Bufomix isiheiler

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BUFOMIX EASYHALER

Composition:

Active substances: budesonide, formoterol fumarate dihydrate;

One dose contains budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg;

Excipient: lactose monohydrate.

Pharmaceutical form. Powder for inhalation.

Main physicochemical characteristics: white or yellowish-white powder.

Pharmacotherapeutic group.

Agents used in obstructive airway diseases. Adrenergic agents in combination with corticosteroids or other agents, excluding anticholinergic agents. Formoterol and budesonide. ATC code R03AK07.

Pharmacological properties.

Pharmacodynamics.

Mechanisms of action and pharmacodynamic effects

The medicinal product Bufomix Easyhaler contains formoterol and budesonide, which have different mechanisms of action and exhibit additive effects in reducing exacerbations of bronchial asthma. The specific properties of budesonide and formoterol allow the combination to be used for maintenance therapy and symptom relief or for maintenance treatment of bronchial asthma.

Budesonide. Budesonide is a glucocorticosteroid which, when inhaled, exerts a dose-dependent anti-inflammatory effect in the airways, resulting in reduced symptoms of bronchial asthma. Inhaled budesonide is associated with fewer adverse effects compared to systemic corticosteroids. The precise mechanism of the anti-inflammatory effect of glucocorticosteroids is unknown.

Formoterol. Formoterol is a selective β2-adrenoceptor agonist which, when inhaled, provides rapid and prolonged relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The bronchodilating effect is dose-dependent and occurs within 1–3 minutes. The duration of effect is at least 12 hours after a single dose.

Clinical efficacy and safety

Clinical efficacy of maintenance therapy with budesonide/formoterol

Clinical studies in adult patients have shown that adding formoterol to budesonide improves asthma symptoms, enhances lung function, and reduces the frequency of exacerbations.

Two 12-week studies were conducted in pediatric populations, in which 265 children aged 6–11 years received treatment with maintenance doses of budesonide/formoterol (two inhalations of 80 mcg/4.5 mcg per inhalation twice daily) and a short-acting β2-adrenoceptor agonist as needed. In both studies, improvements in lung function were observed, and treatment was well tolerated compared to the use of the corresponding dose of budesonide as monotherapy.

Clinical efficacy of maintenance therapy and use of budesonide/formoterol for symptom relief

The use of budesonide/formoterol for maintenance therapy and symptom relief provided a statistically and clinically significant reduction in the rate of severe exacerbations of bronchial asthma compared to all other medicinal products.

In studies involving patients requiring medical attention due to acute asthma symptoms, the use of budesonide/formoterol provided rapid and effective relief of bronchospasm symptoms, similar to that of salbutamol and formoterol.

Comparable efficacy and safety of the medicinal product in adolescents and adults were demonstrated in six double-blind studies, including the five aforementioned studies and one additional study using a higher maintenance dose—two inhalations of 160/4.5 mcg twice daily. Assessments were based on data from a total of 14,385 asthma patients, of whom 1,847 were adolescents. A limited number of adolescent patients used more than 8 inhalations of the drug (but infrequently) on at least one day during treatment with budesonide/formoterol for maintenance and symptom relief.

Pharmacokinetics.

Absorption

Fixed-dose combinations of budesonide and formoterol have been shown to be bioequivalent to the corresponding monoproducts with respect to the systemic exposure of budesonide and formoterol, respectively. Despite this, a slight suppression of cortisol was observed after administration of the fixed-dose combination compared to the monoproducts. This difference is considered not to impact clinical efficacy.

There is no evidence of pharmacokinetic interactions between budesonide and formoterol.

Pharmacokinetic parameters of budesonide and formoterol were comparable after administration as monoproducts or as a fixed-dose combination. For budesonide, the area under the concentration-time curve (AUC) and the rate of absorption were slightly higher, and the maximum plasma concentration (Cmax) was higher after administration of the fixed-dose combination. For formoterol, Cmax was similar after administration of the fixed-dose combination. Inhaled budesonide is rapidly absorbed, and Cmax is reached within 30 minutes after inhalation. In studies, the average lung deposition of budesonide after inhalation via a dry powder inhaler ranged from 32% to 44% of the delivered dose. Systemic bioavailability was approximately 49% of the delivered dose. In children aged 6 to 16 years, lung deposition is within the same range as in adults when the same dose is administered. Resulting plasma concentrations were not detectable.

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

Distribution and metabolism

Plasma protein binding is approximately 50% for formoterol and 90% for budesonide. The volume of distribution is approximately 4 L/kg for formoterol and 3 L/kg for budesonide. Formoterol is inactivated through conjugation reactions (producing active O-demethylated and deformedylated metabolites, although they are predominantly observed as inactivated conjugates). Budesonide undergoes extensive (approximately 90%) biotransformation during first-pass metabolism in the liver to metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the main metabolites—6-β-hydroxy-budesonide and 16-α-hydroxyprednisolone—is less than 1% of the glucocorticosteroid activity of budesonide. There are no indications of any metabolic interactions or displacement reactions between formoterol and budesonide.

