Eirbufo forspiro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EIRBUFU FORSPIRO (AIRBUFO® FORSPIRO®)

Composition:

Active substances: budesonide, formoterol fumarate dihydrate;

One dose contains 160 mcg budesonide and 4.5 mcg formoterol fumarate dihydrate or 320 mcg budesonide and 9 mcg formoterol fumarate dihydrate;

Excipient: lactose monohydrate.

Pharmaceutical form. Powder for inhalation, metered.

Main physicochemical properties: powder from white to almost white or light yellow in color, free from agglomerates.

Pharmacotherapeutic group. Adrenergic agents in combination with corticosteroids or other drugs, excluding anticholinergic agents. Formoterol and budesonide.

ATC code R03AK07.

Pharmacological Properties

Pharmacodynamics

Mechanisms of Action and Pharmacodynamic Effects

The medicinal product Eurbufo Forspiro contains formoterol and budesonide, which have different mechanisms of action and exhibit an additive effect in reducing the frequency of asthma exacerbations. The mechanisms of action of both compounds are described below.

Budesonide

Budesonide is a glucocorticosteroid that, when administered by inhalation, exerts a dose-dependent anti-inflammatory action in the airways, leading to a reduction in symptoms and decreased frequency of asthma exacerbations. Inhaled budesonide causes fewer adverse reactions than systemic corticosteroids. The precise mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.

Formoterol

Formoterol is a selective β2-adrenergic agonist that, when administered by inhalation, induces rapid and prolonged relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The bronchodilating effect is dose-dependent, with onset of action within 1–3 minutes after inhalation. The duration of effect lasts at least 12 hours after a single dose.

Clinical Efficacy and Safety

Bronchial Asthma

Clinical studies in adult patients have shown that adding formoterol to budesonide improves asthma symptoms, enhances lung function, and reduces the frequency of exacerbations. In two 12-week studies, the effect of the fixed combination of budesonide/formoterol on lung function was equivalent to that of the free combination of budesonide and formoterol, and superior to budesonide monotherapy. All treatment groups used short-acting β2-adrenergic agonists as needed. There was no evidence of waning anti-asthmatic effect over time.

Two 12-week studies were conducted in pediatric patients, in which 265 individuals aged 6–11 years received maintenance therapy with budesonide/formoterol (2 inhalations of 80 mcg/4.5 mcg per inhalation twice daily) and short-acting β2-adrenergic agonists as needed. In both studies, improvements in lung function were observed, and treatment was well tolerated compared to budesonide monotherapy at the corresponding dose.

COPD

Two 12-month studies evaluated the effect of the medicinal product on lung function and the frequency of exacerbations (defined by the number of courses of oral steroids and/or antibiotics and/or hospitalizations) in patients with moderate to severe COPD. The inclusion criterion for both studies was a pre-bronchodilator FEV1 value of < 50% of predicted normal. The median post-bronchodilator FEV1 at study entry was 42% of predicted normal.

The mean number of exacerbations per year (as defined above) was significantly reduced in the budesonide/formoterol group compared to formoterol monotherapy or placebo (mean rate 1.4 vs. 1.8–1.9 in the placebo/formoterol groups). The mean number of days of oral corticosteroid use per patient over 12 months was slightly reduced in the budesonide/formoterol group (7–8 days/patient/year compared to 11–12 and 9–12 days in the placebo and formoterol groups, respectively). Regarding changes in lung function parameters such as FEV1, treatment with budesonide/formoterol was not more effective than treatment with formoterol alone.

Pharmacokinetics

Absorption

The fixed-dose combination of budesonide and formoterol was found to be bioequivalent to the corresponding monoproducts in terms of systemic exposure to budesonide and formoterol. Despite this, a slight increase in cortisol secretion suppression was observed after administration of the fixed-dose combination compared to administration of the drugs separately. This difference was considered clinically insignificant with regard to safety.

There was no evidence of pharmacokinetic interaction between budesonide and formoterol.

