Foracort Respules (Formoterol fumarate dihydrate plus Budesonide) Monograph

21 Jan, 13

Foracort Respules (Formoterol + Budesonide)
0.5Mg/1Mg
Deliver Benefits Of Ics + Laba With The Ease Of A Nebuliser

Understanding COPD

COPD (chronic obstructive pulmonary disease) is a major cause of chronic morbidity and mortality throughout the world. Many people suffer from this disease for years and die prematurely from it or its complications. It is currently the fourth leading cause of death in the world. It is predicted that by the year 2020, COPD will be the fifth most common cause of disability worldwide.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines has defined COPD as "a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients".

Worldwide, cigarette smoking and exposure to pollution resulting from burning of wood and other biomass fuels are the most important risk factors for COPD. Other risk factors include occupational exposure to dust and chemicals, environmental pollution and alpha₁ -antitrypsin deficiency.

The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person.

(Figure 1)

Figure 1: Mechanisms underlying airflow limitation in COPD

Inhaled cigarette smoke and other noxious particles cause pathological changes characteristic of COPD such as chronic inflammation and structural changes due to repeated injury and repair in the proximal airways, peripheral airways, lung parenchyma and pulmonary vasculature. There is a characteristic pattern of inflammation in the lungs of COPD patients, with increased numbers of neutrophils, macrophages and CD8+ lymphocytes.

Chronic inflammation causes structural changes and narrowing of the small airways. Destruction of the lung parenchyma leads to the loss of alveolar attachments to the small airways and decreases the lung elastic recoil which in turn diminishes the ability of the airways to remain open during expiration (Figure 1). Airflow limitation is best measured by spirometry because of its easy reproducibility.

Spirometry is essential for diagnosis and provides a useful description of the severity of pathological changes in COPD. Spirometric staging (Table 1) is a pragmatic approach towards the general indication to the initial management of COPD. Spirometry should be performed after the administration of an adequate dose of an inhaled bronchodilator in order to minimize variability.

Table 1: Spirometric classification of COPD severity, based on post-bronchodilator FEV₁

FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity

However, it must be borne in mind that the impact of COPD on an individual patient depends not just on the degree of airflow limitation, but also on the severity of symptoms such as chronic and progressive dyspnoea, cough and sputum production.

While disease prevention is the ultimate goal, once COPD has been diagnosed, effective management should be aimed at relieving symptoms, preventing disease progression, improving exercise tolerance, improving health status, preventing and treating complications as well as exacerbations and reducing mortality. The management plan for COPD involves assessing and monitoring the disease, reduction of risk factors through education and management of stable COPD as well as exacerbations through pharmacotherapy.

Pharmacotherapy in COPD

Pharmacotherapy for COPD is mainly used to decrease symptoms and/or complications. COPD is a progressive disease and treatment tends to be cumulative, with more medications being required as the disease state worsens. Regular treatment needs to be maintained at the same level for long periods of time and requires careful monitoring of the patient.

To date, the only interventions shown to prolong life in patients with COPD are smoking cessation and long-term oxygen therapy, although recent data indicate an association between increased survival and the use of inhaled glucocorticosteroids (ICS) alone or in combination with long-acting beta₂-agonists (LABAs). The current aims of pharmacotherapy in COPD are to prevent and control symptoms, reduce the frequency and severity of exacerbations, improve health status and improve exercise tolerance.

The combination of an ICS and a LABA is more effective than the individual components in reducing exacerbations and improving lung function and health status.

Role of the ICS/LABA Combination in COPD

Indications for the use of ICS/LABA in COPD patients are described in the various international guidelines. All guidelines acknowledge that regular treatment with ICS is appropriate for patients with symptomatic COPD and an FEV₁ <50% who experience repeated exacerbations. In order to assess the additive effect of combination treatment in patients with COPD, it is imperative to consider the effect of treatment at the molecular as well as clinical level.

Molecular Interactions and Clinical Impact of the Combination:

Figure 2: Rationale of ICS / LABA combination in COPD

It has been suggested that the LABA enhances the steroid receptor translocation within the macrophages and increases the anti-inflammatory activity of the steroid several-fold. Hence, while ICS themselves may not show significant anti-inflammatory activity when given with LABAs, airway biopsies and sputum studies demonstrate a reduction in inflammatory cells and markers. In patients, the combination of the two drugs has resulted in a significant reduction in exacerbations, and an improvement in lung function and quality of life compared to individual drugs. (Figure 2)

Budesonide/Formoterol Fumarate Combination in COPD

Four large randomized controlled trials evaluated the efficacy and safety of the budesonide/formoterol combination compared with budesonide, formoterol and placebo in patients with moderate-to-severe COPD and a history of at least one exacerbation within the 1 year prior to screening.

The duration of these studies ranged from 6 to 12 months, with the number of participants ranging from 812 to 1,964, and all studies included changes in the FEV₁ from baseline as one of the primary endpoints.

Demographic and baseline characteristics were very similar among the four trials (Table 2).

Table 2: Major inclusion criteria in pivotal studies of the budesonide/formoterol combination in COPD

Efficacy of the budesonide/ formoterol combination

Lung function: In all the four studies, the budesonide/formoterol combination, particularly at higher doses (320/9 mcg b.i.d. which is the delivered dose of 400/12 meg b.i.d.) improved the pre - as well as post-dose FEV₁ (Figures 3A and B).

Figure 3A and B: Change in lung function as depicted by pre- and post-dose FEV₁ in the four pivotal studies of the budesonide/formoterol combination

[Note: * Combination (denoted as BFC) significant compared with placebo (denoted as PLB); # Combination (BFC) significant compared with budesonide (denoted as B); $ Combination (BFC) significant compared with formoterol (denoted as F).]

Acute exacerbations of COPD: The reduction in COPD exacerbation rates observed with the budesonide/formoterol combination (320/9 mcg and 160/9 mcg) was beyond the reduction achieved with formoterol alone (9 mcg), thus further demonstrating the important contribution of the combination product (Figure 4).

