Chronic overdosage may result in signs/symptoms of hypercorticism. There are no data available on the effects of acute or chronic overdosage with QNASL Nasal Aerosol.
Acute: Inhalation of the drug in doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not require emergency action. In these patients treatment with QVAR diproprionate by inhalation should be continued at a dose sufficient to control asthma; adrenal function recovers in a few days and can be verified by measuring plasma cortisol.
Chronic: Use of inhaled QVAR dipropionate in daily doses in excess of 1,500 micrograms over prolonged periods may lead to some degree of adrenal suppression. Monitoring of adrenal reserve may be indicated. Treatment should be continued at a dose sufficient to control asthma.
Acute overdosage is unlikely to cause problems. The only harmful effect that follows inhalation of large amounts of the drug over a short time period is suppression of HPA function. Specific emergency action need not be taken. Treatment with Qvar should be continued at the recommended dose to control the asthma; HPA function recovers in a day or two.
If excessive doses of beclometasone dipropionate were taken over a prolonged period a degree of atrophy of the adrenal cortex could occur in addition to HPA suppression. In this event the patient should be treated as steroid dependent and transferred to a suitable maintenance dose of a systemic steroid such as prednisolone.
The only harmful effect that follows inhalation of large amounts of the drug over a short time period is suppression of Hypothalamic-Pituitary-Adrenal (HPA) function. No special emergency action need be taken. Treatment with QVAR Aqueous Nasal Spray should be continued at the recommended dose. HPA function recovers in a day or two.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
There is no specific treatment for an overdose of beclometasone dipropionate. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary
None
Not applicable.
Not applicable
Systemic and local corticosteroid use may result in the following:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults And Adolescents 12 Years Of Age And OlderThe safety data described below for adults and adolescents 12 years of age and older with seasonal or perennial allergic rhinitis are based on 4 placebo-controlled clinical trials of 2 to 6 weeks duration evaluating doses of beclomethasone nasal aerosol from 80 to 320 mcg once daily. These short-term trials included a total of 1394 patients with either seasonal or perennial allergic rhinitis. Of these, 575 (378 female and 197 male) received at least one dose of QNASL Nasal Aerosol, 320 mcg once daily and 578 (360 female and 218 male) received placebo. Patient ages ranged from 12 to 82 years and the racial distribution of patients was 81% white, 16% black, and 4% other.
Short-Term (2–6 Weeks) TrialsLess than 2% of patients in the clinical trials discontinued treatment because of adverse reactions with the rate of withdrawal among patients who received QNASL Nasal Aerosol similar to or lower than the rate among patients who received placebo. Table 1 displays the common adverse reactions (≥ 1% and greater than placebo-treated patients).
Table 1. Adverse Events With ≥ 1% Incidence and Greater than Placebo in QNASL Nasal Aerosol-Treated Adult and Adolescent Patients with Seasonal or Perennial Allergic Rhinitis in Controlled Clinical Trials of 2 to 6 Weeks Duration (Safety Population)
| Adult and Adolescent Patients 12 Years of Age and Older | ||
| QNASL Nasal Aerosol 320 mcg (N = 575) n (%) | Placebo (N = 578) n (%) | |
| Nasal Discomfort | 30 (5.2) | 28 (4.8) |
| Epistaxis | 11 (1.9) | 7 (1.2) |
| Headache | 13 (2.3) | 9 (1.6) |
Nasal ulcerations occurred in 2 patients treated with placebo and in 1 patient treated with QNASL Nasal Aerosol. There were no differences in the incidence of adverse reactions based on gender or race. Clinical trials did not have sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients.
Long-Term 52-Week Safety TrialIn a 52-week placebo-controlled long-term safety trial in patients with PAR, 415 patients (128 males and 287 females, aged 12 to 74 years) were treated with QNASL Nasal Aerosol at a dose of 320 mcg once daily and 111 patients (44 males and 67 females, aged 12 to 67 years) were treated with placebo. Of the 415 patients treated with QNASL Nasal Aerosol, 219 patients were treated for 52 weeks and 196 patients were treated for 30 weeks. While most adverse events were similar in type and rate between the treatment groups, epistaxis occurred more frequently in patients who received QNASL Nasal Aerosol (45 out of 415, 11%) than in patients who received placebo (2 out of 111, 2%). Epistaxis also tended to be more severe in patients treated with QNASL Nasal Aerosol. In 45 reports of epistaxis in patients who received QNASL Nasal Aerosol, 27, 13, and 5 cases were of mild, moderate, and severe intensity, respectively, while the reports of epistaxis in patients who received placebo were of mild (1) and moderate (1) intensity. Seventeen patients treated with QNASL Nasal Aerosol experienced adverse reactions that led to withdrawal from the trial compared to 3 patients treated with placebo. There were 4 nasal erosions and 1 nasal septum ulceration which occurred in patients who received QNASL Nasal Aerosol, and no erosions or ulcerations noted in patients who received placebo. No patient experienced a nasal septum perforation during the trial.
