Pharmacotherapeutic group: Adrenergics, inhalants: formoterol and other drugs for obstructive airway diseases. ATC-code: R03AK08.
Pharmacology: Pharmacodynamics: Mechanisms of action and pharmacodynamic effects: Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) contains beclometasone dipropionate and formoterol in a dry powder formulation resulting in an extrafine aerosol with an average mass median aerodynamic diameter (MMAD) of 1.4-1.5 micrometers and co-deposition of the two components. The aerosol particles of Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) are on average much smaller than the particles delivered in non-extrafine formulations.
A radio-labelled drug deposition study in asthmatic adults has demonstrated that a high proportion of the drug (estimated 42% of the nominal dose) is deposited in the lung, with a homogenous deposition through the airways. These delivery characteristics support the use of a low corticosteroid dose with enhanced local pharmacodynamic effects, which were shown to be equivalent to the corresponding pressurised inhalation solution (see Clinical experience as follows).
The two actives of Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) have different modes of action. In common with other inhaled corticosteroids and beta2-agonist combinations, additive effects are seen in respect of reduction in asthma exacerbations.
Beclometasone dipropionate: Beclometasone dipropionate given by inhalation at recommended doses has a glucocorticoid antiinflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma with less adverse effects than when corticosteroids are administered systemically.
Formoterol: Formoterol is a selective beta2-adrenergic agonist that produces 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 dose administration.
Clinical experience: The efficacy of the two components of Foster inhalation powder has been assessed in three separate studies in comparison with the 100 micrograms/6 micrograms pressurised inhalation solution formulation in moderate to severe patients with persistent asthma. Overall, the efficacy of the two inhalers is expected to be equivalent in clinical practice at both 1 and 2 inhalations bid.
In one study, the primary objective was the efficacy evaluation of the inhaled corticosteroid component measured on bronchodilation (pre-dose FEV1). A clinically significant improvement in pre-dose FEV1 was seen in 696 patients with moderate to severe symptomatic asthma at the end of a 3 months treatment period in comparison with baseline values, with 1 inhalation bid and 2 inhalations bid of both formulations. A mean increase of at least 250 mL was observed. There was no clinically relevant difference in pre-dose FEV1 between Foster inhalation powder and the pressurised inhalation solution at either dosage. A significant dose-response was observed for morning PEF. Statistical significance for the dose-response in pre-dose FEV1 was not reached. Measurements of control of asthma such as morning and evening asthma symptoms scores and percentage of days without symptoms improved significantly from baseline through to the end of the treatment period, particularly for the two high doses of both formulations.
In the second study, the primary aim was the efficacy evaluation on the long-acting beta2-agonist component of Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler). In this study, bronchodilation at the onset and up to 12 hrs after single doses administration was measured by serial spirometric evaluations of FEV1 (FEV1 AUC over at least 80% of formoterol duration of action). Compared with placebo, Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler), one inhalation and four inhalations of both actives significantly improved the FEV1 AUC0-12. Both doses of Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) inhalation powder were non-inferior to the corresponding dose of the pressurised inhalation solution formulation. A statistically significant dose-response was found with both formulations between the low and high dose.
In the third study, after a 4-week run-in period with beclometasone dipropionate/formoterol pressurised inhalation solution fixed combination, 1 inhalation bid, 755 controlled asthmatic patients were randomised to 8 weeks of treatment with the same inhaler, with Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) inhalation powder or with beclometasone dipropionate 100 micrograms per dose inhalation powder, all given at 1 inhalation bid. The primary objective was the change from baseline over the entire treatment period in mean morning expiratory flow (PEF). After 8 weeks of treatment there was no difference in the primary endpoint between the two combination inhalers, both being significantly better than beclometasone dipropionate monotherapy. No differences were found between the two combination inhalers in measures of symptoms such as the asthma control questionnaire score and the number of rescue-free days.
An open-label placebo study was conducted to verify that the inspiratory flow which could be generated through the device inhaler is not influenced by patient's age, disease and disease severity, and therefore the activation and drug delivery from the device could be achieved in all patients. The primary endpoint was the percentage of patients in each age and disease group able to activate the inhaler. Eighty-nine patients, in the age range 5-84 years, including moderate and severe asthmatics (FEV1 >60% and ≤60% predicted, respectively), and moderate and severe COPD patients (FEV1 ≥50% and <50% predicted, respectively) participated in the trial. All patients, irrespective of age, disease and disease severity, were able to generate sufficient inspiratory flow to activate the device inhaler.