Figure 4: Annual rate of acute exacerbations of COPD (requiring systemic steroid or hospitalization) in four pivotal studies of the budesonide/formoterol combination

Note: * Combination (denoted as BFC) significant compared with placebo (denoted as PLB); $ Combination (BFC) significant compared with formoterol (denoted as F).

Patient-reported outcomes: There have been only few studies that investigated the effects of the budesonide/formoterol combination on patient-reported outcomes. The following is a compilation of the results from these studies:

Most of these studies measured the quality of life using the Saint George's Respiratory Questionnaire (SGRQ) and reported an improvement in this parameter when compared with budesonide, formoterol and placebo.
A few of these studies also reported an improvement in the symptoms such as cough and breathlessness after budesonide/formoterol combination treatment when compared to the other treatment arms.
Rescue medication use was significantly decreased and rescue medication-free days were significantly increased with the use of the budesonide/formoterol combination when compared with the budesonide and placebo treatment arms (P<0.0001).
Budesonide/formoterol combination also significantly reduced the use of rescue medication by 0.8 inhalations per day compared with both the budesonide and placebo treatment arms (both P<0.001), and by 0.3 inhalations per day when compared with formoterol (P<0.05).
Budesonide/formoterol combination improved the night time awakenings score compared with placebo (mean change of 0.16 from run-in to the end of treatment period [P<0.004] in the night time awakening score). The combination also improved the sleep score and percentage of awakening-free nights when compared to placebo (P≤0.029).

Safety of the budesonide/formoterol combination:

The four large pivotal studies of the budesonide/formoterol combination described earlier evaluated the safety of the study medications. These studies did not detect clinically meaningful differences among the various study arms with regards to adverse events, mostly judged as being of mild-to-moderate intensity by the study physicians. In two out of these important studies, the common adverse events noted were nasopharyngitis (7.3% and 4.9%), oral candidiasis (6% and 1.8%), bronchitis (5.4% and 3.5%), sinusitis (3.5% and 1.8%) and viral respiratory tract infection (3.5% and 2.7%) in the budesonide/formoterol combination and placebo groups, respectively. Adverse event-related withdrawals ranged between 6.9% and 11.3% in patients receiving the budesonide/formoterol combination. No significant difference was detected in the incidence of pneumonia between the combination and placebo treatment arms.

Devices: A Neglected Aspect in COPD Management

Guidelines for COPD increasingly rely on the pharmacological management with inhaled drugs. The preference for the inhaled route is for reasons that include both efficacy and safety. Indeed, although COPD patients, especially those with severe disease, may require higher inhaled doses to penetrate the lung than patients with asthma, inhalation (as opposed to systemic administration) allows drug dosages to be kept relatively low while remaining sufficiently effective because the drug is delivered directly to the airways, the site of action.

Consequently, systemic availability and, therefore, the potential for extra-pulmonary side effects, is minimized due to the improved topical/systemic ratio afforded by the inhaled route, which is safer and better tolerated than oral administration. Furthermore, efficacious and safe administration of drugs may enhance patient adherence to the prescribed treatment.

However, effective use of inhalers requires a proper inhalation technique. Despite advancements in technology, which have permitted the introduction of more user-friendly devices, a recent cross-sectional, observational study with 1,664 patients affected mostly by COPD (52%) and asthma (42%), has shown that inhaler mishandling remains a serious issue for currently available inhalers, including DPIs (dry powder inhalers).

Previously, it had been suggested that it was easier to learn how to use a DPI as compared to a pMDI (pressurized metered dose inhaler). This same study observed that in real life, many patients do not receive any inhaler education and the rate of critical errors for DPIs was not lower than that of pMDIs. Independently of the type of inhaler used, the strongest association is between inhaler misuse and older age (P=0.008), lower schooling (P=0.001) and lack of instruction received for inhaler technique by health caregivers (P<0.001). More importantly, inhaler misuse was associated with increased risk of hospitalization (P=0.001), emergency room visits (P<0.001), courses of oral steroids (P<0.001) and antimicrobials (P<0.001) and poor disease control (P<0.0001).

In another study of 300 patients seen in pulmonology clinics, up to 43% of DPI users and 75% of pMDI users displayed incorrect inhaler technique.

Interestingly, the prevalence of COPD rises with age and the selection of inhaler devices for elderly patients is often complicated by cognitive, physical and educational challenges. Cognitive impairment is common in patients with COPD and is often related to comorbid conditions such as Alzheimer's disease, Parkinson's disease and stroke. Also, manual dexterity is affected by age-related osteoarthritis and neurologic conditions, and there is also evidence that up to one-third of older patients may lack the hand strength to generate the minimum force required to activate a pMDI device.

To learn the appropriate inhaler technique, written instructions alone are insufficient and yet up to 25% of patients may not receive oral instructions on inhaler use.

Many patients derive incomplete benefit from their inhaled medication because they do not use the devices correctly or they fail to maintain correct inhaler technique and this is clearly one of the major limitations to treatment.

Role of Nebulization in COPD

Nebulizers have been available in one form or another for over a century and are the easiest for the patients to use of all the aerosolized drug delivery systems, requiring minimum cognitive abilities and virtually no hand-breath coordination, manual dexterity or hand strength. They produce a fine mist of droplets that contains the active drug and may foster confidence in patients by providing visible evidence that they are receiving the medication. Nebulizers are a practical means of administering inhaled medications to patients who are unable to use other inhaler devices, such as the elderly and very young children. The principle advantages of nebulizer treatment are as follows:

Removes the need for patient coordination or effort.
Large dosages can be given.
In acute cases, when needed, oxygen may be used to deliver the drug.
Many patients prefer a nebulizer.