Pediatric Patients Aged 4 to 11 YearsThe safety data described below for pediatric patients 4 to 11 years of age with seasonal or perennial allergic rhinitis are based on 3 placebo-controlled clinical trials. These trials were 2 to 12 weeks in duration, evaluated doses of beclomethasone nasal aerosol 80 mcg to 160 mcg once daily and included a total of 1360 patients with either seasonal or perennial allergic rhinitis. Of these, 668 (312 female and 356 male) received at least one dose of QNASL Nasal Aerosol, 80 mcg once daily, 241 (116 female and 125 male) received QNASL Nasal Aerosol 160 mcg once daily, and 451 (203 female and 248 male) received placebo. The racial distribution of patients was 73% white, 20% black, and 6% other. Based on the results from the dose ranging trial, 80 mcg once daily was chosen as the dose in pediatric patients.
Less than 1.5% of patients in the clinical trials discontinued treatment because of adverse reactions with the rate of withdrawal among patients who received QNASL Nasal Aerosol 80 mcg once daily similar to or lower than the rate among patients who received placebo. Table 2 displays the common adverse reactions (≥ 2% and greater than placebo-treated patients). Additionally, epistaxis was reported at a rate of 4% for both QNASL Nasal Aerosol 80 mcg once daily and placebo treated patients.
Table 2. Adverse Events With ≥ 2% Incidence and Greater than Placebo in QNASL Nasal Aerosol-Treated Pediatric Patients with Seasonal or Perennial Allergic Rhinitis in Controlled Clinical Trials of 2 to 12 weeks Duration (Safety Population)
| Pediatric Patients 4 to 11 Years of Age | ||
| QNASL Nasal Aerosol 80 mcg (N=668) n (%) | Placebo (N=451) n (%) | |
| Headache | 23 (3.4) | 15 (3.3) |
| Pyrexia | 19 (2.8) | 7 (1.6) |
| Upper respiratory tract infection | 17 (2.5) | 8 (1.8) |
| Nasopharyngitis | 15 (2.2) | 6 (1.3) |
In addition to adverse reactions reported from clinical trials for QNASL Nasal Aerosol, the following adverse events have been reported during postmarketing use of QNASL Nasal Aerosol or other intranasal and inhaled formulations of beclomethasone dipropionate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to beclomethasone dipropionate or a combination of these factors.
QNASL Nasal Aerosol: sneezing, burning sensation
Intranasal beclomethasone dipropionate: Nasal septal perforation, blurred vision, glaucoma, cataracts, central serous chorioretinopathy (CSC), loss of taste and smell, and hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported following intranasal administration of beclomethasone dipropionate.
Inhaled beclomethasone dipropionate: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, and bronchospasm have been reported following the oral inhalation of beclomethasone dipropionate.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common ( 1/10), common ( 1/100 and <1/10), uncommon ( 1/1000 and <1/100), rare ( 1/10,000 and <1/1000), very rare (<1/10,000) including isolated reports and not known (cannot be estimated from the available data). Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo and comparator group has not been taken into account in estimation of these frequencies. Rare and very rare events were generally determined from spontaneous data.
| System Organ Class | Adverse Event | Frequency |
| Infections & Infestations | Candidiasis of the mouth and throat. | Very Common |
| Immune System Disorders | Hypersensitivity reactions with the following manifestations: | |
| Rashes, urticaria, pruritis, erythema. | Uncommon | |
| Oedema of the eyes, face, lips and throat | Very Rare | |
| Respiratory symptoms (dyspnoea and/or bronchospasm) | Very Rare | |
| Anaphylactoid/anaphylactic reactions | Very Rare | |
| Endocrine Disorders | Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma | Very Rare |
| Psychiatric Disorders | Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children) | Not known |
| Respiratory, Thoracic & Mediastinal Disorders | Hoarseness/throat irritation, cough | Common |
| Paradoxical bronchospasm | Very Rare | |
| Eosinophilic pneumonia | Not Known | |
| Skin and subcutaneous tissue disorders | Easy bruising, skin thinning | Not known |
Candidiasis of the mouth and throat (thrush) occurs in some patients, the incidence increasing with doses greater than 400 micrograms of QVAR dipropionate per day. Patients with high blood levels of Candida precipitins, indicating a previous infection, are most likely to develop this complication. Patients may find it helpful to rinse their mouth thoroughly with water after using the inhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with Easyhaler® QVAR 200 micrograms/dose treatment.
