Vannair

Budesonide, formoterol fumarate dihydrate.

Vannair pMDI is a pressurised metered dose inhaler (pMDI). The following strengths are registered: Vannair pMDI 80/4.5: Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 80 μg/inhalation and formoterol 4.5 μg/inhalation.
Vannair pMDI 160/4.5: Each delivered dose (the dose that leaves the mouthpiece) contains as active constituents: budesonide 160 μg/inhalation and formoterol 4.5 μg/inhalation.
Each inhaler contains 120 actuations. Vannair pMDI is presented in a pack of one inhaler.
The following table gives the corresponding dose delivered to the patient. (See Table 1.)

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Physicochemical properties: See Table 2.

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Excipients/Inactive Ingredients: Vannair pMDI contains the inactive ingredients povidone (polyvinylpyrolidone K25), macrogol (polyethylene glycol) 1000 and apaflurane (known as hydrofluroalkane (HFA)-227).

Pharmacology: Pharmacodynamics: Mechanism of action: Vannair contains budesonide and formoterol, which have different modes of action and show additive effects in terms of reduction of asthma and COPD exacerbations. The specific properties of budesonide and formoterol allow the combination to be used as maintenance treatment for asthma, and for symptomatic treatment of patients with moderate to severe COPD.
Budesonide is a non-halogenated glucocorticosteroid structurally related to 16α hydroxyprednisolone with a high local anti-inflammatory effect. Budesonide has shown anti-anaphylactic and anti-inflammatory effects in provocation studies in animals and humans, manifested as decreased bronchial obstruction in the immediate as well as the late phase of an allergic reaction. Budesonide has also been shown to decrease airway reactivity to both direct (histamine, methacholine) and indirect (exercise) challenge in hyper-reactive patients. Budesonide, when inhaled, has a rapid (within hours) and dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer 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 is a potent selective β₂-adrenergic agonist that produces relaxation of bronchial smooth muscle. Therefore, it has a bronchodilating effect in patients with reversible airways obstruction and in patients with bronchospasm induced by direct (methacholine) and indirect (eg, exercise) stimuli. The bronchodilating effect is dose dependent with an onset of effect within 1 to 3 minutes after inhalation. The duration of effect is at least 12 hours after a single dose.
Clinical trials: Asthma: Therapeutic equivalent between Vannair pMDI and Symbicort Turbuhaler was demonstrated in three clinical efficacy and safety studies in adults and adolescents with asthma. They included two randomised, double-blind, active controlled, parallel-group studies, Studies 681 (12 weeks duration) and 003 (6 weeks duration); and one randomised, open-label, parallel group, long term (12 months) study, Study 715.
No clinical studies have been conducted to directly compare the efficacy and safety of Vannair pMDI 80/2.25 with Symbicort Turbuhaler 160/4.5.
In Study 681, Vannair pMDI 160/4.5 mcg (2 inhalations twice daily) was compared with the corresponding dose of budesonide pMDI (160 μg; 2 inhalations twice daily), or Symbicort Turbuhaler (160/4.5; 2 inhalations twice daily) in adults and adolescents (≥12 years) with moderate to severe asthma (eg mean forced expiratory volume during the first second (FEV₁) ≥50% and ≤90% of predicted normal (PN) and FEV₁ reversibility ≥12%). Vannair pMDI was shown to significantly improve morning peak expiratory flow rate (primary efficacy variable), other lung function parameters, symptom scores and use of rescue medication compared to budesonide and was equivalent to Symbicort Turbuhaler (see Table 3).