There is some controversy amongst respiratory physicians over the value of domiciliary nebulizer use for chronic lung conditions. Most recommendations for the assessment of the suitability of this form of treatment rely upon the response to lung function tests and reported improvements in exercise ability. Relatively little emphasis has been placed upon the patient view of this therapy.

A survey was conducted to examine the subjective views regarding domiciliary nebulizer therapy amongst patients who were receiving this treatment. A postal questionnaire was sent to 82 patients who had been prescribed home nebulizer therapy, in accordance with the British Thoracic Society (BTS) guidelines, at a respiratory clinic and 75 patients responded.

Table 3: Perceived advantages of nebulizer therapy

*P<0.05, Chi square

The main perceived advantages were the ability of patients to control their symptoms themselves and to be less dependent on their healthcare provider, or hospitals and carers. Compliance was generally excellent, and the reported side effects were minor and relatively infrequent. The questionnaire items were derived from the following ideas that came up in a patient support group as relevant to the quality of life: well-being and symptom control, self-confidence, dependency, and time and technical issues. The results of this survey are shown in Table 3.

Drawbacks included a feeling of dependency on the nebulizer and, as reported by some patients, treatment took up a lot of time.

Problems with maintenance of the equipment or technical difficulties were identified as another drawback, but seen only as a minor disadvantage of home nebulizer treatment. Most patients did not experience any problems with keeping their equipment clean.

Despite the fact that patients perceived some disadvantages of nebulizer therapy, overall, they overwhelmingly reported that the benefits of using a nebulizer at home outweighed the disadvantages (98% versus 2%). Thus approximately 56-91% of patients reported that nebulizer use conferred improved symptom control, well-being and self confidence despite the relatively long duration of administration, and device reliability and technical issues.

Another study which analysed seven different studies comparing various devices (i.e., nebulizer, pMDI, or MDI with spacer) showed that all three devices were equally effective. Although pMDIs were found more acceptable, patients felt that nebulizers were more effective.

The results strongly support the view that nebulizers are helpful in managing chronic lung disease in the community, resulting in benefits such as patient well-being and potential health-cost savings.

Patients with COPD who are unable or unwilling to use these hand-held devices may experience subjective and objective improvement with nebulizer therapy not apparent with pMDI/DPI therapy.

Proper breathing technique and repeated instruction can be problematic for older patients with COPD as well as for patients with recognized physical and/or cognitive limitations.

In elderly patients and those with severe COPD and disabling dyspnoea, delivering the total dose over several breaths by nebulizer may be more effective than delivery during a single breath by a DPI or pMDI.

Table 4 describes the various clinical scenarios where maintenance therapy through nebulization would be preferred in patients with COPD.

Table 4: Clinical scenarios where maintenance nebulizer therapy is preferred in patients with COPD

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Also, for some patients with COPD, the dual use of nebulizers and a pMDI/DPI may achieve the best combination of efficacy and convenience. However, to minimize confusion, clinicians should make efforts to employ a single platform for delivery of all inhaled medications. A nebulizer could fulfil this requirement for many patients with COPD.

Nebulized Budesonide and Formoterol

A) Rationale

The availability of budesonide plus formoterol in a respule form for nebulization now permits the extension of benefits of the ICS/LABA combination therapy to all patients, including those who are unable or unwilling to use hand-held inhaler devices. This will also include patients who are currently taking the beta₂-agonist and steroid by nebulization separately. A single respule will now be available for them to use twice daily.

B) Pharmacology

There are pharmacological studies which have compared both budesonide and formoterol in nebulized formulation with either pMDIs or DPIs in patients with asthma and COPD, respectively. Both dosage forms were found to be comparable in these studies, proving beyond doubt the equipotency of these drugs when delivered either by a pMDI and DPI or a nebulizer. The following is an account of the pharmacological properties of both formoterol and budesonide.

Formoterol

The pharmacological effects of beta₂-agonists, including formoterol, are at least partly attributable to their ability to activate intracellular adenyl cyclase, which stimulates the conversion of adenosine triphosphate to cyclic-3', 5'-adenosine monophosphate (cAMP) in bronchial smooth muscle cells. Increased cAMP causes relaxation of the smooth muscle and results in bronchodilation. The bronchodilator response to a given beta₂-agonist is determined by the amount of the drug in the vicinity of the beta₂-adrenergic receptor, the degree of which depends on the lipophilicity and chemical structure of the drug. The intrinsic efficacy of beta₂-agonists has also an important role in determining the clinical response to these agents.

Formoterol, unlike other bronchodilators, has physiochemical properties that provide a rapid onset and long duration of action. The lipophilicity of formoterol, like salmeterol, allows it to penetrate and be stored in smooth muscle cell membranes, resulting in a long duration of bronchodilatory action. Formoterol also has hydrophilic properties like salbutamol, which enables it to access and activate the beta₂-receptor rapidly and exert a rapid onset of action. Furthermore, in contrast to other existing beta₂-agonists, formoterol has a very high intrinsic efficacy at the beta₂-receptor.

Formoterol has a plasma protein binding of approximately 60% in in vitro studies and is metabolized primarily through direct glucuronidation. In healthy volunteers who received high-dose formoterol in through a DPI, the C_max of formoterol was observed within 5 minutes of dosing in the majority of subjects, indicating that formoterol is rapidly absorbed from the large and small airways after inhalation. The mean terminal half-life was 10 hours.

Budesonide

Budesonide is an inflammatory, synthetic corticosteroid. It is a non-halogenated corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. Budesonide is provided as the mixture of two epimers (22R and 22S). Corticosteroid actions in the human body are mediated by the glucocorticoid receptor (GR). This receptor is found in the cytoplasm of most cell types. Corticosteroids like budesonide have a wide range of inhibitory activities against many cell types, including lymphocytes, eosinophils, mast cells, neutrophils and macrophages.

