Pharmacotherapeutic group: Drugs for obstructive airway diseases: Adrenergics, Inhalants. ATC-code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanisms of action and pharmacodynamic effects: Symbicort Rapihaler contains budesonide and formoterol, which have different modes of action and show additive effects in case of obstructive airways diseases.
Budesonide: Budesonide is a glucocorticosteroid which when inhaled has a dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer COPD 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 β2- adrenoceptor agonist that when inhaled results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly (within 1-3 minutes after inhalation) and has a duration of 12 hours after a single dose.
Clinical efficacy of Symbicort Rapihaler: Asthma: Therapeutic equivalence between Symbicort Rapihaler and Symbicort Turbuhaler was demonstrated in two clinical efficacy and safety studies in medium and high doses, including asthmatic patients from 6 to 79 years of age. Clinical comparability was strengthened by a long-term safety study, which also showed that the safety profile and tolerability of Symbicort Rapihaler were similar to that of Symbicort Turbuhaler.
Clinical studies in adults have shown that the addition of formoterol to budesonide improved asthma symptoms and lung function, and reduced asthma exacerbations.
The effect on lung function of Symbicort Turbuhaler in adults, given as maintenance dose only, was equal to that of the free combination of budesonide and formoterol in separate inhalers and exceeded that of budesonide alone in adults and children. All treatment arms used a short acting beta2-agonist as needed. There was no sign of attenuation of the anti-asthmatic effect over time.
COPD: The efficacy and safety of Symbicort Rapihaler in the treatment of patients with moderate to severe COPD (pre-bronchodilator FEV1 ≤50% predicted normal) has been evaluated in: one 12-month and one 6-month study (studies 001 and 002, respectively).
Studies 001 and 002: In both studies, Symbicort Rapihaler 160/4.5 was compared with placebo and formoterol Turbuhaler 6 μg, and, in Study 002, it was also compared with budesonide pMDI 200 μg, all taken as two inhalations twice daily. A total of 1964 and 1704 patients with mainly severe COPD were randomised, of which 494 and 277 were treated with Symbicort Rapihaler 160/4.5. The study populations had a mean age of 63 years and mean FEV1 of 1.04-1.05 L or 34% of predicted normal at baseline.
Study 001: In Study 001, efficacy was evaluated over 12 months using the co-primary efficacy variables of change from baseline in average pre-dose and 1-hour post-dose FEV1 over the treatment period.
Symbicort Rapihaler 160/4.5 significantly improved 1-hour pre-dose FEV1 compared with formoterol and placebo by 0.04 L (p=0.008) and 0.09 L (p<0.001), respectively.
Symbicort Rapihaler 160/4.5 significantly improved post-dose FEV1 over the treatment period compared with formoterol and placebo by 0.03 L (p=0.023) and 0.18 L (p<0.001), respectively.
Serial FEV1 measures over 12 hours were obtained in a subset of patients (N=491). The median time to onset of bronchodilation (>15% improvement in FEV1) was seen within 5 minutes at the end of treatment time point in patients receiving Symbicort Rapihaler 160/4.5 (N=121). Maximum improvement in FEV1 occurred at approximately 2 hours post-dose, and clinically significant improvement was maintained over 12 hours.
Symbicort Rapihaler significantly reduced the number of severe exacerbations (defined as a worsening of COPD requiring oral steroid use and/or hospitalisation), compared with placebo and formoterol by 37% (p<0.001) and 25% (p=0.004), respectively. Symbicort Rapihaler significantly prolonged the time to first severe COPD exacerbation compared to placebo, reducing the instantaneous risk of experiencing a severe COPD exacerbation by 26% (p=0.009). Symbicort Rapihaler provided a statistically significant improvement in patient quality of life (as measure by St. George's Respiratory Questionnaire total score) compared with placebo (-2.39 units; p=0.006).
Study 002: In Study 002, efficacy was evaluated over 6 months using the co-primary efficacy variables of change from baseline in average pre-dose and 1-hour post-dose FEV1 over the treatment period.
Symbicort Rapihaler 160/4.5 significantly improved pre-dose FEV1 compared with formoterol by 0.04 L (p=0.026) and compared with placebo and budesonide by 0.08 L (p<0.001) for both comparators.
Symbicort Rapihaler 160/4.5 significantly improved 1-hour post-dose FEV1 compared with formoterol by 0.04 L (p=0.039) and compared with placebo and budesonide by 0.17 L (p<0.001) for both comparators.
Study 002 was not powered for showing effect on severe COPD exacerbations. However, the estimates for treatment differences, though not statistically significant, were consistent with Study 001, with 20% fewer exacerbations with Symbicort Rapihaler 160/4.5 as compared with placebo and formoterol.
Serial FEV1 measures over 12 hours were obtained in subsets of patients (n=618). The median time to onset of bronchodilation (>15% improvement in FEV1) was seen within 5 minutes at the end of treatment in patients receiving Symbicort Rapihaler 160/4.5 (N=101). Maximum improvement in FEV1 occurred at approximately 2 hours post-dose, and clinically significant improvement was maintained over 12 hours.
Symbicort Rapihaler 160/4.5 provided a statistically significant improvement in patient quality of life (as measure by St. George's Respiratory Questionnaire total score) compared with placebo (-3.12 units; p=0.003), budesonide (- 2.42 units; p=0.024), and formoterol (-2.56 units; p=0.017).
Pharmacokinetics: Absorption: The fixed-dose combination of budesonide and formoterol, and the corresponding monoproducts have been shown to be bioequivalent with regard to systemic exposure of budesonide and formoterol, respectively. In spite of this, a small increase in cortisol suppression was seen after administration of the fixed-dose combination compared to the monoproducts. The difference is considered not to have an impact on clinical safety.
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.
Pharmacokinetic parameters for the respective substances were comparable after the administration of budesonide and formoterol as monoproducts or as the fixed-dose combination. For budesonide, AUC was slightly higher, rate of absorption more rapid and maximal plasma concentration higher after administration of the fixed combination. For formoterol, maximal plasma concentration was similar after administration of the fixed combination. Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation. In studies, mean lung deposition of budesonide after inhalation via Turbuhaler ranged from 32% to 44% of the delivered dose. The systemic bioavailability is approximately 49% of the delivered dose. In children 6-16 years of age the lung deposition fall in the same range as in adults for the same given dose, the resulting plasma concentrations were not determined.
Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached within 10 minutes after inhalation. In studies the mean lung deposition of formoterol after inhalation via Turbuhaler ranged from 28% to 49% of the delivered dose. The systemic bioavailability is about 61% of the delivered dose.
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 16-alfa-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 transformed by liver metabolism followed by renal elimination. After inhalation, 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 eliminated 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.
The pharmacokinetics of formoterol in children have not been studied. The pharmacokinetics of budesonide and formoterol in patients with renal failure are unknown. The exposure of budesonide and formoterol may be increased in patients with liver disease.
Linearity/non-linearity: Systemic exposure for both budesonide and formoterol correlates in a linear fashion to administered dose.
Toxicology: Preclinical Data: The toxicity observed in animal studies with budesonide and formoterol given in combination or separately, were effects associated with an exaggerated pharmacological activity.
In animal reproduction studies, corticosteroids 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 dose. 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 in humans.
Symbicort Rapihaler contains the excipients povidone (polyvinylpyrrolidone) K25, macrogol (polyethylene glycol) 1000 and the pressurised liquid propellant apaflurane (HFA227). 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 Symbicort Rapihaler have shown no evidence of any local or systemic toxicity or irritation attributable to the excipients.