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Study 003 was a 6-week study with similar design to Study 681. In this study, Vannair pMDI 40/2.25 (2 inhalations twice daily) was compared primarily (as regular therapy) with the corresponding dose of budesonide Turbuhaler 80 μg (1 inhalation twice daily), or and secondarily with Symbicort Turbuhaler 80/4.5 (1 inhalation twice daily) in adults and adolescents (≥12 years) with asthma (mean FEV₁ 74% PN and FEV₁ reversibility 24%). The primary efficacy variable was the change in morning peak expiratory flow (mPEF) from baseline (mean of the 10 last days of the run-in period) to the treatment period (mean of the 6-week treatment period). The primary objective was to demonstrate that Vannair pMDI 40/2.25 was more efficacious than budesonide Turbuhaler 80 μg. The adjusted mean mPEF increased by 12.2 L/min with Vannair pMDI 40/2.25, 4.15 L/min with budesonide Turbuhaler, and 13.1 L/min with Symbicort Turbuhaler 80/4.5. The results showed that the mean change from baseline in mPEF was greater with Vannair pMDI 40/2.25 than with budesonide Turbuhaler, and that the mean difference was statistically significant (mean difference of 8.07 L/min [95% Cl: 3.26 to 12.9], p=0.001). The secondary objective was to demonstrate therapeutic equivalence of Vannair pMDI 40/2.25 and Symbicort Turbuhaler 80/4.5. The results supported equivalence of the two Vannair pMDI and Symbicort Turbuhaler formulations as regular treatment in both the ITT and per-protocol analyses. There was no statistically significant difference between the Vannair pMDI and Symbicort Turbuhaler formulations for any outcome variable in this study.
Study 715 investigated primarily the safety of Vannair pMDI 160/4.5 (2 inhalations twice daily) during 12 months. The reference treatment was the corresponding dose of Symbicort Turbuhaler 160/4.5 and in a population consisting of adults and adolescents (≥12 years) with moderate to severe asthma (eg mean FEV₁ of ≥50% of PN and FEV₁ reversibility ≥12%). The study was of an open-label design.
There was no statistically significant difference between Vannair pMDI and Symbicort Turbuhaler regarding FEV₁ and FVC (forced vital capacity). The percentage of patients experiencing one or more severe asthma exacerbations did not differ between the Vannair pMDI and Symbicort Turbuhaler groups: 11% in the Vannair pMDI group and 13% in the Symbicort Turbuhaler group. The maximum number of severe exacerbations per patient was 6 in the Vannair pMDI group and 4 in the Symbicort Turbuhaler group. There was no statistical significant difference in time to first severe asthma exacerbation between the two treatment groups.
COPD: The efficacy and safety of Vannair in the treatment of patients with moderate to severe COPD (pre-bronchodilator FEV₁ ≤50% predicted normal) has been evaluated in four randomised, double-blind, placebo and active controlled, parallel-group, multi-centre clinical studies. Two 12-month studies were performed with the dry powder inhaler Symbicort Turbuhaler (studies 629 and 670), and one 12-month and one 6-month study were performed with the pressurised metered dose inhaler (pMDI) Vannair pMDI (studies 001 and 002, respectively).
Studies 629 and 670: In both studies, Symbicort Turbuhaler 160/4.5 was compared with placebo and the corresponding mono-products (budesonide Turbuhaler 160 μg and formoterol Turbuhaler 4.5 μg), all taken as two inhalations twice daily. A total of 812 and 1022 patients with moderate to severe COPD were randomised, of which 208 and 254 were treated with Symbicort Turbuhaler. Patients in both studies had a mean age of 64 years and FEV₁ of 0.99 L or 36% of predicted normal at baseline.
Studies 001 and 002: The study plans were similar. Both studies used Vannair pMDI.
For Study 001, after a screening visit (visit 1), subjects entered a two weeks run-in period after which they were randomly assigned (visit 2) to one of the four following treatments: 1) Vannair pMDI 160/4.5, fixed combination of 160 μg budesonide and 4.5 μg formoterol per actuation, administered as 2 actuations twice daily; 2) Vannair pMDI 80/4.5, fixed combination of 80 μg budesonide and 4.5 μg formoterol per actuation, administered as 2 actuations twice daily; 3) Formoterol Turbuhaler, 4.5 μg per inhalation, administered as 2 actuations twice daily; 4) Placebo.
Study 002 had two additional treatment groups: 5) Budesonide pMDI 160 μg per actuation, administered as 2 actuations twice daily; 6) Free combination of budesonide pMDI 160 μg per actuation plus formoterol Turbuhaler 4.5 μg per actuation, administered as 2 actuations of each twice daily.
A total of 1964 (Study 001) and 1704 (Study 002) patients with moderate to severe COPD were randomised, of which 494 and 277 were treated with Vannair pMDI 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 629: In Study 629, efficacy was evaluated over 12 months using the co-primary endpoints of post-dose FEV₁ and number of severe COPD exacerbations (defined as intake of a course of oral steroids and/or antibiotics and/or hospitalisation due to respiratory symptoms).
Symbicort Turbuhaler significantly improved mean FEV₁ compared with placebo and budesonide by 15% (p<0.001) and 9% (p<0.001), respectively.
Symbicort Turbuhaler significantly reduced the number of severe exacerbations compared with placebo and formoterol by 24% (p=0.035) and 23% (p=0.043), respectively. The number needed to treat (NNT) to prevent one severe COPD exacerbation in a year for Symbicort Turbuhaler compared with formoterol was 2.4.
Study 670: In Study 670, efficacy was evaluated over 12 months using the co-primary endpoints of post dose-FEV₁ and time to first severe COPD exacerbation (defined as intake of a course of oral steroids and/or antibiotics and/or hospitalisation due to respiratory symptoms).
Symbicort Turbuhaler significantly improved mean FEV₁ compared with placebo, budesonide, and formoterol by 14% (p<0.001), 11% (p<0.001), and 5% (p=0.002), respectively.
Symbicort Turbuhaler significantly prolonged the time to first severe COPD exacerbation compared to all comparator treatments. The instantaneous risk of experiencing a severe COPD exacerbation compared to placebo, budesonide, and formoterol was reduced by 29% (p=0.006), 23% (p=0.033), and 30% (p=0.003), respectively.
Symbicort Turbuhaler also significantly reduced the number of severe COPD exacerbations compared to placebo and formoterol by 24% (p=0.029) and 26% (p=0.015), respectively. The NNT to prevent one COPD exacerbation in a year compared to formoterol was 2.1.
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.