Budesonide has a high topical potency and a low systemic bioavailability. The relative affinity of budesonide for the GR is higher compared with previously developed ICS. In standard in vitro tests and animal models, budesonide was found to have an approximately 200-fold higher affinity for the GR and a 1,000-fold higher topical anti-inflammatory potency than cortisol. Inhaled budesonide is a good medium of drug delivery as the compound is a moderately lipophilic agent, with rapid uptake into airway mucosa.

Tests performed showed that after oral administration of budesonide in healthy adults, the peak plasma concentration was reached within approximately 1-2 hours. Budesonide has a high affinity for the lungs, thereby increasing its usefulness as an inhaled medication and animal studies have shown that a substantial fraction of budesonide present in the lungs is bound to tissue components and is retained for an extended time period. It seems that budesonide fatty acid conjugates are formed and retained in the lungs on inhalation. Overall, the pharmacokinetic profile of inhaled budesonide allows for a long duration of local therapeutic effects in the lungs with minimal systemic exposure.

C) Clinical Studies of Nebulized Formoterol and Nebulized Budesonide in COPD

Studies evaluating the effects of both drugs given by nebulization independently have been published and demonstrated the safety and efficacy of both drugs.

Findings from a dose-ranging and pharmacokinetics/pharmacodynamics study in 47 COPD patients have confirmed that a 20 meg dose of nebulized formoterol was comparable to formoterol DPI (12 meg) and have demonstrated the dose -proportionality and linear kinetics of nebulized formoterol.

The efficacy of nebulized formoterol has been compared to the dry powder formulation of formoterol and placebo in a randomized, double-blind, double-dummy, 12-week trial. In this trial, the FEV₁ area under the curve at week 12 (AUC_0-12) was significantly improved by 185 ml with nebulized formoterol, compared to placebo (P<0.0001). The improvements in bronchodilation were observed right from day 1 of treatment and did not diminish over the 12 weeks of treatment (Figure 5).

Figure 5: Time course of mean FEV₁ response after first dose (day 1) and 12 weeks of treatment

FFIS: formoterol fumarate inhalation solution 20 pg b.i.d.; FA: formoterol fumarate DPI 12 μg b.i.d. Data expressed as LS means adjusted for baseline FEV¹. LS mean difference at each time point on day 1 and week 12, P≤ 0.0007 and FA versus placebo, ≤0.05.

Health-related quality of life improvements, as demonstrated by the total scores on the SGRQ as well as symptoms and impact scores, were observed with nebulized formoterol treatment, whereas formoterol DPI-treated participants only demonstrated improvements in the symptom scores (Figure 6).

Figure 6: Change from baseline in SGRQ scores (LS means) after 12 weeks of treatment. FFIS: formoterol fumarate inhalation solution 20 μg b.i.d.; FA: formoterol fumarate DPI 12 μg b.i.d. *P≤0.03 versus placebo, (---): clinically meaningful change.

In another study, the effect of twice-daily nebulized formoterol on pulmonary function was also compared to that of the four-times-daily pMDI combination of ipratropium/salbutamol in an open-label, crossover study. The study reported significantly higher mean morning pre-dose FEV₁ or trough with nebulized formoterol, greater patient satisfaction, greater perception amongst patients that medication reached the lungs and more control of their COPD as compared to the ipratropium/salbutamol combination after 2 weeks of treatment. Further sub-group analysis revealed greater satisfaction with nebulized formoterol in patients who were older, male or had a more severe disease as compared to the ipratropium/salbutamol combination.

D) Clinical Studies of Nebulized Formoterol and Nebulized Budesonide in Asthma

Formoterol (as a LABA) is used in combination with budesonide (as a controller) in the regular treatment of moderate-to-severe persistent asthma.

The equipotency between budesonide pMDI (800 mcg b.i.d.) administered via a large volume spacer and nebulized budesonide suspension (1 mg and 4 mg b.i.d.) was demonstrated in a double-blind, double-dummy, crossover, 4-week study with 26 adult asthmatics. Spirometry assessments at the clinic revealed no statistically significant difference between the treatment groups. Also, the consistent trend in the symptom scores, peak expiratory flow (PEF) and rescue medication use demonstrated that the nebulizer regimes were as efficient as or more efficient than a pMDI plus spacer (Figures 7 and 8).

Figure 7: Symptoms scores versus the nominal dose of budesonide. Red bars: 800 mcg pMDI plus spacer b.i.d.; Blue bars: 1 mg nebulized budesonide b.i.d.; Green bars: 4 mg nebulized budesonide b.i.d.

Figure 8: PEF, morning and evening, as well as the use of rescue medication versus the nominal dose of budesonide. Red bars: 800 mcg pMDI plus spacer b.i.d.; Blue bars: 1 mg nebulized budesonide b.i.d.; Green bars: 4 mg nebulized budesonide b.i.d.

Additionally, evidence from another double-blind, double-dummy, crossover study suggests that budesonide inhalation suspension is effective in patients whose asthma is not controlled on moderate dosages of ICS.

In a double-blind, randomized controlled trial with 26 adults with moderate-to-severe unstable asthma not controlled by ICS and beta₂-agonists, and treated with 4 weeks of either nebulized budesonide (1 mg and 4 mg) twice daily or budesonide pMDI (0.8 mg twice daily) with spacer, significant improvements in asthma symptoms (P<0.05) as well as morning and evening PEF (P<0.01) were noted in the 4 mg twice-daily nebulized budesonide group, compared with the pMDI plus spacer device (Figure 9).