Pharmacokinetic parameters of the respective active substances were similar after administration of budesonide and formoterol as monoproducts and as part of the fixed-dose combination. After administration of the combination product, the AUC of budesonide, rate of absorption, and maximum plasma concentration were slightly higher. The maximum plasma concentration of formoterol after administration of the fixed combination was similar to that after administration of the monoproduct. Inhaled budesonide is rapidly absorbed; peak plasma concentration is reached within 30 minutes after inhalation. In studies, the mean lung deposition of budesonide after inhalation via a dry powder inhaler ranged from 32% to 44% of the delivered dose. Systemic bioavailability is approximately 49% of the delivered dose. In children aged 6–16 years, lung deposition is within the same range as in adults at the same doses. Corresponding plasma concentrations were not detectable.

Inhaled formoterol is rapidly absorbed; peak plasma concentration is reached within 10 minutes after inhalation. In studies, the mean lung deposition of formoterol after inhalation via a dry powder inhaler ranged from 28% to 49% of the delivered dose. Systemic bioavailability is approximately 61% of the delivered dose.

Distribution and Metabolism

Approximately 50% of formoterol and 90% of budesonide are bound to plasma proteins. The volume of distribution is approximately 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol is inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are predominantly present as inactivated conjugates). Budesonide undergoes extensive (approximately 90%) biotransformation during first-pass metabolism in the liver, forming metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the main metabolites, 6-β-hydroxy-budesonide and 16-α-hydroxy-prednisolone, does not exceed 1% of that of budesonide. There is no evidence of metabolic interaction or displacement reactions between formoterol and budesonide.

Elimination

The majority of the formoterol dose undergoes hepatic metabolism and is subsequently excreted by the kidneys. After inhalation, 8–13% of the administered dose of formoterol is excreted unchanged in urine.

Formoterol has a high systemic clearance (approximately 1.4 L/min), and its terminal half-life averages 17 hours.

Budesonide is metabolized primarily by the CYP3A4 enzyme. Budesonide metabolites are excreted in urine in unchanged or conjugated form. Only a small amount of unchanged budesonide is detected in urine. Budesonide has a high systemic clearance (approximately 1.2 L/min), and its plasma half-life after intravenous administration is approximately 4 hours.

The pharmacokinetics of budesonide or formoterol in children and patients with renal impairment is unknown. In patients with hepatic disease, systemic exposure to budesonide and formoterol may be increased.

Linearity/Non-linearity

Systemic exposure to budesonide and formoterol is linearly correlated with the administered dose.

Clinical characteristics

Indications

Bronchial asthma

Eirbufo Forspiro is indicated for adults and children aged 12 years and older for regular treatment of bronchial asthma when combination therapy (inhaled corticosteroid and long-acting β2-adrenergic agonist) is appropriate:

• when their condition is not adequately controlled with inhaled corticosteroids and short-acting β2-adrenergic agonists used as needed, or – when their condition is adequately controlled with inhaled corticosteroids and long-acting β2-adrenergic agonists.

Chronic obstructive pulmonary disease (COPD)

Eirbufo Forspiro is indicated for symptomatic treatment in adult patients aged 18 years and older with COPD, with forced expiratory volume in 1 second (FEV1) < 70 % of predicted normal (post-bronchodilator) and a history of exacerbations despite regular bronchodilator therapy.

Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section "Composition" (lactose, which contains a small amount of milk proteins).

Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Plasma levels of budesonide may markedly increase when the medicinal product is used concomitantly with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and HIV protease inhibitors); therefore, concomitant use of these medicinal products should be avoided. If avoidance is not possible, the interval between administration of the inhibitor and budesonide should be as long as possible (see section "Special precautions for use").

Concomitant use of Eirbufo Forspiro for maintenance therapy and symptom relief is not recommended in patients taking potent CYP3A4 inhibitors.

The potent CYP3A4 inhibitor ketoconazole, administered at a dose of 200 mg once daily, increased plasma concentrations of oral budesonide (3 mg as a single dose) by an average of 6-fold when co-administered. When ketoconazole was administered 12 hours after budesonide, budesonide concentrations increased on average by 3-fold, indicating that staggered administration with an interval between drugs may reduce the increase in plasma budesonide concentrations. Limited data on this interaction with high doses of inhaled budesonide show that when itraconazole 200 mg once daily was co-administered with inhaled budesonide (1000 mcg as a single dose), plasma budesonide levels may markedly increase (on average by four times).