Elimination

The majority of the formoterol dose is transformed via hepatic metabolism, followed by renal excretion. After inhalation, 8–13% of the delivered formoterol dose is excreted in urine in unchanged form. Formoterol has a high systemic clearance (approximately 1.4 L/min), and the terminal half-life averages 17 hours.

Budesonide is eliminated via metabolism, primarily catalyzed by the CYP3A4 enzyme. Budesonide metabolites are excreted in urine either in free form or as conjugates. Only a very small amount of unchanged budesonide is detected in urine. Budesonide has a high systemic clearance (approximately 1.2 L/min), and the elimination half-life from plasma after intravenous administration is 4 hours.

The pharmacokinetics of budesonide or formoterol in patients with renal impairment is unknown. The effects of budesonide and formoterol may be increased in patients with hepatic disease.

Linearity/non-linearity

Systemic exposure to budesonide and formoterol is in linear correlation with the administered dose.

Clinical characteristics.

Indications.

Bufomix Iziheiler (80 mcg/4.5 mcg) is indicated for use in adults, adolescents, and children aged 6 years and older.

The medicinal product is indicated for regular treatment of bronchial asthma when combined therapy (inhaled corticosteroid and long-acting β2-agonist) is appropriate:

• in patients whose condition is not adequately controlled with inhaled corticosteroids and short-acting β2-agonists used as needed;
• in patients whose condition is well controlled with inhaled corticosteroids and long-acting β2-agonists.

Bufomix Iziheiler (80 mcg/4.5 mcg/dose) is not used in patients with severe bronchial asthma.

Contraindications.

Hypersensitivity to budesonide, formoterol, or lactose, which contains a small amount of milk protein.

Interaction with other medicinal products and other types of interactions.

Pharmacokinetic interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, cobicistat, and HIV protease inhibitors) are highly likely to increase plasma levels of budesonide; therefore, their concomitant use should be avoided. If concomitant use cannot be avoided, the interval between administration of these drugs should be as long as possible (see section "Special precautions for use"). Maintenance therapy is not recommended for patients taking strong CYP3A4 inhibitors.

The strong CYP3A4 inhibitor ketoconazole, at a dose of 200 mg once daily, increases plasma levels of orally administered budesonide (single dose of 3 mg) by an average of 6-fold. When ketoconazole was administered 12 hours after budesonide, plasma concentrations increased only 3-fold on average, indicating that staggered administration may reduce the increase in plasma budesonide levels. Some data indicate that a significant increase in plasma budesonide levels (on average 4-fold) may occur when inhaled budesonide (single dose 1000 mcg) is taken concomitantly with itraconazole 200 mg once daily.

Concomitant use of medicinal products containing cobicistat is expected to increase the risk of systemic adverse effects. Such combinations should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects. In such cases, patients should be monitored for systemic corticosteroid-related adverse effects.

Pharmacodynamic interactions

β-adrenergic blockers may reduce the effect of formoterol. Therefore, Bufomix Iziheiler should not be used concomitantly with β-adrenergic blockers (including ophthalmic drops), unless there are compelling reasons.

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

Additionally, levodopa, levothyroxine, 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 cause hypertensive reactions.

The risk of arrhythmia increases during anesthesia with halogenated hydrocarbons.

Concomitant use of other β-adrenergic agents or anticholinergic drugs may enhance the bronchodilator effect.

Hypokalemia may increase susceptibility to cardiac arrhythmias in patients treated with digitalis glycosides.

Hypokalemia may occur during 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 of the medicinal products used for the treatment of bronchial asthma have been observed.

Paediatric populations

Drug interaction studies have only been conducted in adults.

Special precautions for use.

It is recommended to gradually reduce the dose when discontinuing the medication and not to stop treatment abruptly.

If patients feel that treatment is ineffective or there is a need to exceed the maximum recommended dose of Bufomix Iziheiler, they should consult a physician. Sudden and rapid worsening of bronchial asthma control is potentially life-threatening, so the patient must seek immediate medical evaluation. In such cases, intensification of corticosteroid therapy should be considered, for example, a course of oral corticosteroids, or antibiotic treatment if infection is present.

Patients should be advised to always carry an inhaler as a rescue medication: either Bufomix Iziheiler (for patients with bronchial asthma using Bufomix Iziheiler for maintenance and symptom relief), or a separate short-acting bronchodilator (for all patients using Bufomix Iziheiler as maintenance therapy).