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma (see 4.4 Special Warnings and Precautions for Use).
In some patients inhaled QVAR dipropionate may cause hoarseness, cough, throat irritation and sore throat. It may be helpful to rinse the mouth out with water immediately after inhalation.
As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. The QVAR dipropionate preparation should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
A serious hypersensitivity reaction including oedema of the eye, face, lips and throat (angioedema) has been reported rarely.
As with other inhaled therapy, paradoxical bronchospasm may occur after dosing. Immediate treatment with a short-acting bronchodilator should be initiated, Qvar should be discontinued immediately and an alternate prophylactic treatment introduced.
Systemic effects of inhaled corticosteroids may occur, particularly with high doses prescribed for prolonged periods. These include adrenal suppression, growth retardation in children, decrease in bone mineral density and the occurrence of cataract and glaucoma.
Commonly, when taking Qvar, hoarseness and candidiasis of the throat and mouth may occur. To reduce the risk of hoarseness and candida infection, patients are advised to rinse their mouth after using their inhaler.
Based on the MedDra system organ class and frequencies, adverse events are listed in the table below according to the following frequency estimate: very common (> 1/10); common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
| MedDra - system organ class | Frequency and Symptom |
| Infections and infestations | Common: Candidiasis in mouth and throat |
| Immune system disorders | Rare: Allergic reactions, angioedema in eyes, throat, lips and face |
| Endocrine disorders | Very rare: Adrenal suppression*, growth retardation* (in children and adolescents), bone density decreased* |
| Nervous system disorders | Uncommon: Headache, vertigo, tremor |
| Eye disorders | Uncommon: ) Very rare: Cataract*, glaucoma* Not known: Central serous retinopathy |
| Respiratory, thoracic and mediastinal disorders | Common: Hoarseness, pharyngitis Uncommon: Cough, increased asthma symptoms Rare: Paradoxical bronchospasm |
| Gastrointestinal disorders | Common: Taste disturbances Uncommon: Nausea |
| Skin and subcutaneous tissue disorders | Uncommon: Urticaria, rash, pruritus, erythema, purpura |
| Musculoskeletal and connective tissue disorders | Very rare: Decrease bone mineral density |
| Psychiatric Disorders | Unknown: Psychomotor hyperactivity, sleep disorders, anxiety, depression, aggression, behavioural changes (predominantly in children) |
*).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
.
Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000) and very rare (<1/10,000) including isolated reports. Very common, common and uncommon reactions were generally determined from clinical trial data. Rare and very rare reactions were generally determined from spontaneous data. In assigning adverse reaction frequencies, the background rates in placebo groups were not taken into account, since these rates were generally comparable to those in the active treatment group.
| System Organ Class | Adverse Event | Frequency |
| Immune system disorders | Hypersensitivity reactions including: | |
| Rash, urticaria, pruritis, erythema. | Common | |
| Angioedema | Very rare | |
| Dyspnoea and/or bronchospasm | Very rare | |
| Anaphylactoid/anaphylactic reactions | Very rare | |
| Nervous system disorders | Unpleasant taste, unpleasant smell. | Common |
| Eye disorders | Glaucoma, raised intraocular pressure, cataract. | Very rare |
| ) | Not known | |
| Respiratory, Thoracic & Mediastinal disorders | Epistaxis, nasal dryness, nasal irritation, throat dryness, throat irritation. | Common |
| Nasal septum perforation. | Very rare |
Systemic effects of nasal corticosteroids may occur particularly when used at high doses for prolonged periods.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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 this product 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 Qvar Aerosol (an equivalent inhaler) in rats did not exhibit any teratogenic effects.
Adrenal Function: The effects of QNASL Nasal Aerosol on the HPA axis were evaluated in two 6- week, randomized, double-blind, parallel-group perennial allergic rhinitis trials – one in adult and adolescent patients 12 to 45 years of age and another in children 6 to 11 years of age. In the first study with adolescent and adult patients aged 12 to 45, QNASL Nasal Aerosol 320 mcg, once daily, was compared with both placebo nasal aerosol and a positive control (a placebo/prednisone group that received prednisone 10 mg orally once daily for the final 7 days of the treatment period). In the second study with pediatric patients aged 6 to 11, QNASL Nasal Aerosol 80 mcg once daily was compared to placebo nasal aerosol. HPA-axis function was assessed by 24-hour serial serum cortisol levels prior to the first dose and after 6 weeks of treatment. Patients were domiciled for the 24-hour serum cortisol assessments. The change from baseline in the 24-hour serum cortisol weighted mean for QNASL Nasal Aerosol and placebo after 6 weeks of treatment were compared.