Primary endpoints: Vannair pMDI 80/4.5 produced a significantly greater change in post-dose FEV₁ compared to placebo (LS mean = 0.16 L; p<0.001); however the change in pre-dose FEV₁ was not significantly different to formoterol 6 μg (LS mean = 0.02 L; p=0.161).
Vannair pMDI 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.
Vannair pMDI 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 Vannair pMDI 160/4.5 (N=121). Maximum improvement in FEV₁ occurred at approximately 2 hours post-dose and post-dose bronchodilator effect was maintained over 12 hours.
Exacerbations (secondary variable): Vannair pMDI reduced the number of severe COPD exacerbations (defined as a worsening of COPD requiring oral steroid use and/or hospitalisation) to a statistically significant degree. Overall 34.1% of subjects experienced 1159 exacerbations: Vannair pMDI 160/4.5, 30.8%; Vannair pMDI 80/4.5, 32.6%; placebo 37.2%. The majority of exacerbations were treated with oral glucocorticosteroids: Vannair pMDI 160/4.5, 96.5% of exacerbations; Vannair pMDI 80/4.5, 94.1%; placebo 97.4%. Treatment comparisons were by means of rate ratios (RR) estimates, CIs and p-values derived from a Poisson regression adjusted for treatment, country and differential treatment exposure. Vannair pMDI 160/4.5 demonstrated a statistically significant reduction of 37% (p<0.001) and 25% (p=0.004) in the rate of exacerbations per subject-treatment year compared with placebo and formoterol respectively. Vannair pMDI 80/4.5 reduced the exacerbation rate by 41% compared with placebo (p<0.001).
Vannair pMDI 160/4.5 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). The NNT to prevent one severe COPD exacerbation in a year for Vannair pMDI compared with formoterol was 5.4.
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.
Vannair pMDI 80/4.5: Post-dose FEV₁ increased significantly from baseline to the average of the treatment period (LS mean [95%CI] = 0.19 [0.17, 0.22]). Vannair pMDI 80/4.5 caused a significantly greater change from baseline compared to budesonide (LS mean = 0.16; p<0.001). Pre-dose FEV₁ increased significantly from baseline to the average of the treatment period, LS mean = 0.06 [0.03, 0.08]. However, the change from baseline, compared to formoterol, for pre-dose FEV₁ was not statistically significant, LS mean = 0.02 [-0.02, 0.05; p=0.335].
Vannair pMDI 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.
Vannair pMDI 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.
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 Vannair pMDI 160/4.5 (N=101). Maximal improvement in FEV₁ occurred at approximately 2 hours post-dose and post-dose bronchodilator effect was generally maintained over 12 hours.
Pharmacokinetics: The budesonide and formoterol bioavailability of Vannair pMDI and Symbicort Turbuhaler were similar after single doses containing 1280 μg budesonide and 36 μg formoterol (8 inhalations) in healthy adult volunteers. The budesonide and formoterol bioavailability from Vannair pMDI was also comparable with that from similar doses of the component products, Pulmicort (budesonide) Turbuhaler, Oxis (formoterol) Turbuhaler and a specially prepared budesonide HFA pressurised inhalation suspension.
There was no evidence of pharmacokinetic interactions between budesonide and formoterol.
Absorption: Inhaled budesonide is rapidly absorbed and the maximum plasma concentration is reached within 30 minutes after inhalation.
Inhaled formoterol is rapidly absorbed and the maximum plasma concentration is reached within 10 minutes after inhalation.
Distribution: Plasma protein binding is approximately 90% for budesonide and volume of distribution is 3 L/kg.
Plasma protein binding is approximately 50% for formoterol and volume of distribution is about 4 L/kg.
Metabolism: 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, 6β-hydroxy-budesonide and 16α-hydroxy-prednisolone is less than 1% of that of budesonide.
Formoterol is inactivated via conjugation reactions (active-0-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates).
Excretion: Budesonide is eliminated via metabolism mainly catalysed by the enzyme CYP3A4. The metabolites of budesonide are excreted 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 major part of a dose of formoterol is eliminated by metabolism in the liver followed by renal excretion. After inhalation of formoterol via a Turbuhaler, 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 terminal elimination half-life averages 17 hours.
Special patient populations - children, elderly patients, renal and/or hepatic impairment: The pharmacokinetics of budesonide or formoterol in children, elderly patients, and patients with renal failure is unknown. The systemic availability of budesonide and formoterol may be increased in patients with liver disease.
Toxicology: Preclinical safety data: Genotoxicity: Individually, budesonide and formoterol were not genotoxic in a series of assays for gene mutations (except for a slight increase in reverse mutation frequency in Salmonella typhimurium at high concentrations of formoterol), chromosomal damage, and DNA repair. The combination of budesonide and formoterol has not been tested in genotoxicity assays.
Carcinogenicity: The carcinogenic potential of the budesonide/formoterol combination has not been investigated in animal studies.
In formoterol carcinogenicity studies performed by AstraZeneca, there was a dose dependent increase in the incidence of uterine leiomyomas in mice dosed orally at 0.1, 0.5, and 2.5 mg/kg/day for 2 years, and a mesovarian leiomyoma was observed in a female rat dosed by inhalation at 0.13 mg/kg/day for 2 years. The effects observed are expected findings with high-dose exposure to β₂-agonists.
Formoterol carcinogenicity studies performed by other companies used systemic exposure levels 800 to 4800-fold higher than those expected upon clinical use of formoterol (based on an 18 μg daily dose).
Some carcinogenicity activity was observed in rats and mice. However, in view of the dose levels at which these effects were observed and the fact that formoterol is not mutagenic (except for very weak activity at high concentrations in one test system), it is concluded that the cancer risk in patients treated with formoterol fumarate is no greater than for other β₂-adrenoceptor agonists.
The carcinogenic potential of budesonide has been evaluated in the mouse and rat at oral doses up to 200 and 50 μg/kg/day respectively. In male rats dosed with 10, 25, and 50 μg budesonide/kg/day, those receiving 25 and 50 μg/kg/day showed an increased incidence of primary hepatocellular tumours. In a repeat study, this effect was observed in a number of steroid groups (budesonide, prednisolone, triamcinolone acetonide), thus indicating a class effect of corticosteroids.

