Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Teva UK Limited, Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, United Kingdom
Pharmacotherapeutic group: Glucocorticoids
ATC Code: R03BA01
Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity. It is extensively hydrolysed via esterase enzymes to the active metabolite beclometasone 17-monohydrate, which is a potent topical anti-inflammatory agent.
Qvar contains beclometasone dipropionate in solution with propellant HFA-134a resulting in an extrafine aerosol. The aerosol droplets are on average much smaller than the beclometasone dipropionate particles delivered by CFC-containing suspension formulations or dry powder formulations of beclometasone dipropionate. The extrafine particle fraction will be 60% ± 20% of the drug particles ≤3.3 microns per shot, ex-actuator.
Radio-labelled deposition studies in adults with mild asthma have demonstrated that the majority of drug (>55% ex-actuator) is deposited in the lung and a small amount (<35% ex-actuator) is deposited in the oropharynx. These delivery characteristics result in equivalent therapeutic effects at lower total daily doses of Qvar, compared with CFC beclometasone dipropionate formulations.
Inhaled beclometasone dipropionate is well established in the management of asthma. It is a synthetic glucocorticoid and exerts a topical, anti-inflammatory effect on the lungs, with fewer systemic effects than oral corticosteroids.
Comparative clinical studies have demonstrated that asthma patients achieve equivalent pulmonary function and control of symptoms with Qvar at lower total daily doses than CFC containing beclometasone dipropionate aerosol inhalers.
Pharmacodynamic studies in patients with mild asthma given Qvar for 14 days, have shown that there is a linear correlation among urinary free cortisol suppression, dose administered, and serum total-beclometasone levels obtained. At a daily dose of 800 micrograms Qvar, suppression of urinary free cortisol was comparable with that observed with the same daily dose of CFC containing beclometasone dipropionate, indicating a wider safety margin, as Qvar is administered at lower doses than the CFC-containing product.
The pharmacokinetic profile of Qvar shows that the peak serum concentration for total- beclometasone (BOH) (total of any beclometasone OH and beclometasone dipropionate or monopropionate hydrolysed to beclometasone OH) after single and multiple doses is achieved after 30 minutes.
The value at the peak is approximately 2 nanograms/ml after a total daily dose of 800 micrograms and the serum levels after 100, 200 and 400 micrograms are proportional. The principal route of elimination of beclometasone dipropionate and its several metabolites is in the faeces. Between 10% and 15% of an orally administered dose is excreted in the urine, as both conjugated and free metabolites of the drug.
In both single dose and multiple dose pharmacokinetic studies, a dose of 200 micrograms of Qvar achieved comparable total-BOH levels, as a dose of 400 micrograms of CFC containing beclometasone dipropionate aerosol. This provided the scientific rationale for investigating lower total daily doses of Qvar to achieve the same clinical effect.
Pharmacokinetic studies with Qvar have not been carried out in any other special populations.
In a single dose pharmacokinetic study in children, a dose of 200 micrograms of extrafine beclometasone dipropionate delivered without a spacer achieved comparable AUC (beclometasone 17 monopropionate) levels as a dose of 400 micrograms of a CFC-containing beclometasone dipropionate product delivered via a spacer.
In animal studies, propellant HFA-134a has been shown to have no significant pharmacological effects other than at very high exposure concentrations, then narcosis and a relatively weak cardiac sensitising effect were found. The potency of the cardiac sensitisation was less than that of CFC-11 (trichlorofluoromethane).
In studies to detect toxicity, repeated high dose levels of propellant HFA-134a indicated that safety margins based on systemic exposure would be of the order 2200, 1314 and 381 for mouse, rat and dog with respect to humans.
There are no reasons to consider propellant HFA-134a as a potential mutagen, clastogen or carcinogen judged from in vitro and in vivo studies including long-term administration by inhalation in rodents.
Studies of propellant HFA-134a administered to pregnant and lactating rats and rabbits have not revealed any special hazard.
In animals, systemic administration of relatively high doses can cause abnormalities of foetal development including growth retardation and cleft palate. There may therefore be a very small risk of such effects in the human foetus. However, inhalation of beclometasone dipropionate into the lungs avoids the high level of exposure that occurs with administration by systemic routes.
Safety studies with Qvar in rat and dog showed few, if any, adverse effects other than those normally associated with general steroid exposure including lymphoid tissue alterations such as reduction in thymus, adrenal and spleen weights. An inhalation reproductive study with this product in rats did not exhibit any teratogenic effects.
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