In the HPA–axis study in patients 12 to 45 years of age, baseline geometric mean serum cortisol weighted mean values were similar in the QNASL Nasal Aerosol 320 mcg/day and placebo treatment groups (9.04 and 8.45 mcg/dL, respectively). After 6 weeks of treatment, the geometric mean values were 8.18 and 8.01 mcg/dL, respectively, with a change from baseline in 24-hour serum cortisol weighted mean for the QNASL Nasal Aerosol and placebo groups of 0.86 and 0.44, resulting in a difference of 0.42. The geometric mean ratio for QNASL Nasal Aerosol 320 mcg/day to placebo was 0.96 (95% CI: 0.87, 1.06). For comparison, in the positive-control (prednisone) treatment group, the geometric mean ratio for placebo to placebo/prednisone 10 mg/day was 3.17 (95% CI: 2.68, 3.74).
In the HPA-axis study in patients 6 to 11 years of age, baseline geometric mean serum cortisol weighted mean values were similar in the QNASL Nasal Aerosol 80 mcg/day and placebo treatment groups (5.97 and 6.47 mcg/dL, respectively). After 6 weeks of treatment the geometric mean values were 6.19 and 7.13 mcg/dL, respectively with no decrease from baseline values in both treatment groups. The geometric mean ratio for QNASL Nasal Aerosol 80 mcg/day to placebo was 0.91 (95% CI; 0.81, 1.03).
QVAR dipropionate (BDP) is a pro-drug with weak glucocorticoid receptor binding activity. It is hydrolysed via esterase enzymes to the active metabolite QVAR-17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity.
Pharmacotherapeutic group: Glucocorticoids, ATC Code: R03B A01
Qvar contains beclometasone dipropionate in solution in propellant HFA-134a resulting in an extrafine aerosol. The aerosol droplets are on average much smaller than the beclometasone dipropionate particles delivered by CFC-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 studies were performed with Qvar Aerosol. Qvar Aerosol is a 'press and breathe' inhaler, whereas QVAR is a breath-activated inhaler.
Inhaled beclometasone dipropionate is now 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 product.
Following topical administration beclometasone 17,21-dipropionate (BDP) produces potent anti-inflammatory and vasoconstrictor effects.
BDP is a pro-drug with weak corticosteroid receptor binding affinity. It is hydrolysed via esterase enzymes to the highly active metabolite beclometasone-17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity.
Beclometasone dipropionate offers a preventative background treatment for hayfever when taken prior to allergen challenge. After which with regular use, BDP can continue to prevent allergy symptoms from reappearing.
Following intranasal administration, most of the beclomethasone dipropionate undergoes extensive conversion to its active metabolite, beclomethasone-17-monopropionate, during absorption. Plasma concentrations of beclomethasone dipropionate and beclomethasone-17-monopropionate have been measured with QNASL Nasal Aerosol in 2 adult and/or adolescent clinical trials and 1 pediatric clinical trial.
The single-dose pharmacokinetics of QNASL Nasal Aerosol were evaluated in a randomized, openlabel, 3-period, crossover trial in healthy adult volunteers. Systemic levels of beclomethasone-17- monopropionate and beclomethasone dipropionate after single-dose intranasal administration of beclomethasone dipropionate at doses of 80 and 320 mcg were compared with the systemic levels of beclomethasone-17-monopropionate and beclomethasone dipropionate after administration of orally inhaled beclomethasone dipropionate HFA at a dose of 320 mcg (QVAR® Inhalation Aerosol). The results of this trial demonstrated that the systemic bioavailability of QNASL Nasal Aerosol 320 mcg was approximately 27.5% (approximately 4-fold lower) of that of orally inhaled beclomethasone dipropionate HFA 320 mcg/day based on the plasma concentrations of beclomethasone-17- monopropionate (AUClast: 1139.7 vs 4140.3 hr*pg/mL; GMR: 0.275; 90% CI for the GMR: 0.214, 0.354). The peak exposure to QNASL Nasal Aerosol 320 mcg/day was approximately 19.5% (approximately 5-fold lower) of that of orally inhaled beclomethasone dipropionate HFA 320 mcg/day as measured by beclomethasone-17-monopropionate (Cmax: 262.7 vs 1343.7 pg/mL; GMR: 0.195; 90% CI for the GMR: 0.158, 0.241).
Following repeated once-daily administration of QNASL Nasal Aerosol, there was no accumulation or increase in plasma exposure to beclomethasone-17-monopropionate or beclomethasone dipropionate, most likely due to the short plasma half-life relative to the dosing frequency.