Asthma: Vannair pMDI is indicated for the regular treatment of asthma where use of a combination (inhaled corticosteroid and long-acting β₂-agonist (LABA)) is appropriate in adults and adolescents. This includes: patients who are symptomatic on inhaled corticosteroid therapy; patients who are established on regular long acting β₂-agonist and inhaled corticosteroid therapy.
Chronic obstructive pulmonary disease (COPD): Vannair is indicated for the symptomatic treatment of moderate to severe COPD (FEV₁ ≤50% predicted normal) in adults with frequent symptoms despite long-acting bronchodilator use, and/or a history of recurrent exacerbations. Vannair is not indicated for the initiation of bronchodilator therapy in COPD.

Asthma: Vannair pMDI taken as regular maintenance treatment, with a separate rapid-acting bronchodilator as rescue. Patients should be advised to have their separate rapid-acting bronchodilator available for rescue use at all times.
Increasing use of rescue bronchodilators indicates a worsening of the underlying condition and warrants reassessment of the asthma therapy. The dosage of Vannair pMDI should be individualised according to disease severity. When control of asthma has been achieved, the dose should be titrated to the lowest dose at which effective asthma control is maintained.
Adults and adolescents (12 years and older): Vannair pMDI 80/4.5: 2 inhalations of Vannair pMDI 80/4.5 twice daily. The maximum recommended daily maintenance dose is 4 inhalations (2 inhalations twice daily corresponding to 320 μg budesonide / 18 μg formoterol).
Vannair pMDI 160/4.5: 2 inhalations of Vannair pMDI 160/4.5 twice daily. The maximum recommended daily maintenance dose is 4 inhalations (2 inhalations twice daily corresponding to 640 μg budesonide / 18 μg formoterol).
COPD - Adults: 2 inhalations of Vannair pMDI 160/4.5 twice daily. The maximum recommended daily dose is 4 inhalations (corresponding to 640 μg budesonide / 18 μg formoterol).
Special patient populations: Renal Impairment: There are no data available for use of Vannair pMDI in patients with renal impairment.
Hepatic Impairment: There are no data available for use of Vannair pMDI in patients with hepatic impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased systemic availability can be expected in patients with severe liver disease.
Elderly: There is no need to adjust the dose in elderly patients.
Use in paediatric patients: Vannair pMDI is not recommended for children below 12 years of age.
General information: For optimal benefit the patient should be instructed to take Vannair pMDI even when asymptomatic.