Pharmacodynamic interactions

β-adrenergic blockers may attenuate or antagonize the effect of formoterol. Therefore, the medicinal product should not be used concomitantly with β-adrenergic blockers (including ophthalmic drops), unless there are compelling reasons.

Concomitant use of quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), and tricyclic antidepressants may prolong the QTc interval and increase the risk of ventricular arrhythmias.

In addition, L-dopa, L-thyroxine, oxytocin, and alcohol may impair cardiac tolerance to β2-sympathomimetics.

Concomitant use of monoamine oxidase inhibitors, including medicinal products with similar properties such as furazolidone and procarbazine, may provoke hypertensive reactions.

Patients undergoing concomitant anesthesia with halogenated hydrocarbons are at increased risk of developing arrhythmias.

Concomitant use of other β-adrenergic or anticholinergic medicinal products may have a potentially additive bronchodilator effect.

Hypokalemia may increase susceptibility to arrhythmias in patients receiving cardiac glycosides.

Hypokalemia may occur as a result of β2-agonist therapy and may be potentiated by concomitant use of xanthine derivatives, corticosteroids, and diuretics (see section "Special precautions for use").

No interactions between budesonide and formoterol with any other medicinal products used for the treatment of bronchial asthma have been observed.

Children. Drug interaction studies have been conducted only in adults.

Special precautions for use

If discontinuation of treatment is necessary, it is recommended to gradually reduce the dose rather than abruptly stop therapy.

Patients should rinse their mouth with water after each inhalation of the maintenance dose to minimize the risk of oropharyngeal candidiasis (see section "Side effects"). If oral thrush develops in the oropharynx, patients should also rinse their mouth with water after additional inhalations used to treat symptoms.

Patients should consult a physician if they consider the treatment ineffective or if the maximum recommended daily dose of Eairbufo Forspiro has been exceeded (see section "Dosage and administration"). More frequent use of short-acting bronchodilators indicates worsening of the patient's condition and the need to reassess bronchial asthma treatment. Sudden and progressive deterioration in control of bronchial asthma or COPD may be potentially life-threatening; therefore, the patient should undergo urgent medical evaluation. In such cases, intensification of therapy should be considered, for example, initiating a course of oral corticosteroids or antibiotic treatment if bacterial infection is present.

Patients should be advised to always carry a "rescue" inhaler.

Patients should be reminded of the necessity to continue maintenance therapy with Eairbufo Forspiro as prescribed, even in the absence of symptoms.

After achieving control of bronchial asthma symptoms, gradual dose reduction of Eairbufo Forspiro may be considered. It is important that the patient undergoes regular monitoring. The lowest effective dose of Eairbufo Forspiro should be used (see section "Dosage and administration").

Patients should not initiate treatment with Eairbufo Forspiro during periods of exacerbation, acute or significant worsening of bronchial asthma.

During treatment with Eairbufo Forspiro, serious adverse reactions related to bronchial asthma or exacerbations of the disease may occur. Patients should continue treatment and consult a physician if symptoms of bronchial asthma do not resolve or worsen after starting therapy with Eairbufo Forspiro.

There are no clinical data on the use of Eairbufo Forspiro in COPD patients with pre-bronchodilator FEV1 > 50% of predicted normal and post-bronchodilator FEV1 < 70% of predicted normal (see section "Pharmacodynamics").

As with any other inhaled therapy, paradoxical bronchospasm with immediate increase in wheezing and onset of dyspnea after drug administration may occur. If paradoxical bronchospasm develops, Eairbufo Forspiro should be discontinued immediately, the patient's condition assessed, and alternative therapy initiated if necessary. Paradoxical bronchospasm, which requires immediate treatment, responds to a fast-acting inhaled bronchodilator (see section "Side effects").

Systemic effects may occur with inhaled administration of all corticosteroids, especially at high doses and during prolonged treatment. The likelihood of such effects is much lower with inhaled corticosteroids compared to oral forms. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children, decreased bone mineral density, cataract and glaucoma, and less frequently, psychiatric disturbances or behavioral changes, including psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (especially in children) (see section "Side effects").

The potential impact on bone mineral density should be considered, particularly in patients receiving high doses over a prolonged period, which is an additional risk factor for osteoporosis. In long-term studies of inhaled budesonide at average daily doses of 400 mcg (delivered dose) in children or 800 mcg (delivered dose) in adults, no significant effect on bone mineral density was observed. Information on the effect of Eairbufo Forspiro at higher doses is lacking.