In an additional open label placebo study, it was demonstrated by assessing the inspiration profile through the Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler), that mild to severe COPD patients, regardless of their functional limitation, were able to effectively activate and use the device.
Paediatric population: The European Medicines Agency has deferred the obligation to submit the results of studies in asthma with Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) in the 5-11 and 12-17 years subsets of the paediatric population.
At time of writing, there is no clinical experience on Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) in children 5-11 years of age, and only limited information in adolescents 12-17 years of age.
In a 3 months randomised clinical trial 162 adolescents aged 12-17 years with a diagnosis of moderate to severe asthma received either Foster or the corresponding pressurised inhalation solution formulation, 1 or 2 inhalations bid. The change in pre-dose FEV1 at the end of treatment was greater in the adolescents than in adults.
See also Dosage & Administration and Adverse Reactions for information on paediatric use.
Pharmacokinetics: Beclometasone dipropionate: Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclometasone-17-monopropionate which has a more potent topical anti-inflammatory activity compared with the pro-drug beclometasone dipropionate.
Absorption, distribution and metabolism: Inhaled beclometasone dipropionate is rapidly absorbed through the lungs; prior to absorption there is extensive conversion to its active metabolite beclometasone-17-monopropionate via esterase enzymes that are found in most tissues. The systemic availability of the active metabolite arises from lung and from gastrointestinal absorption of the swallowed dose. The bioavailability of swallowed beclometasone dipropionate is negligible however, pre-systemic conversion to beclometasone-17-monopropionate results in part of the dose being absorbed as the active metabolite.
There is an approximately linear increase in systemic exposure with increasing inhaled dose.
The absolute bioavailability following inhalation from a pressurised metered dose inhaler is approximately 2% and 62% of the nominal dose for unchanged beclometasone dipropionate and beclometasone-17-monopropionate respectively.
Following intravenous dosing, the disposition of beclometasone dipropionate and its active metabolite are characterised by high plasma clearance (150 and 120 L/h respectively), with a small volume of distribution at steady state for beclometasone dipropionate (20 L) and larger tissue distribution for its active metabolite (424 L). Metabolic disposition of beclometasone dipropionate mainly (82%) results in its active metabolite beclometasone-17-monopropionate.
Plasma protein binding is moderately high (87%).
Excretion: Faecal excretion is the major route of beclometasone dipropionate elimination mainly as polar metabolites. The renal excretion of beclometasone dipropionate and its metabolites is negligible. The terminal elimination half-lives are 0.5 h and 2.7 h for beclometasone dipropionate and beclometasone-17-monopropionate respectively.
Special populations: The pharmacokinetics of beclometasone dipropionate in patients with renal or hepatic impairment has not been studied; however, as beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver, to originate the more polar products beclometasone-21-monopropionate, beclometasone-17-monopropionate and beclometasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclometasone dipropionate.
As beclometasone dipropionate or its metabolites were not traced in the urine, an increase in systemic exposure is not envisaged in patients with renal impairment.
Formoterol: Absorption and distribution: Following inhalation, formoterol is absorbed both from the lung and from the gastrointestinal tract. The fraction of an inhaled dose that is swallowed after administration with a metered dose inhaler (MDI) may range between 60% and 90%. At least 65% of the fraction that is swallowed is absorbed from the gastrointestinal tract. Peak plasma concentrations of unchanged drug occur within 0.5 to 1 hours after oral administration. Plasma protein binding of formoterol is 61-64% with 34% bound to albumin. There was no saturation of binding in the concentration range attained with therapeutic doses. The elimination half-life determined after oral administration is 2-3 hours. Absorption of formoterol is linear following inhalation of 12 to 96 μg of formoterol fumarate.
Metabolism: Formoterol is widely metabolised and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Cytochrome P450 isoenzymes CYP2D6, CYP2C19 and CYP2C9 are involved in the O-demethylation of formoterol. Liver appears to be the primary site of metabolism. Formoterol does not inhibit CYP450 enzymes at therapeutically relevant concentrations.