An overdose of formoterol may lead to effects that are typical for β₂-adrenergic agonists: tremor, headache, palpitations, and tachycardia. Monitoring of serum potassium concentrations may be warranted. Hypotension, metabolic acidosis, hypokalaemia, and hyperglycaemia may also occur. Supportive and symptomatic treatment may be indicated. β-blockers should be used with care because of the possibility of inducing bronchospasm in sensitive individuals. A metered dose of 120 μg administered during 3 hours in patients with acute bronchial obstruction raised no safety concerns.
Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. However, the plasma cortisol level will decrease and number and percentage of circulating neutrophils will increase. The number and percentage of lymphocytes and eosinophils will decrease concurrently. When used chronically in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.
Withdrawing Vannair pMDI or decreasing the dose of budesonide will abolish these effects, although the normalisation of the HPA‑axis may be a slow process.

Hypersensitivity to budesonide, formoterol, or any other ingredients present in this formulation.

This medicine should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.
This medicine should be used for the shortest duration of time required to achieve control of asthma symptoms. Once asthma control is achieved and maintained, patients should be regularly reassessed by their prescriber/health care provider so that the dosage of Vannair remains optimal.
When long-term control of symptoms is maintained with the lowest recommended dosage, then the next step, if possible, could include a discontinuation of Vannair and a test of inhaled corticosteroid alone.
Treatment of asthma or COPD should be in accordance with current national treatment guidelines.
Patients with asthma should have a personal asthma action plan designed in association with their general practitioner. This plan should incorporate a stepwise treatment regimen which can be instituted if the patients asthma improves or deteriorates. It is recommended that the dose is tapered when long-term treatment is discontinued and should not be stopped abruptly.
Sudden and progressive deterioration in control of asthma or COPD is potentially life threatening and the patient should undergo urgent medical assessment. In this situation, consideration should be given to the need for increased therapy with corticosteroids (eg a course of oral corticosteroids) or antibiotic treatment if a bacterial infection is present. Patients should be advised to seek medical attention if they find the treatment ineffective or they have exceeded the prescribed dose of Vannair.
Patients should be advised to have their rescue inhaler available at all times, eg a separate rapid-acting bronchodilator.
Vannair therapy should not be initiated to treat a severe exacerbation.
Oral corticosteroid usage: Vannair should not be used to initiate treatment with inhaled steroids in patients being transferred from oral steroids. Care should be taken when commencing Vannair treatment, particularly if there is any reason to suspect that adrenal function is impaired from previous systemic steroid therapy.
Potential systemic effects of inhaled corticosteroids: Inhaled steroids are designed to direct glucocorticoid delivery to the lungs in order to reduce overall systemic glucocorticoid exposure and side effects. However, in higher than recommended doses, inhaled steroids may have adverse effects; possible systemic effects of inhaled steroids include depression of the HPA axis, reduction of bone density, cataract and glaucoma, and retardation of growth rate in children and adolescents. In steroid-dependent patients, prior systemic steroid usage may be a contributing factor but such effects may occur amongst patients who use only inhaled steroids regularly.
HPA axis suppression and adrenal insufficiency: Dose-dependent HPA axis suppression (as indicated by 24‑hour urinary and/or plasma cortisol AUC) has been observed with inhaled budesonide, although the physiological circadian rhythms of plasma cortisol were preserved. This indicates that the HPA axis suppression represents a physiological adaption in response to inhaled budesonide, not necessarily adrenal insufficiency. The lowest dose that results in clinically relevant adrenal insufficiency has not been established. Very rare cases of clinically relevant adrenal dysfunction have been reported in patients using inhaled budesonide at recommended doses.
Clinically important disturbances of the HPA axis and/or adrenal insufficiency induced by severe stress (eg trauma, surgery, infection in particular gastroenteritis or other conditions associated with severe electrolyte loss) may be related to inhaled budesonide in specific patient populations. These are patients switched from oral corticosteroids (see Oral corticosteroid usage as previously mentioned) and patients administering concomitant medication metabolised by CYP3A4 (see Pharmacokinetic interactions under Interactions). Monitoring for signs of adrenal dysfunction is advisable in these patient groups. For these patients additional systemic glucocorticosteroid treatment should be considered during periods of stress, a severe asthma attack or elective surgery.