Precautions should be taken when switching patients from previous systemic steroid therapy with suspected adrenal suppression to treatment with Eairbufo Forspiro.

The benefits of inhaled budesonide therapy generally minimize the need for oral steroids, but patients previously treated with oral steroids over a long period may still be at risk of adrenal suppression. Recovery after discontinuation of oral steroids may take a considerable amount of time; thus, patients previously treated with oral steroids and switched to inhaled budesonide may remain at risk for a prolonged period due to adrenal dysfunction. In such cases, the function of the hypothalamic-pituitary-adrenal system should be monitored regularly.

Prolonged treatment with high doses of inhaled corticosteroids, particularly when doses higher than recommended are used, may also lead to clinically significant adrenal suppression. Therefore, additional systemic steroid therapy should be considered during periods of stress (e.g., severe infections) or planned surgical procedures. Rapid dose reduction of steroids may lead to acute adrenal crisis. Symptoms and signs that may occur during acute adrenal crisis may be somewhat nonspecific but may include anorexia, abdominal pain, weight loss, increased fatigue, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension, and hypoglycemia.

Treatment with additional systemic steroids or inhaled budesonide should not be abruptly discontinued.

During transition from oral steroid therapy to Eairbufo Forspiro, a lower systemic steroid effect is generally observed, which may lead to the emergence of allergy symptoms or arthritis symptoms such as rhinitis, eczema, and muscle or joint pain. If these conditions develop, specific treatment should be initiated. Glucocorticoid insufficiency should be suspected if, rarely, symptoms such as increased fatigue, headache, nausea, and vomiting occur. In such cases, temporary increase in the dose of oral glucocorticoids may sometimes be necessary.

To reduce the risk of oropharyngeal candidiasis (see section "Side effects"), patients should be instructed to rinse their mouth with water after each maintenance dose.

Concomitant use of itraconazole, ritonavir, or other potent CYP3A4 inhibitors should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). If this is unavoidable, the time interval between administration of interacting drugs should be as long as possible.

Eairbufo Forspiro should be used with caution in patients with thyrotoxicosis, pheochromocytoma, diabetes mellitus, untreated hypokalemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe arterial hypertension, aneurysm, or other severe cardiovascular diseases such as ischemic heart disease, tachyarrhythmia, or severe heart failure.

The drug should be used with caution in patients with QTc interval prolongation. Formoterol may cause QTc interval prolongation.

The need for inhaled corticosteroids and their dosage should be reviewed in patients with active or inactive pulmonary tuberculosis, or fungal or viral respiratory tract infections.

Potentially serious hypokalemia may occur with high-dose use of β2-adrenergic agonists. When β2-adrenergic agonists are used concomitantly with medicinal products that may cause hypokalemia or enhance its effect (e.g., xanthine derivatives, steroids, and diuretics), the hypokalemic effect of β2-adrenergic agonists may be intensified. Particular caution is required in patients with unstable bronchial asthma receiving various short-acting bronchodilators, or in acute severe bronchial asthma, as the risk of hypokalemia is increased in the presence of hypoxia and other conditions that increase the likelihood of this complication. In such cases, serum potassium levels should be monitored.

As with other β2-adrenergic agonists, blood glucose levels should be monitored more closely in patients with diabetes mellitus.

Vision disorders may occur with systemic and local use of corticosteroids. If patients experience symptoms such as blurred vision or other visual disturbances, they should consult an ophthalmologist to evaluate possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSC), which has been reported after systemic or local corticosteroid use.

Eairbufo Forspiro contains lactose monohydrate (< 1 mg/inhalation). This amount usually does not cause problems in patients with lactose intolerance. This excipient contains small amounts of milk proteins, which may cause allergic reactions.

Pneumonia in COPD patients

An increased incidence of pneumonia, including cases requiring hospitalization, has been observed in COPD patients receiving inhaled corticosteroids. Some data suggest an increased risk of pneumonia with higher steroid doses, although this has not been consistently demonstrated in all studies.