Excretion: The cumulative urinary excretion of formoterol after single inhalation from a dry powder inhaler increased linearly in the 12-96 μg dose range. On average, 8% and 25% of the dose was excreted as unchanged and total formoterol, respectively. Based on plasma concentrations measured following inhalation of a single 120 μg dose by 12 healthy subjects, the mean terminal elimination half-life was determined to be 10 hours. The (R,R)- and (S,S)-enantiomers represented about 40% and 60% of unchanged drug excreted in the urine, respectively. The relative proportion of the two enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of one enantiomer over the other after repeated dosing.
After oral administration (40 to 80 μg), 6% to 10% of the dose was recovered in urine as unchanged drug in healthy subjects; up to 8% of the dose was recovered as the glucuronide.
A total 67% of an oral dose of formoterol is excreted in urine (mainly as metabolites) and the remainder in the faeces. The renal clearance of formoterol is 150 ml/min.
Special populations: Hepatic/Renal impairment: the pharmacokinetics of formoterol has not been studied in patients with hepatic or renal impairment.
Clinical experience: The systemic exposure to beclometasone dipropionate and formoterol in the combination has been compared to the single components. There was no evidence of pharmacokinetic or pharmacodynamic (systemic) interactions between beclometasone dipropionate and formoterol.
The pharmacokinetics of Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) inhalation powder has been compared with that of the corresponding pressurised inhalation solution formulation. The analysis of the steroid component focused on beclometasone-17-monopropionate, the main active metabolite of beclometasone dipropionate.
Systemic absorption and metabolism of beclometasone dipropionate was rapid and Cmax was reached 5 min postdose for both treatments but was higher (+ 68 %) with Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) inhalation powder. AUCt was about 3 times higher after inhalation of Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) through the device inhaler compared with the pressurised inhalation solution. Cmax for beclometasone-17-monopropionate, the main active metabolite, representing about 82% of the total blood level, was reached on average after 30 min and 15 min with the device and with the pressurised inhalation solution, respectively. Plasma concentration of beclometasone-17-monopropionate was lower (Cmax -49% and AUCt -29%), after inhalation of the inhalation powder than via the pressurised inhalation solution. After inhalation of Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) with the device inhaler, the peak concentration (Cmax) of formoterol was reached within 5 minutes and was higher (+ 47 %) for the inhalation powder, whereas the overall exposure (AUCt) was comparable in the two treatments.
In one study, the relative lung delivery was investigated by using a charcoal blockade to exclude drug absorption from the gastrointestinal tract, and adopting an approved spacer for the reference product (the pressurised inhalation solution). In this setting, the device and the pressurised inhalation solution were shown to be equivalent for the AUCt of both beclometasone-17-monopropionate and formoterol (the ratio inhalation powder/pressurised inhalation solution and the 90% confidence intervals were within 80-125%); however, Cmax of beclometasone-17-monopropionate was lower (-38%) following inhalation from the device.
Toxicology: Preclinical safety data: Non-clinical data of the individual components of Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler) reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. The toxicity profile of the combination reflected that of single components with no increase in toxicity or unexpected findings.
Reproduction studies in rats showed dose-dependent effects. The presence of beclometasone dipropionate at high doses was associated with reduced female fertility, decrease in the number of implantations and embryofetal toxicity. High doses of corticosteroids to pregnant animals are known to cause abnormalities of fetal development including cleft palate and intra-uterine growth retardation, and it is likely that the effects seen with the beclometasone dipropionate/formoterol combination were due to beclometasone dipropionate. These effects were noted only with high systemic exposure to the active metabolite beclometasone-17-monopropionate (more than 200 fold the expected plasma levels in patients). Additionally, increased duration of gestation and parturition, an effect attributable to the known tocolytic effects of beta2-sympathomimetics, was seen in animal studies. These effects were noted when maternal plasma formoterol levels were below the levels expected in patients treated with Beclometasone dipropionate/Formoterol fumarate dihydrate (Foster Nexthaler).
Genotoxicity studies performed with a beclometasone dipropionate/formoterol combination do not indicate mutagenic potential. No carcinogenicity studies have been performed with the proposed combination. However animal data reported for the individual constituents do not suggest any potential risk of carcinogenicity in man.