Figure 9: Morning and evening PEF during twice-daily treatment with budesonide nebulizing solution 1 mg or 4 mg, or budesonide 800 mcg via pMDI with spacer in patients with moderate-to-servere unstable asthma

Several small studies suggest that budesonide inhalation suspension has an oral steroid-sparing effect in adult patients with persistent asthma. A subsequent non-comparative 12-week study in 42 oral corticosteroid-dependent adults (patients were receiving ≥10 mg/day of prednisolone or equivalent) with an FEV₁ ≤50% of predicted showed that the addition of nebulized budesonide 2 mg/day allowed 23 patients (55%) to reduce their prednisolone dose by a mean of 59%. In addition to oral corticosteroids, these patients were also using ICS 2 mg/day plus nebulized beta₂-agonist bronchodilators at study enrolment. A reduction was seen in the prednisolone dose within 3-4 weeks of starting budesonide; most of the prednisolone dose reductions occurred by the fifth or sixth week of budesonide treatment and were maintained for the remainder of the 12 weeks. Lung function as assessed by the PEF was maintained throughout the 12-week study and asthma symptom scores decreased significantly from baseline (P<0.01).

E) Safety

In a pivotal safety and efficacy study with nebulized formoterol, the incidence of adverse events was similar across treatment groups (51-60%), with the number of respiratory events, including COPD exacerbations, trending higher in the placebo group. The most frequently reported adverse events were as follows:

There were no deaths or drug-related serious adverse events, and the discontinuations from adverse events occurred in 3.3%, 3.5% and 8.8% of participants in the nebulized formoterol, dry powder formoterol and placebo groups, respectively.

Long-term safety was assessed in 569 participants in a 52-week, active-control, open-label, safety study. Most participants treated with nebulized formoterol (86%) completed at least 6 months of treatment compared with 88% treated with dry powder formoterol. Comparable numbers of nebulized formoterol and dry powder formoterol participants experienced at least one adverse event (Table 5), most of which were mild or moderate. There was no significant difference between the formoterol administered by dry powder and nebulization in terms of serious adverse events, discontinuations or deaths.

Table 5: Treatment-emergent adverse events reported in ≥3% of participants in either group

In the nebulized formoterol group, mean changes from baseline to week 52 for serum glucose and potassium were 0.4 mg/dL and 0.0 mEq/L, respectively. The incidence of clinically significant changes in laboratory values was low in each group.
Cardiac effects of formoterol fumarate inhalation solution treatment were monitored carefully in the 12-week pivotal study. Although patients were excluded from the trial if they had an unstable cardiac condition, recent myocardial infarction or QTc interval >0.46 ms, approximately 50% of the enrolled patients demonstrated cardiac abnormalities on screening ECGs, which was similar across treatment groups. The underlying co-morbidities associated with COPD, including increased incidence of cardiovascular disease, are confounding factors in any analysis of COPD treatment. As many as half of the COPD patients may have undiagnosed atrial tachycardia and one-fifth may have heart failure. Neither nebulized formoterol nor dry powder formoterol treatment had clinically meaningful effects on the mean or maximum heart rate or incidence of ventricular premature beats found with 24-hour Holter monitoring. The incidence of arrhythmic events was also similar across groups and did not increase significantly throughout the study. ECG measurements demonstrated that mean changes from baseline in heart rate, PR interval, QRS complex, QT interval, and R-R interval were comparable among the treatment groups at each time point. The proportions of participants who had a mean maximum change in the QTc of ≥60 ms at any time during the study were also comparable among groups.
Cardiovascular safety was also monitored in the 52-week study with ECGs at baseline, week 10 and week 52 (or early termination). Effects were small and comparable between treatment groups.

For nebulized budesonide, the equipotency study of nebulized budesonide (1 mg and 4 mg b.i.d.) versus inhaled budesonide through pMDI (800 mcg b.i.d.) plus spacer demonstrated, as expected, a dose-related suppression of plasma cortisol determined prior to the morning administration of the drug regimens (Figure 10).

Figure 10: Plasma Cortisol versus the nominal dose of budesonide. Red bars: 800 mcg pMDI plus spacer b.i.d.; Blue bars: 1 mg nebulized budesonide b.i.d.; Green bars: 4 mg nebulized budesonide b.i.d.

The plasma cortisol level was significantly lower during the treatment with 4 mg budesonide suspension b.i.d. as compared to pMDI 800 mcg b.i.d. The 2-hour AUC obtained from pooled plasma budesonide concentrations after treatment effect with specified drug regimens showed a similar dose-effect relationship (Figure 11).

Figure 11: Plasma budesonide versus the nominal dose of budesonide. Red bars: 800 mcg pMDI plus spacer b.i.d.; Blue bars: 1 mg nebulized budesonide b.i.d.; Green bars: 4 mg nebulized budesonide b.i.d.

Keeping these results in mind, the study suggested that the systemically available dose of budesonide is mainly attributable to the lung deposition from which budesonide is completely absorbed whereas efficient first-pass metabolism assures only marginal systemic bioavailability of the swallowed fraction of budesonide. Furthermore, the swallowed fraction of budesonide is probably not increased from nebulizer administration as compared to pMDI plus spacer administration. The dose-related plasma levels of budesonide and cortisol regardless of device, therefore, point to comparable lung deposition from the two delivery systems and, hence, the apparent clinical equipotency between nebulized budesonide and budesonide through a pMDI plus spacer.

In adult patients with both oral corticosteroids and ICS-dependent asthma, 12-weeks' treatment with budesonide inhalation suspension as a substitute for the ICS, in conjunction with reduced doses of oral prednisolone, resulted in the resolution of adverse effects in 9 of 37 (24%) patients studied. The incidence of purpura, moon face, skin thinning and weight gain were reduced overall. Treatment-emergent adverse events were reported in 23 of 37 patients (62%); the vast majority was musculoskeletal or respiratory in nature, which is consistent with systemic corticosteroid withdrawal.