There is no convincing clinical evidence of differences in pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for possible pneumonia in COPD patients, as clinical signs of such infections overlap with symptoms of COPD exacerbation.

Risk factors for pneumonia in COPD patients include smoking, older age, low body mass index (BMI), and severe COPD.

Children

Regular monitoring of growth in children receiving long-term inhaled corticosteroid therapy is recommended. If growth retardation occurs, therapy should be reviewed with the aim of reducing the inhaled corticosteroid dose to the lowest dose that maintains effective control of bronchial asthma symptoms, if possible. The benefit of corticosteroid use and the potential risk of growth suppression should be carefully weighed. Additionally, referral to a pediatric respiratory specialist may be appropriate.

Due to limited long-term data on glucocorticoid treatment, it can be assumed that most children receiving inhaled budesonide therapy will eventually achieve normal adult growth parameters. However, an initial slight and transient reduction in growth velocity (approximately 1 cm) has been observed. This delay is typically noted during the first year of treatment.

Use during pregnancy or breastfeeding

Pregnancy

There are no clinical data on the use of Eairbufo Forspiro or concomitant therapy with formoterol and budesonide during pregnancy. Data from animal studies on the effects of this combination on embryofetal development did not reveal any additional adverse effects when the combination was used.

There are insufficient data on the use of formoterol in pregnant women. Reproductive toxicity studies in animals showed adverse effects with formoterol at very high systemic doses.

Data from approximately 2000 pregnancies did not show any increased teratogenic risk associated with inhaled budesonide. Animal studies have shown that glucocorticoids can cause congenital malformations. However, these data are likely not relevant to humans when the drug is used at recommended doses.

Animal studies have also shown that high-dose glucocorticoid use during pregnancy increases the risk of intrauterine growth retardation, cardiovascular disease in adult animals, and permanent changes in glucocorticoid receptor density, metabolism, and neurotransmitter profiles when administered at doses below teratogenic levels.

Eairbufo Forspiro should only be used during pregnancy if the benefit to the mother outweighs the potential risks to the fetus. The lowest effective budesonide dose that provides adequate control of bronchial asthma symptoms should be used.

Breastfeeding

Budesonide passes into breast milk. However, no adverse effects on the infant are expected when the drug is used at therapeutic doses. It is unknown whether formoterol passes into human breast milk.

In rats, small amounts of formoterol were detected in maternal milk. The use of Eairbufo Forspiro in breastfeeding women should only be considered if the expected benefit to the mother outweighs any potential risk to the infant.

Fertility

There are no data on the potential effect of budesonide on fertility. Reproductive function studies in animals showed a slightly reduced fertility in male rats at high systemic exposure to formoterol.

Ability to influence reaction rate while driving or operating machinery

Eairbufo Forspiro has no effect or negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Route of administration: inhalation.

Dosage 160 mcg/4.5 mcg

Bronchial Asthma

Eirbifo Forspiro is not indicated for initial treatment of bronchial asthma. The doses of the components of Eirbifo Forspiro should be individually adjusted and modified according to the severity of the disease. This should be taken into account not only at the beginning of treatment with combination medicinal products but also when adjusting the maintenance dose. If a patient requires a combination of doses different from those available in the combined inhaler, appropriate doses of β2-adrenergic agonists and/or corticosteroids should be prescribed using separate inhalers.

The dose should be gradually reduced to the lowest dose that effectively controls symptoms. Patients should undergo regular follow-up examinations by the physician who prescribed the medicinal product to ensure that the dose of Eirbifo Forspiro remains optimal. After achieving long-term control of symptoms with the lowest recommended dose, consideration should be given to controlling symptoms with an inhaled corticosteroid alone.

There are two options for using Eirbifo Forspiro:

A. Use of the medicinal product for maintenance therapy: Eirbifo Forspiro is used for regular maintenance therapy in combination with a separate short-acting bronchodilator used as a reliever medication.

B. Use of the medicinal product for maintenance therapy and symptom relief: Eirbifo Forspiro is used for regular maintenance therapy and, as needed, for symptom relief.

A. Use of the medicinal product for maintenance therapy

Patients should be advised to always carry a separate short-acting bronchodilator for immediate symptom relief.

Recommended doses

Adults (aged 18 years and older): 1–2 inhalations twice daily. Some patients may require up to 4 inhalations twice daily.