DistributionThe in vitro protein binding for beclomethasone-17-monopropionate was reported to be 94% to 96% over the concentration range of 1000 to 5000 pg/mL. The volume of distribution at steady state for beclomethasone dipropionate is moderate (20 L) but more extensive for beclomethasone-17- monopropionate (424 L).
MetabolismBeclomethasone dipropionate undergoes extensive first-pass metabolism, forming three metabolites via CYP3A4, beclomethasone-17-monopropionate, beclomethasone-21-monopropionate, and beclomethasone. Beclomethasone-17-monopropionate is the major and most active metabolite.
EliminationThe major route of elimination of inhaled beclomethasone dipropionate appears to be via metabolism. More than 90% of inhaled beclomethasone dipropionate is found as beclomethasone-17- monopropionate in the systemic circulation. The mean elimination half-life of beclomethasone-17- monopropionate is 2.8 hours. The terminal elimination half-lives of beclomethasone dipropionate and beclomethasone-17-monopropionate following intranasal dosing with QNASL Nasal Aerosol (320 mcg) were approximately 0.3 hours and 4.5 hours, respectively. Irrespective of the route of administration (injection, oral, or inhalation), beclomethasone dipropionate and its metabolites are mainly excreted in the feces. Less than 10% of the drug and its metabolites are excreted in the urine. It is likely that intranasal beclomethasone dipropionate follows a similar elimination pathway.
Absorption
When administered via inhalation (via metered dose inhaler) there is extensive conversion of BDP to the active metabolite B-17-MP within the lungs prior to systemic absorption. The systemic absorption of B-17-MP arises from both lung deposition and oral absorption of the swallowed dose. When administered orally, in healthy male volunteers, the bioavailability of BDP is negligible but pre-systemic conversion to B-17-MP results in 41% (95% CI 27- 62 %) of the dose being available as B-17-MP.
Metabolism
BDP is cleared very rapidly from the systemic circulation, owing to extensive first pass metabolism. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, QVAR-21-monopropionate (B-21-MP) and QVAR (BOH), are also formed but these contribute little to systemic exposure.
Distribution
The tissue distribution at steady state for BDP is moderate (20L) but more extensive for B-17-MP (424L). Plasma protein binding is moderately high (87%).
Elimination
The elimination of BDP and B-17-MP are characterised by high plasma clearance (150 and 120L/h) with corresponding terminal elimination half lives of 0.5h and 2.7h. Following oral administration of tritiated BDP, approximately 60% of the dose was excreted in the faeces within 96 hours mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine.
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 special populations.
Absorption
Following intranasal administration of BDP in healthy males, the systemic absorption was assessed by measuring the plasma concentrations of its active metabolite B-17-MP, for which the absolute bioavailability following intranasal administration is 44% (95% CI 28%, 70%). After intranasal administration, <1% of the dose is absorbed by the nasal mucosa. The remainder after being cleared from the nose, either by drainage or mucocilary clearance, is available for absorption from the gastrointestinal tract. Plasma B-17-MP is almost entirely due to conversion of BDP absorbed from the swallowed dose.
Following oral administration of BDP in healthy males, the systemic absorption was also assessed by measuring the plasma concentrations of its active metabolite B-17-MP, for which the absolute bioavailability following oral administration is 41% (95% CI 27%, 62%).
Following an oral dose, B-17-MP is absorbed slowly with peak plasma levels reached 3-5 hours after dosing.
Metabolism
BDP is cleared very rapidly from the circulation and plasma concentrations are undetectable (< 50pg/ml) following oral or intranasal dosing. There is rapid metabolism of the majority of the swallowed portion of BDP during its first passage through the liver. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclometasone-21-monopropionate (B-21-MP) and beclometasone (BOH), are also formed but these contribute little to systemic exposure.
Distribution
The tissue distribution at steady-state for BDP is moderate (20l) but more extensive for B-17-MP (424l). Plasma protein binding of BDP is moderately high (87%).
Elimination
The elimination of BDP and B-17-MP are characterised by high plasma clearance (150 and 120l/h) with corresponding terminal elimination half-lives of 0.5h and 2.7h. Following oral administration of tritiated BDP, approximately 60% of the dose was excreted in the faeces within 96 hours mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine.
No adverse effect has been reported.
Not relevant.
Not relevant
Patients have to be instructed to perform a rapid and forced inhalation through the Easyhaler device. Patients have to be instructed not to exhale into the device. Illustrated user's instructions for use accompany each package.
Not applicable.
Refer to Patient Information Leaflet.