Place in Therapy

Keeping the above points in mind, the nebulized combination of budesonide/formoterol would be of great benefit to not just patients but also physicians who want to prescribe this well-known and beneficial combination without causing any inconvenience to COPD and asthma patients with regards to inhalation therapy. The combination of budesonide/formoterol in nebulized form would be the most useful in various clinical situations such as the following:

Elderly patients, particularly those over 65 years of age
Patients with severe disease low inspiratory flow rate
Patients who have physical and/or cognitive limitations
When higher doses of the budesonide/formoterol combination are required
Patients who prefer nebulized therapy over other inhalers
Patients admitted in wards post exacerbations

In fact, this combination is currently the only ICS/LABA combination available for inhalation in not just a nebulized formulation but also a pMDI (including a breath-actuated inhaler) and dry powder formulation, thus allowing a physician and the patient to decide as a team as to which delivery system is the best for them.

Prescribing Information

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only Formoterol Fumarate Dihydrate and Budesonide Respules

FORACORT

Composition

FORACORT 0.5 mg Respules
Formoterol fumarate......20 mcg
Budesonide.................0.5 mg

FORACORT 1 mg Respules
Formoterol fumarate............20 mcg
Budesonide....................... 1 mg

Dosage Form

Suspension for inhalation via a nebulizer

Description

FORACORT Respules are a combination of budesonide, a potent glucocorticoid, and formoterol fumarate, a selective, long-acting beta₂-adrenoceptor-agonist (beta₂-agonist [LABA]).

Budesonide is a potent glucocorticoid that binds with high affinity to the glucocorticoid receptor. It has a high ratio of topical to systemic activity.

Formoterol fumarate is a very potent LABA with a high intrinsic activity and a rapid onset of action.

Pharmacology

Pharmacodynamics
FORACORT Respules contain an aqueous suspension of budesonide and formoterol fumarate, both of which have different effects on the clinical, physiological and inflammatory indices of asthma.

Budesonide
Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1,000-fold higher topical anti-inflammatory potency than cortisol.

In glucocorticoid-receptor affinity studies, the 22R form of budesonide was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.

Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Studies in asthmatic patients have shown a favourable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of budesonide. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first-pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites.

Formoterol Fumarate
Formoterol fumarate is a selective LABA. Inhaled formoterol fumarate dihydrate acts locally in the lungs as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta₂-receptors than at beta₁-receptors. Although beta₂-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta₁-receptors are the predominant receptors in the heart, there are also beta₂-receptors in the human heart comprising 10-50% of the total beta-adrenergic-receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta₂-agonists may have cardiac effects.

The pharmacological effects of beta₂-adrenoceptor-agonist drugs, including formoterol, are at least in part attributable to the stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lungs. Formoterol also inhibits histamine-induced plasma albumin extravasation in anaesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans with chronic obstructive pulmonary disease (COPD) is unknown.

Pharmacokinetics
Budesonide is primarily cleared by the liver. In asthmatic children, 4 to 6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight. Also, after a single dose of 1 mg budesonide, a peak plasma concentration of 2.6 nmol/L was obtained approximately 20 minutes after nebulization. Moreover, the exposure (AUC) of budesonide, following administration of a single 1 mg dose of budesonide by nebulization, is comparable to healthy adults given a single 2 mg dose by nebulization.

Information on the pharmacokinetics of formoterol (dry powder and/or inhalation solution) in plasma and/or urine is available in healthy subjects as well as patients with COPD after oral inhalation of doses at and above the therapeutic dose. Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar.

Absorption

Budesonide
In asthmatic children, 4 to 6 years of age, the total absolute bioavailability (i.e., lungs plus oral) following administration of budesonide respules via a jet nebulizer was approximately 6% of the labelled dose. The peak plasma concentration of budesonide occurred 10-30 minutes after the start of nebulization.

Formoterol Fumarate
Pharmacokinetic properties of formoterol fumarate were evaluated in 12 COPD patients following inhalation of single doses of formoterol inhalation solution containing 10, 20 and 244 mcg of formoterol sis) and 12 mcg formoterol fumarate dry powder, through 36 hours after single-dose administration. Formoterol fumarate concentrations in plasma following the 10 mcg and 20 mcg doses of formoterol inhalation solution and the 12 mcg dose of formoterol fumarate dry powder were undetectable or only detected sporadically at very low concentrations. Following a single 244 mcg dose of formoterol inhalation solution (approximately 12 times the recommended clinical dose), formoterol fumarate concentrations were readily measurable in plasma, exhibiting rapid absorption into plasma, and reaching a maximum drug concentration of 72 pg/mL within approximately 12 minutes of dosing. The mean amount of formoterol excreted unchanged in 24-hour urine following single oral inhalation doses of 10, 20 and 244 mcg formoterol inhalation solution were found to be 109.7 ng, 349.6 ng and 3317.5 ng, respectively. These findings indicate a near dose-proportional increase in systemic exposure within the dose range tested. When 12 mcg of a dry powder formulation of formoterol fumarate was given twice daily to COPD patients by oral inhalation for 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol, was 1.19 to 1.38. This suggests some accumulation of formoterol in plasma with multiple dosing. Although multiple-dose pharmacokinetic data is unavailable from formoterol inhalation solution, assumption of linear pharmacokinetics allows a reasonable prediction of minimal accumulation based on single-dose pharmacokinetics. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract.

Distribution

Budesonide
In asthmatic children, 4 to 6 years of age, the volume of distribution of budesonide at the steady state was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85-90% bound to plasma proteins, the degree of binding being constant over the concentration range (1 to 100 nmol/L) achieved with, and exceeding, recommended doses. Budesonide showed little or no binding to corticosteroid-binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration-independent manner, with a blood/plasma ratio of about 0.8.

Formoterol Fumarate
The binding of formoterol to human plasma proteins in vitro ranged from 61% to 64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31% to 38% over a range of 5 to 500 ng/mL The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 244 mcg dose of formoterol inhalation solution.

Metabolism

Budesonide
In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized in the liver. Two major metabolites, formed via the cytochrome P450 (CYP450) isoenzyme 3A4 (CYP3A4)-catalysed biotransformation, have been isolated and identified as 16-alpha-hydroxyprednisolone and 6-beta-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the In vitro and In vivo metabolic patterns has been detected. Negligible metabolic inactivation was observed in the human lungs and in serum preparations.