Children (aged 12–17 years): 1–2 inhalations twice daily.

After achieving control of disease symptoms with twice-daily administration, the dose is usually titrated down to the lowest effective dose, including once-daily administration of Eirbifo Forspiro, when, in the physician’s opinion, the patient requires maintenance therapy with a long-acting bronchodilator in combination with an inhaled corticosteroid.

An increased need for a separate short-acting bronchodilator indicates worsening of the underlying disease and requires re-evaluation of bronchial asthma treatment.

B. Use of the medicinal product for maintenance therapy and symptom relief

Patients should take the daily maintenance dose of Eirbifo Forspiro and also use this medicinal product as needed for symptom relief. Patients should be advised to always carry Eirbifo Forspiro for immediate symptom relief in emergency situations. Patients using Eirbifo Forspiro for symptom relief should discuss with their physician the possibility of using this medicinal product for prevention of bronchoconstriction induced by allergens or physical exertion; in such cases, the frequency of as-needed use should be considered. If bronchodilators are frequently needed without a corresponding need to increase the dose of inhaled corticosteroids, alternative medications for symptom relief should be considered.

The use of Eirbifo Forspiro for maintenance therapy and symptom relief should be particularly considered for patients:

• with inadequate control of bronchial asthma who frequently require reliever medications;
• with a history of asthma exacerbations requiring medical intervention.

Patients who frequently and in large amounts use Eirbifo Forspiro inhalations as needed should be carefully monitored for dose-dependent adverse reactions.

Recommended doses

Adults and children aged 12 years and older: The recommended maintenance dose is 2 inhalations per day: 1 inhalation in the morning and 1 in the evening, or 2 inhalations either in the morning or in the evening. Some patients may require a maintenance dose of 2 inhalations twice daily. As needed, when symptoms occur, 1 additional inhalation should be taken. If symptoms do not resolve within a few minutes, an additional inhalation should be taken. In any single episode, no more than 6 inhalations should be used.

A total daily dose exceeding 8 inhalations is generally not required; however, during a limited period, the total daily dose may reach up to 12 inhalations. Patients using more than 8 inhalations per day are strongly advised to consult their physician. They should undergo re-evaluation and review of their maintenance therapy regimen.

Children under 12 years of age: Eirbifo Forspiro is not recommended for use in children under 12 years of age for maintenance therapy and symptom relief.

Chronic obstructive pulmonary disease (COPD)

Recommended doses

Adults: 2 inhalations twice daily.

Dosage (320 mcg/9 mcg)

Bronchial Asthma

Eirbifo Forspiro is not indicated for initial treatment of bronchial asthma. The doses of the components of the medicinal product should be individually adjusted and modified according to the severity of the disease. This should be taken into account not only at the beginning of treatment with combination medicinal products but also when adjusting the maintenance dose. If a patient requires a combination of doses different from those available in the combined inhaler, appropriate doses of β2-adrenergic agonists and/or corticosteroids should be prescribed using separate inhalers.

Patients should undergo regular follow-up examinations by the physician who prescribed the medicinal product to ensure that the dose of Eirbifo Forspiro remains optimal. The dose should be gradually reduced to the lowest dose that effectively controls symptoms. After achieving long-term control of symptoms with the lowest recommended dose, consideration should be given to controlling symptoms with an inhaled corticosteroid alone.

After achieving control of disease symptoms with twice-daily administration, the dose is usually titrated down to the lowest effective dose, including once-daily administration of Eirbifo Forspiro, when, in the physician’s opinion, the patient requires maintenance therapy with a long-acting bronchodilator.

More frequent use of a separate short-acting bronchodilator indicates worsening of the patient’s condition and the need to re-evaluate treatment for bronchial asthma.

Eirbifo Forspiro in the 320 mcg/9 mcg dosage should only be used for maintenance therapy.

For maintenance therapy and symptom relief with Eirbifo Forspiro, a lower-strength formulation of this medicinal product—160 mcg/4.5 mcg—is available.

Recommended doses

Adults (aged 18 years and older): 1 inhalation twice daily. Some patients may require up to 2 inhalations twice daily.

Children (aged 12–17 years): 1 inhalation twice daily.

