Pharmacotherapeutic Group: Adrenergics and other drugs for obstructive airway diseases. ATC Code: R03AK07.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic Effects: Innovair contains beclometasone dipropionate and formoterol, which have different modes of action. In common with other inhaled corticosteroids and β2-agonists combinations, additive effects are seen in terms of reduction of 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 β2-adrenergic agonist that produces relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect sets in rapidly, within 1-3 min after inhalation, and has a duration of 12 hrs after a single dose.
Innovair: In clinical trials in adults, the addition of formoterol to beclometasone dipropionate improved asthma symptoms and lung function and reduced exacerbations.
In a 24-week study, the effect on lung function of Innovair was at least equal to that of the free combination of beclometasone dipropionate and formoterol and exceeded that of beclometasone dipropionate alone.
Pharmacokinetics: The systemic exposure to the active substances beclometasone dipropionate and formoterol in the fixed combination Innovair have been compared to the single components.
In a pharmacokinetic study conducted in healthy subjects treated with a single dose of Innovair fixed combination (4 puffs of 100/6 mcg) or a single dose of beclometasone dipropionate chlorofluorocarbon (CFC) (4 puffs of 250 mcg) and formoterol HFA (4 puffs of 6 mcg), the area under the concentration-time curve (AUC) of beclometasone dipropionate main active metabolite (beclometasone-17-monopropionate), and its maximal plasma concentration (Cmax) were, respectively, 35% and 19% lower with the fixed combination, than with non-extrafine beclometasone dipropionate CFC formulation, in contrast, the rate of absorption was more rapid (0.5 vs 2 hr) with the fixed combination compared to non-extrafine beclometasone dipropionate CFC alone.
For formoterol, Cmax was similar after administration of the fixed or the extemporary combination and the systemic exposure was slightly higher after administration of Innovair than with the extemporary combination.
There was no evidence of pharmacokinetic or pharmacodynamic (systemic) interactions between beclometasone dipropionate and formoterol.
Beclometasone Dipropionate: Beclometasone dipropionate is a prodrug 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 prodrug 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 beclometasone-17-monopropionate arises from lung (36%) and from gastrointestinal absorption of the swallowed dose. The bioavailability of swallowed beclometasone dipropionate is negligible however, presystemic conversion to beclometasone-17-monopropionate results in 41% 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 is approximately 2% and 62% of the nominal dose for unchanged beclometasone dipropionate and beclometasone-17-monopropionate, respectively.
Following IV dosing, the disposition of beclometasone dipropionate and its active metabolite are characterised by high plasma clearance (150 and 120 L/hr, respectively), with a small volume of distribution at steady-state (Vss) for beclometasone dipropionate (20 L) and larger tissue distribution for its active metabolite (424 L).
Plasma protein-binding is moderately high.
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-life (t½) are 0.5 hrs and 2.7 hrs 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.
The pharmacokinetics of beclometasone dipropionate in patients with renal impairment has not been studied. 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 0.5-1 hr 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 t½ determined after oral administration is 2-3 hrs. Absorption of formoterol is linear following inhalation of formoterol fumarate 12-96 g.
Metabolism: Formoterol is widely metabolised and the prominent pathway involves direct conjugation at the phenolic hydroxyl group. Glucuronide acid conjugate is inactive. The 2nd major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Cytochrome P-450 (CYP450) 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 g 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 g dose by 12 healthy subjects, the mean terminal elimination t½ was determined to be 10 hrs. 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 2 enantiomers remained constant over the dose range studied and there was no evidence of relative accumulation of 1 enantiomer over the other after repeated dosing.
After oral administration (40-80 g), 6-10% 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.
Toxicology: Preclinical Safety Data: The toxicity observed in animal studies with beclometasone dipropionate and formoterol, given in combination or separately, consisted mainly of effects associated with exaggerated pharmacological activity. They are related to the immunosuppressive activity of beclometasone dipropionate and to the known cardiovascular effects of formoterol evident mainly in dogs. Neither increase in toxicity nor occurrence of unexpected findings were observed upon administration of the combination.
Reproduction studies in rats showed dose-dependent effects. The combination was associated with reduced female fertility and embryofetal toxicity. High doses of corticosteroids to pregnant animals are known to cause abnormalities of fetal development including cleft palate and intrauterine 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-monoproprionate (200-fold the expected plasma levels in patients). Additionally, increased duration of gestation and parturition, an effect attributable to the known tocolytic effects of β2-sympathomimetics, was seen in animal studies. These effects were noted when maternal plasma formoterol levels were below the levels expected in patients treated with Innovair.
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.
Preclinical data on the CFC free propellant HFA-134a reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.