Formoterol Fumarate
Formoterol fumarate is metabolized primarily by direct glucuronidation at either the phenolic 2'- or aliphatic-hydroxyl group, and O-demethylation followed by glucuronide conjugation at either phenolic 2'-hydroxyl groups. Minor pathways involve sulphate conjugation of formoterol and deformylation followed by sulphate conjugation. The most prominent pathway involves direct conjugation at the phenolic 2'-hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. In vitro studies showed that multiple drug-metabolizing enzymes catalyse glucuronidation (UGT1A1, 1A8, 1A9, 2B7 and 2B15 were the most predominant enzymes) and O-demethylation (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) of formoterol. Formoterol fumarate did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. It has not been adequately explored as to whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects.

Excretion

Budesonide
Budesonide is excreted in the urine and the faeces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine.

Formoterol Fumarate
Following administration, via a nebulizer, of single 10, 20 and 244 mcg formoterol inhalation solution doses (calculated on an anhydrous basis) in 12 COPD patients, on average, about 1.1% to 1.7% of the dose was excreted in the urine as unchanged formoterol as compared to about 3.4% excreted unchanged following inhalation administration of 12 mcg of formoterol fumarate dry powder. Renal clearance of formoterol following inhalation administration of formoterol inhalation solution in these subjects was about 157 mL/min. Based on plasma concentrations measured following the 244 mcg dose, the mean terminal elimination half-life was determined to be 7 hours.

Special Populations

Geriatric, Paediatric and Hepatic/Renal Impairment
The pharmacokinetics of FORACORT Respules has not been studied in elderly and paediatric patient populations and in subjects with renal impairment. There are no data regarding the specific use of the FORACORT Respules in patients with hepatic impairment. But since formoterol and budesonide are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver impairment.

Indications

FORACORT Respules are indicated in the regular treatment of asthma, where the use of a combination (LABA and inhaled corticosteroid [ICS]) has been found to be appropriate.

They are also indicated in the regular treatment of moderate-to-severe COPD, with frequent symptoms and a history of repeated exacerbations despite regular therapy with long-acting bronchodilators.

Dosage and Administration

Asthma

Adults
FORACORT 0.5/1 mg Respules
One respule twice a day.

COPD

FORACORT 1 mg Respules
One respule twice a day.

Contraindications

Hypersensitivity to any ingredient of the formulation.

Warnings and Precautions

If patients find the treatment ineffective, or exceed the highest recommended dose of FORACORT Respules, medical attention must be sought. Sudden and progressive deterioration in the control of asthma 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, e.g., a course of oral corticosteroids, or antibiotic treatment if an infection is present. Patients should be advised to have their rescue inhaler available at all times.

Patients should be reminded to take their FORACORT Respules maintenance dose as prescribed, even when asymptomatic.

The prophylactic use of FORACORT Respules, e.g., before exercise, has not been studied. For such use, a separate rapid-acting bronchodilator should be considered.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of FORACORT Respules. It is recommended that the dose is tapered when the treatment is discontinued and should not be stopped abruptly. Regular review of patients as treatment is stepped down is important. The lowest effective dose of FORACORT Respules should be used.

Patients should not be initiated on FORACORT Respules during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

Serious asthma-related adverse events and exacerbations may occur during treatment with FORACORT Respules. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with FORACORT Respules.

As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. FORACORT Respules should then be discontinued; treatment should be re-assessed and alternative therapy instituted if necessary. Systemic effects may occur with any ICS, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, and cataract and glaucoma. It is recommended that the height of children receiving prolonged treatment with ICS is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of ICS. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition consideration should be given to referring the patient to a paediatric respiratory specialist.

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 in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.

Long-term studies with inhaled budesonide in children at mean daily doses of 400 micrograms (metered dose) or in adults at daily doses of 800 micrograms (metered dose) regarding the effect of formoterol/budesonide at higher doses is available. If there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy, care should be taken when transferring patients to FORACORT Respules therapy.

The benefits of inhaled budesonide therapy would normally minimize the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high-dose emergency corticosteroid therapy in the past or prolonged treatment with high doses of ICS may also be at risk. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery. To minimize the risk of oropharyngeal Candida infection, the patient should be instructed to rinse their mouth out with water after inhaling the maintenance dose. In some cases, facial skin irritation has occurred when a nebulizer with a face mask has been used. To prevent such irritation, the face should be washed after using the face mask.

FORACORT Respules should be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure. Caution should be observed when treating patients with prolongation of the QTc interval. Formoterol fumarate itself may induce prolongation of the QTc interval, and increase pulse rate and systolic/diastolic blood pressure.

The need for, and the dose of, ICS should be re-evaluated in patients with active or quiescent pulmonary tuberculosis, or fungal and viral infections in the airways.

Potentially serious hypokalaemia may result from high doses of beta₂-agonists. Concomitant treatment of beta₂-agonists with drugs which can induce hypokalaemia or potentiate a hypokalaemic effect, e.g., xanthine-derivatives, steroids and diuretics, may add to a possible hypokalaemic effect of the beta₂-agonist. Particular caution is recommended in unstable asthma with variable use of rescue bronchodilators, in acute severe asthma as the associated risk may be augmented by hypoxia, and in other conditions when the likelihood for hypokalaemia adverse effects is increased. It is recommended that serum potassium levels are monitored during these circumstances. As for all beta₂-agonists, additional blood glucose controls should be considered in diabetic patients.

Drug Interactions

Pharmacokinetic Interactions
The metabolic conversion of budesonide is impeded by substances metabolized by CYP450 3A4 (e.g., itraconazole, ketoconazole, ritonavir). The concomitant administration of these potent inhibitors of CYP450 3A4 may increase plasma levels of budesonide. The concomitant use of these drugs should be avoided unless the benefit outweighs the increased risk of systemic side effects. At recommended doses, cimetidine had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

In patients using potent CYP3A4 inhibitors, FORACORT Respules are not recommended.