Chronic obstructive pulmonary disease (COPD)

Recommended doses

Adults: 1 inhalation twice daily.

General Information

Special patient groups

No special dosage requirements are necessary for elderly patients. Data on the use of the medicinal product in patients with renal or hepatic impairment are lacking. Since budesonide and formoterol are primarily eliminated via hepatic metabolism, increased plasma concentrations of the drug may be expected in patients with severe liver cirrhosis.

Method of Administration

Instructions for using the Eirbifo Forspiro inhaler

Patients should be instructed on the correct use of the inhaler device, and this should be regularly checked.

The inhaler contains 60 doses of the medicinal product in a blister strip (Fig. 1). It has a dose counter that shows the number of doses remaining, counting down from 60 to 0. When the last 10 doses remain, the numbers will appear on a red background.

The inhaler must not be refilled; it should be disposed of when empty and replaced with a new one.

Fig. 1

Before using the inhaler:

• open the transparent side compartment doors;
• carefully detach the blister strip from the side compartment by pulling it along its entire length away from the "teeth" of the side compartment (Fig. 2). Do not pull or jerk the strip;
• close the side compartment doors and dispose of the used strip.

Fig. 2

Note: During use, the side compartment will gradually fill with the used strip. Strips with black bars do not contain the medicinal product. Eventually, the numbered sections of the strip will appear in the side compartment. The side compartment should never contain more than 2 sections of strip, as they may cause the inhaler to jam. The strip should be carefully detached as shown above and safely disposed of.

Using the inhaler

The inhaler should be held as shown in the figures.

1. Open
   • open the protective cap downward to expose the mouthpiece (Fig. 3);
   • check the dose counter to see how many doses remain;

Fig. 3

1. Prepare the dose
   • lift the edge of the white lever upward (Fig. 4); the side compartment must be closed;

Fig. 4

Note: The white lever should only be used when the patient is ready to inhale a dose. Playing with the white lever will result in loss of doses.

• open: fully raise the white lever until it clicks into place (Fig. 5); this action moves a new dose into position with the number on top;

Fig. 5

• close: after this, fully close the white lever until it clicks and returns to its original position (Fig. 6). The inhaler is now ready for immediate use.

Fig. 6

1. Inhale the dose
   • the patient should exhale as deeply as possible, without holding the inhaler in the hands;

Never exhale directly into the inhaler, as this may affect the dose;

• hold the inhaler upright, with the protective cap facing downward;
• lips should be tightly sealed around the mouthpiece (Fig. 7);
• the patient should inhale as deeply and forcefully as possible through the mouth, not through the nose;

Fig. 7

• remove the inhaler from the mouth and hold breath for 5–10 seconds, or as long as possible without discomfort;
• then the patient should exhale slowly, but not into the inhaler;
• replace the protective cap on the mouthpiece;
• rinse the mouth with water and spit it out. This may help prevent fungal infection in the mouth and hoarseness.

Cleaning:

• if necessary, wipe the outer part of the mouthpiece with a clean, dry cloth;
• the inhaler must not be disassembled for cleaning or any other purpose;
• inhaler parts must not be cleaned with water or wet wipes, as moisture may affect the dose;
• never insert pins or other sharp objects into the mouthpiece or any other part of the inhaler, as this may damage the device!

Children

Eirbifo Forspiro is recommended for use in children aged 12 years and older.

Overdose

Overdose of formoterol is likely to cause effects typical of β2-adrenergic agonists: tremor, headache, palpitations. In isolated cases, tachycardia, hyperglycemia, hypokalemia, QTc interval prolongation, arrhythmia, nausea, and vomiting have been reported. Supportive and symptomatic therapy may be indicated. Administration of 90 mcg over 3 hours in patients with acute bronchial obstruction was safe.

Acute overdose of budesonide, even in excessive doses, is not expected to cause clinical problems. However, prolonged use of excessive doses may lead to systemic effects of glucocorticoids, such as hypercorticism and adrenal suppression.

If administration of Eirbifo Forspiro needs to be discontinued due to overdose of formoterol, consideration should be given to using an appropriate inhaled corticosteroid.

