonide or formoterol were given in combination or separately. The effects were associated with pharmacological actions and dose dependent.
In animal reproduction studies, glucocorticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant in humans at the recommended doses (see Use in Pregnancy & Lactation). Animal reproduction studies with formoterol have shown a somewhat reduced fertility in male rats at high systemic exposure and implantation losses, as well as decreased early postnatal survival and birth weight at considerably higher systemic exposures than those reached during clinical use. However, these animal experimental results do not seem to be relevant to man.
Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) contains the excipients povidone (polyvinylpyrrolidone) K25, macrogol (polyethylene glycol) 1000 and the pressurised liquid propellant apaflurane (HFA 227). The safe use of apaflurane has been fully evaluated in preclinical studies. Povidones have a history of safe use in man for many years, which supports the view that povidones are essentially biologically inert. Macrogols are recognized as safe excipients in pharmaceuticals, food and cosmetic products. Furthermore, toxicity studies carried out using Budesonide + Formoterol fumarate dihydrate (SYMBICORT RAPIHALER) have shown no evidence of any local or systemic toxicity or irritation attributable to the excipients.