Bone density: Whilst corticosteroids may have an effect on bone mass at high doses, long‑term follow up (3 to 6 years) studies of budesonide treatment in adults at recommended doses, have not demonstrated a negative effect on bone mass compared to placebo, including a study conducted in patients with a high risk of osteoporosis. The lowest dose that does effect bone mass has not been established.
Bone-mineral density measurements in children should be interpreted with caution as an increase in bone area in growing children may reflect an increase in bone volume. In 3 large, medium-to-long-term (12 months to 6 years) studies in children (5 to 16 years), no effects on bone‑mineral density were observed after treatment with budesonide (189 to 1322 μg/day) compared to nedocromil, placebo, or age matched controls. However, in a randomised 18‑month paediatric study (n=176; 5 to 10 years), bone‑mineral density was significantly decreased by 0.11 g/cm² (p=0.023) in the group treated with inhaled budesonide via Turbuhaler, compared with the group treated with inhaled disodium cromoglycate. The dose of budesonide was 320 μg twice daily for 1 month, 160 μg twice daily for 5 months, and 80 μg twice daily for 12 months, and the dose of disodium cromoglycate 10 mg three times daily. The clinical significance of this result remains uncertain.
Growth: Limited data from long‑term studies suggest that most children and adolescents treated with inhaled budesonide will ultimately achieve their adult target height. However, an initial small but transient reduction of growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment. Physicians should closely follow the growth of children and adolescents taking long-term corticosteroids.
Rare individuals may be exceptionally sensitive to inhaled corticosteroids. Height measurements should be performed to identify patients with increased sensitivity. The potential growth effects of prolonged treatment should be weighed against the clinical benefit. To minimise the systemic effects of inhaled corticosteroids, each patient should be titrated to his/her lowest effective dose (see Dosage & Administration).
Visual disturbance: Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Infections / tuberculosis: Signs of existing infection may be masked by the use of high doses of glucocorticosteroids and new infections may appear during their use. Special care is needed in patients with active or quiescent pulmonary tuberculosis or fungal, bacterial, or viral infections of the respiratory system.
Sensitivity to sympathomimetic amines: In patients with increased susceptibility to sympathomimetic amines (eg inadequately controlled hyperthyroidism), formoterol should be used with caution.
Cardiovascular disorders: β₂-agonists have an arrhythmogenic potential that must be considered before commencing treatment for bronchospasm.
The effects of formoterol in acute as well as chronic toxicity studies were seen mainly on the cardiovascular system and consisted of hyperaemia, tachycardia, arrhythmias and myocardial lesions. These are known pharmacological manifestations seen after administration of high doses of β₂-adrenoceptor agonists.
Patients with pre-existing cardiovascular conditions may be at greater risk of developing adverse cardiovascular effects following administration of β₂-adrenoreceptor agonists. Caution is advised when formoterol is administered to patients with severe cardiovascular disorders such as ischaemic heart disease, tachyarrythmias, or severe heart failure.
Hypokalaemia: High doses of β₂-agonists can lower serum potassium by inducing a redistribution of potassium from the extracellular to the intracellular compartment, via stimulation of Na⁺/K⁺-ATPase in muscle cells.
Potentially serious hypokalaemia may result. Particular caution is advised in acute exacerbation as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatments (see Xanthine derivatives, mineralocorticosteroids, and diuretics under Interactions). Patients receiving digoxin are particularly sensitive to hypokalaemia. Serum potassium levels should therefore be monitored in such situations.
Diabetes: Due to the blood-glucose increasing effects of β₂-stimulants, extra blood glucose controls are initially recommended when diabetic patients are commenced on formoterol.
Pneumonia: Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. Pneumonia has been reported following the administration of inhaled corticosteroids. See Adverse Reactions.
Use in renal impairment: The effect of decreased kidney function on the pharmacokinetics of formoterol and budesonide are not known.
Use in hepatic impairment: The effect of decreased liver function on the pharmacokinetics of formoterol and budesonide are not known. As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver disease.
Effects on laboratory tests: No data available.
Effects on ability to drive and use machines: Driving or using machinery should be undertaken with caution until the effect of Vannair pMDI on the individual is established. Vannair pMDI does not generally affect the ability to drive or use machinery.
Use in Elderly: See Pharmacology: Pharmacodynamics: Clinical trials under Actions.
Use in Children: Vannair pMDI is not recommended for children under the age of 12 years because of lack of data on efficacy and safety.