Pharmacodynamic Interactions

Concomitant use of other beta-adrenergic drugs can have a potentially additive effect. Hypokalaemia may increase the disposition towards arrhythmias in patients who are treated with digitalis glycosides.

Beta-adrenergic blockers can weaken or inhibit the effect of formoterol. FORACORT Respules should, therefore, not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons. In such cases, cardioselective beta-blockers could be considered, although they should be administered with caution.

Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors and tricyclic antidepressants can prolong the QTc interval and increase the risk of ventricular arrhythmias.

In addition, L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta₂-sympathomimetics.

Caution is advised in the co-administration of beta-agonists with non-potassium-sparing diuretics (such as loop or thiazide diuretics) as these may acutely worsen the electrocardiogram (ECG) changes and/or hypokalaemia.

Concomitant treatment with xanthine derivatives or steroids may potentiate any hypokalaemic effect.

There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.

Budesonide and formoterol have not been observed to interact with any other drugs used in the treatment of asthma.

Pregnancy

There are no adequate data from the use of formoterol and budesonide in pregnant women.

Administration of FORACORT Respules in pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used.

Lactation

Budesonide is excreted in breast milk. However, at therapeutic doses, no effects on the breastfeeding child are anticipated. It is not known whether formoterol passes into human breast milk. Administration of FORACORT Respules 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.

Paediatric Use

The growth of paediatric patients receiving ICS orally, including FORACORT Respules, should be monitored. If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of ICS given orally, including FORACORT Respules, each patient should be titrated to the lowest strength that effectively controls his/her asthma.

Geriatric Use

No overall differences in safety were observed between these patients and younger patients. As with other products containing beta₂-agonists, special caution should be observed when using FORACORT Respules in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta₂-agonists.

Undesirable Effects

Since FORACORT Respules contains both budesonide and formoterol, the same pattern of undesirable effects as reported for these substances may occur. 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 beta₂-agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment.

The common side effects observed in clinical trials with budesonide inhalation suspension and occurring at the incidence of ≥3% as compared to placebo were as follows: respiratory infection, rhinitis, coughing, otitis media, viral infection, moniliasis, gastroenteritis, vomiting, diarrhoea, abdominal pain, ear infection, epistaxis, and conjunctivitis and rash.

Following are some common, uncommon and rare adverse events that occurred in the groups receiving formoterol/budesonide inhaler and formoterol and budesonide nebulizing preparations:

Cardiac Disorders:
Palpitations, tachycardia, cardiac arrhythmias, e.g., atrial fibrillation, supraventricular tachycardia, extrasystoles, angina pectoris.

Endocrine Disorders:
Signs or symptoms of systemic glucocorticosteroid effects, e.g., adrenal suppression, growth retardation, decrease in bone mineral density, cataract and glaucoma, hypocorticism and hypercorticism.

Gastrointestinal Disorders:
Nausea, diarrhoea, vomiting.

Immune System Disorders:
Immediate and delayed hypersensitivity reactions, e.g., exanthema, urticaria, pruritus, dermatitis, angio-oedema and anaphylactic reactions, eye infection, herpes simplex, external ear infection, infection, bronchospasm.

Infections and Infestations:
Candida infections in the oropharynx, sinusitis, pharyngitis, bronchitis.

Metabolic and Nutrition Disorders:
Hypokalemia, hyperglycaemia, anorexia.

Musculoskeletal, connective tissue and bone disorders:
Muscle cramps, myalgia, avascular necrosis of the femoral head, osteoporosis, growth suppression.

Nervous System Disorders:
Headache, tremor, dizziness, taste disturbances, hyperkinesia.

Psychiatric Disorders:
Agitation, restlessness, nervousness, sleep disturbances, depression, behavioural disturbances (mainly in children), psychosis, anxiety, irritability, aggressive reactions.

Respiratory, Thoracic and Mediastinal Disorders:
Mild irritation in the throat, dry mouth, coughing, hoarseness, bronchospasm, nasopharyngitis, chest pain, dysphonia, stridor.

Skin and Subcutaneous Tissue Disorders:
Bruises, facial skin irritation, urticaria, rash, dermatitis, pruritus, purpura.

Vascular Disorders:
Variations in blood pressure.

Blood and Lymphatic System Disorders:
Cervical lymphadenopathy.

Ear and Labyrinth Disorders:
Earache.

General Disorders and Administration Site Conditions:
Fatigue, flu-like disorder, fever, pain.

Injury, Poisoning and Procedural Complication:
Fracture.

As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases.

Treatment with beta₂-agonists may result in an increase in the blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Overdosage

An overdose of formoterol would likely lead to effects that are typical for beta₂-adrenergic agonists: Tremor, headache, palpitations, muscle cramps, dry mouth, nausea, dizziness, fatigue, malaise, insomnia, tachycardia, hyperglycaemia, hypokalaemia, prolonged QTc interval, angina, hypertension or hypotension, arrhythmia and vomiting. Supportive and symptomatic treatment may be indicated. A dose of 90 micrograms 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. When used continually in excessive doses, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression, may appear.

If FORACORT Respules therapy has to be withdrawn due to overdose of the formoterol component of the drug, provision of appropriate ICS therapy must be considered.

Shelf-Life

See on the pack.

Storage and Handling Instructions

Store in the protective foil pouch under refrigeration at 2°-8°C.

Packaging Information

FORACORT Respules 0.5/1 mg.......... Pack of 20 respules

Compatibility with Other COPD Drugs for Co-Administration

FORACORT Respules are compatible with other COPD drugs in a nebulized form, such as ambroxol (Inhalex Respules), N-acetylcysteine (Mucinac Respules) and ipratropium bromide (Ipravent Respules) for co-administration.

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