Adverse reactions

Since Eurbufo Forspiro contains budesonide and formoterol, adverse reactions associated with the use of each of the active substances individually may occur. Concomitant use of the two substances did not increase the frequency of adverse reactions. The most commonly observed adverse reactions associated with the use of the medicinal product are pharmacologically predictable side effects of β2-adrenoceptor agonists, such as tremor and palpitations. These adverse reactions were usually mild in severity and disappeared within a few days of treatment.

The adverse reactions caused by budesonide or formoterol listed below are presented by system organ class and frequency of occurrence. Frequency categories for adverse reactions are defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), and very rare (< 1/10,000).

System organ class (SOC)	Frequency	Adverse reaction to the medicinal product
Infections and infestations	Common	Oral and pharyngeal candidiasis Pneumonia (in COPD patients)
Immune system disorders	Uncommon	Immediate or delayed hypersensitivity reactions, e.g. exanthema, urticaria, pruritus, dermatitis, angioedema, and anaphylactic reactions
Endocrine disorders	Very rare	Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density
Metabolism and nutrition disorders	Uncommon	Hypokalaemia
	Very rare	Hyperglycaemia
Psychiatric disorders	Uncommon	Aggression, psychomotor hyperactivity, anxiety, sleep disorders
	Very rare	Depression, behavioural disturbances (mainly in children)
Nervous system disorders	Common	Headache, tremor
	Uncommon	Dizziness
	Very rare	Disturbances of taste
Eye disorders	Uncommon	Blurred vision (see section "Special precautions for use")
	Very rare	Cataract, glaucoma
Cardiac disorders	Common	Palpitations
	Uncommon	Tachycardia
	Rare	Cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystoles
	Very rare	Angina pectoris, QTc interval prolongation
Vascular disorders	Very rare	Changes in blood pressure
Respiratory, thoracic and mediastinal disorders	Common	Mild irritation in the throat, cough, dysphonia including hoarseness
	Rare	Bronchospasm
Gastrointestinal disorders	Uncommon	Nausea
Skin and subcutaneous tissue disorders	Uncommon	Increased tendency to bruising
Musculoskeletal and connective tissue disorders	Uncommon	Muscle cramps

Candidiasis of the oropharynx results from deposition of the medicinal product in the oral cavity. Patients should be instructed to rinse their mouth with water after each inhalation of the maintenance dose to minimize the risk of oral candidiasis. Oropharyngeal candidiasis usually responds to local antifungal treatment without the need to discontinue inhaled corticosteroid therapy. If oropharyngeal candidiasis develops, patients should also rinse their mouth with water after using the medicinal product as needed.

As with any other inhaled therapy, paradoxical bronchospasm, characterized by immediate wheezing and shortness of breath following drug administration, may very rarely occur (less than 1 case per 10,000 patients). Paradoxical bronchospasm, which requires immediate treatment, responds to administration of a fast-acting inhaled bronchodilator. In such cases, use of the medicinal product Airbufo Forspiro should be discontinued immediately, the patient should be evaluated, and alternative therapy initiated if necessary (see section "Special precautions for use").

Systemic effects may occur with inhaled corticosteroids, particularly at high doses and during prolonged use. The likelihood of such effects is lower with inhaled corticosteroids compared to oral formulations. Potential systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children, decreased bone mineral density, cataract, and glaucoma. Increased susceptibility to infections and impaired ability to adapt to stress may also occur. These effects are likely dependent on dose, duration of exposure, influence of concomitant and previously administered steroids, and individual sensitivity.

Treatment with β2-adrenergic agonists may lead to increased blood levels of insulin, free fatty acids, glycerol, and ketone bodies.

Children. Regular monitoring of growth is recommended in children receiving long-term inhaled corticosteroids (see section "Special precautions for use").

Reporting of adverse reactions

Reporting of adverse reactions after medicinal product registration is highly important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store at a temperature not exceeding 30°C. Keep out of reach and sight of children.

Packaging

60 doses per inhaler containing a blister strip. 1 inhaler per cardboard box.

Prescription status

Prescription only.

Manufacturer

Aeropharm GmbH.

Salutas Pharma GmbH.

Manufacturer's address and place of business

Franz-Mitteneinde-Allee 1, Rudolstadt, 07407, Germany.

Otto-von-Guericke-Allee 1, 39179, Barleben, Saxony-Anhalt, Germany.