Effects on fertility: There are no animal studies on the effect of the budesonide/formoterol combination on fertility.
Long-term treatment of female mice and rats with formoterol fumarate causes ovarian stimulation, the development of ovarian cysts, and hyperplasia of granulosa/theca cells as a result of the β-agonist properties of the compound. A study by another company showed no effect on fertility of female rats dosed orally with formoterol fumarate at 60 mg/kg/day for two weeks. This finding was repeated in an AstraZeneca study where no effect was seen on the fertility of female rats dosed orally with formoterol fumarate at 15 mg/kg/day for two weeks.
Testicular atrophy was observed in mice given formoterol fumarate in the diet at 0.2 to 50 mg/kg/day for 2 years, but no effect on male fertility was observed in rats dosed orally at 60 mg/kg/day for 9 weeks, in studies undertaken by another company.
Use in pregnancy - Category (Category B3): For the concomitant treatment with budesonide and formoterol, no clinical data on exposed pregnancies are available. Fetal malformations (umbilical hernia and cleft palate), typical of glucocorticoid toxicity in animals, occurred in rats dosed with the Vannair pMDI formulation at the inhaled dose of 12 μg/kg/day budesonide and 0.66 μg/kg/day formoterol, with plasma AUC values for both drugs below that expected in patients at the maximum recommended clinical dose. No teratogenic effect was detected at 2.5 μg/kg/day of budesonide and 0.14 μg/kg/day of formoterol.
Vannair pMDI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Only after special consideration should Vannair pMDI be used during the first 3 months and shortly before delivery.
Because β-agonists, including formoterol, may potentially interfere with uterine contractility due to a relaxant effect on uterine smooth muscle, Vannair pMDI should be used during labour only if the potential benefit justifies the potential risk.
Budesonide: Results from a large prospective epidemiological study and from world-wide post marketing experience indicate no adverse effects of inhaled budesonide during pregnancy on the health of the fetus/newborn child.
If treatment with glucocorticosteroids during pregnancy is unavoidable, inhaled corticosteroids such as budesonide should be considered due to their lower systemic effect. The lowest effective dose of budesonide to maintain asthma control should be used.
Formoterol: No teratogenic effects were observed in rats receiving formoterol fumarate at doses up to 60 mg/kg/day orally or 1.2 mg/kg/day by inhalation. Foetal cardiovascular malformations were observed in one study in which pregnant rabbits were dosed orally at 125 or 500 mg/kg/day during the period of organogenesis, but similar results were not obtained in another study at the same dose range. In a third study, an increased incidence of subcapsular hepatic cysts was observed in foetuses from rabbits dosed orally at 60 mg/kg/day. Decreased birth weight and increased perinatal/postnatal mortality were observed when formoterol fumarate was given to rats at oral doses of 0.2 mg/kg/day or greater during late gestation.
Use in lactation: Budesonide is excreted in breast milk. However, due to the relatively low doses used via the inhalational route the amount of drug present in the breast milk, if any, is likely to be low.
It is not known whether formoterol passes into human breast milk. In rats, formoterol was excreted into breast milk. There are no studies in lactating animals using the budesonide/formoterol combination. Increased postnatal mortality at maternal formoterol doses of 0.2 mg/kg/day PO or greater, and retardation of pup growth at 15 mg/kg/day PO were observed in a rat study. There are no well-controlled human studies using Vannair pMDI in nursing mothers. Because many drugs are excreted in human breast milk, administration of Vannair pMDI to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

Since Vannair pMDI contains both budesonide and formoterol, the same adverse effects as reported for these substances may be expected. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. The most common drug related adverse reactions are pharmacologically predictable side-effects of β₂-agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of commencing treatment.
In the clinical program comparing Vannair pMDI with Symbicort Turbuhaler, 679 adults and adolescents (Study 681 and Study 715) were exposed to Vannair pMDI 640/18 μg daily with a median duration of 359 days and a range of 1 to 427 days.
There were no apparent differences in the overall pattern of AE's between the Vannair pMDI and Symbicort Turbuhaler groups in the clinical program. The AEs were generally mild to moderate in intensity and the pattern was that usually seen in a population with persistent asthma and dominated by symptoms of upper respiratory events.
Overall, the AE profile was similar for patients receiving Vannair pMDI and Symbicort Turbuhaler with regard to total daily dose, age, sex, and ethnic group and no new safety concerns were identified with Vannair pMDI.
If oropharyngeal candidiasis develops, it may be treated with appropriate anti‑fungal therapy whilst still continuing with Vannair therapy. The incidence of candidiasis can generally be held to a minimum by having patients rinse their mouth out with water after inhaling their maintenance dose.
Adverse reactions, which have been associated with budesonide, formoterol, and Vannair, are given as follows. (See Table 4.)

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As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases.
Treatment with β-sympathomimetics may result in an increase in blood levels of insulin, free fatty acids, glycerol, and ketone bodies.
Pneumonia: The following table provides the incidence of pneumonia observed in the four pivotal phase III COPD studies (see Pharmacology: Pharmacodynamics: Clinical trials: COPD under Actions) for the Symbicort Turbuhaler or Vannair pMDI 160/4.5 and comparative placebo arms. (See Table 5.)

Click on icon to see table/diagram/image

In these placebo-controlled studies, the incidence of pneumonia was low, with no consistent evidence of increased risk of pneumonia for Symbicort/Vannair-treated patients compared to patients on placebo.
Reporting suspected adverse effects: Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are recommended to report any suspected adverse reactions to AstraZeneca.

Pharmacokinetic interactions: The metabolism of budesonide is primarily mediated by the enzyme CYP3A4. Inhibitors of this enzyme, eg ketoconazole, may therefore increase systemic exposure to budesonide. This is of limited clinical importance for short-term (1 to 2 weeks) treatment with ketoconazole, but should be taken into consideration during long-term treatment with ketoconazole or other potent CYP3A4 inhibitors.
Pharmacodynamic interactions: Neither budesonide nor formoterol have been observed to interact with any other drug used in the treatment of asthma or COPD.
β-receptor blocking agents: β-receptor blocking agents, especially those that are non-selective, may partially or totally inhibit the effect of β₂-agonists. These drugs may also increase airway resistance, therefore the use of these drugs in asthma patients is not recommended.
Other sympathomimetic agents: Other β-adrenergic stimulants or sympathomimetic amines such as ephedrine should not be given concomitantly with formoterol, since the effects will be cumulative. Patients who have already received large doses of sympathomimetic amines should not be given formoterol.
Xanthine derivatives, mineralocorticosteroids, and diuretics: Hypokalaemia may result from β₂-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, mineralocorticosteroids, and diuretics (see Hypokalaemia under Precautions).
Monoamine oxidase inhibitors, tricyclic antidepressants, quinidine, disopyramide, procainamide, phenothiazines, and antihistamines: The adverse cardiovascular effects of formoterol may be exacerbated by concurrent administration of drugs associated with QT-interval prolongation and increased risk of ventricular arrhythmia. For this reason, caution is advised when formoterol is administered to patients already taking monoamine oxidase inhibitors, tricyclic antidepressants, quinidine, disopyramide, procainamide, phenothiazines, or antihistamines associated with QT-interval prolongation (eg terfenadine, astemizole).

Instruction for correct use of Vannair pMDI: On actuation of the Vannair pMDI, a volume of the suspension is expelled from the canister at high velocity. When the patient inhales through the mouthpiece at the same time as actuating the inhaler, the substance will follow the inspired air into the airways.
NOTE: It is important to instruct the patient to: Carefully read the Instruction for correct use of Vannair pMDI.
Shake the inhaler well prior to each use to mix its contents properly.
Prime the inhaler by actuating it twice into the air when the inhaler is new, if it has not been used for more than one week or if it has been dropped.
Place the mouthpiece into the mouth. While breathing in slowly and deeply, press the inhaler firmly to release the medication. Continue to breathe in and hold the breath for approximately 10 seconds or as long as is comfortable. Shake the inhaler again and repeat this step for the second inhalation.
Rinse the mouth with water after inhaling the prescribed dose to minimise the risk of oropharyngeal thrush.
Clean the mouthpiece of the inhaler regularly, at least once a week with a clean dry cloth. Do not put the inhaler into water.
Special precautions for disposal: Always be sure to dispose of Vannair pMDI responsibly, since some of the medicine may remain inside it. The canister in Vannair pMDI contains a pressurized liquid. The canister should not be broken, punctured or burnt, even when it seems empty.
Incompatibilities: Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

The inhaler should be discarded within 3 months after removal from the foil pouch.

Antiasthmatic & COPD Preparations

R03AK07 - formoterol and budesonide ; Belongs to the class of adrenergics in combination with corticosteroids or other drugs, excluding anticholinergics. Used in the treatment of obstructive airway diseases.

P₁S₁S₃