Patients should be reminded to take the maintenance dose of Bufomix Iziheiler as prescribed, even in the absence of symptoms. Prophylactic use of Bufomix Iziheiler, for example before physical exertion, has not been studied. Bufomix Iziheiler inhalations for symptom relief should only be used when symptoms of bronchial asthma occur; they are not intended for regular prophylactic use, such as before physical activity. For this purpose, the use of a separate short-acting bronchodilator should be considered.

Once symptoms of bronchial asthma are under control, gradual dose reduction of Bufomix Iziheiler should be considered. It is important to regularly monitor patients during dose reduction. The lowest effective dose of Bufomix Iziheiler should be used.

Do not initiate treatment with this medicinal product during exacerbations, significant worsening, or sudden complications of bronchial asthma.

Serious adverse reactions and exacerbations related to bronchial asthma may occur during treatment. Patients should be instructed to continue treatment and simultaneously seek medical advice if symptoms of bronchial asthma are not controlled or worsen after starting Bufomix Iziheiler.

As with other forms of inhaled therapy, there is a risk of paradoxical bronchospasm. In this case, the patient experiences increased wheezing and breathlessness immediately after taking a dose. If paradoxical bronchospasm occurs, Bufomix Iziheiler should be discontinued immediately, the patient should be evaluated, and alternative therapy should be initiated if necessary. Paradoxical bronchospasm responds to short-acting inhaled bronchodilators and must be treated promptly.

Systemic effects of inhaled corticosteroids may occur, particularly with long-term use of high doses. These effects are much less likely than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid appearance, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma, and, much less frequently, various psychological and behavioral disturbances, including psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (especially in children).

Visual disturbances may occur with systemic and local corticosteroid use. If a patient reports symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist to evaluate possible causes, which may include cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which has been reported after systemic and local corticosteroid use.

Potential effects on bone density should be considered, especially in patients receiving high doses for prolonged periods and who have concurrent risk factors for osteoporosis. Long-term studies of inhaled budesonide in children at mean daily doses of 400 mcg (delivered dose) or in adults at daily doses of 800 mcg (delivered dose) did not show a significant effect on bone mineral density. Information on the effects of high doses is lacking.

If there is reason to suspect impaired adrenal function due to previous systemic steroid therapy, caution should be exercised when switching patients to Bufomix Iziheiler therapy.

The benefits of inhaled budesonide therapy usually minimize the need for oral steroids; however, patients transitioning from oral steroids have a risk of reduced adrenal reserve for a prolonged period. Recovery may be prolonged after discontinuation of oral steroid therapy, so patients previously treated with oral steroids and switched to inhaled budesonide may remain at risk for adrenal insufficiency for a long time. In such cases, regular monitoring of the hypothalamic-pituitary-adrenal (HPA) axis function is required.

Long-term treatment with high doses of inhaled corticosteroids, especially when higher than recommended doses are used, may lead to clinically significant suppression of adrenal cortex function. Therefore, during periods of stress, such as severe infections or planned surgery, additional systemic corticosteroid therapy should be considered. Rapid dose reduction of steroids may trigger acute adrenal insufficiency. Symptoms of acute adrenal insufficiency may include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, decreased level of consciousness, seizures, hypotension, and hypoglycemia.

Treatment with additional systemic steroids or inhaled budesonide must not be stopped abruptly.

When switching from oral steroids to Bufomix Iziheiler, the overall systemic steroid effect is generally lower, which may lead to the emergence of allergic or arthritic symptoms such as rhinitis, eczema, muscle and joint pain. In such cases, specific treatment should be initiated. General glucocorticoid insufficiency should be suspected if symptoms such as fatigue, headache, nausea, and vomiting appear. In such cases, temporary dose increase of oral glucocorticoids may sometimes be necessary.

To reduce the risk of oropharyngeal candidiasis, patients should thoroughly rinse the mouth with water after inhaling the maintenance dose. If oropharyngeal candidiasis develops, patients should also rinse the mouth with water after using the medication as needed.

Concomitant treatment with itraconazole, ritonavir, or other potent CYP3A4 inhibitors should be avoided. If unavoidable, the interval between administration of the drugs should be as long as possible. For patients taking potent CYP3A4 inhibitors, the use of Bufomix Iziheiler simultaneously for maintenance therapy and symptom relief is not recommended.

Bufomix Iziheiler should be prescribed with caution in patients with thyrotoxicosis, pheochromocytoma, diabetes mellitus, untreated hypokalemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm, or other severe cardiovascular disorders such as ischemic heart disease, tachyarrhythmia, and severe heart failure.

Caution should be exercised when treating patients with prolonged QTc interval. Formoterol itself may cause QTc interval prolongation.

In patients with active or inactive pulmonary tuberculosis, fungal, or viral respiratory infections, the need for and dosage of inhaled corticosteroids should be re-evaluated.

Life-threatening hypokalemia may develop during treatment with high doses of β2-adrenergic agonists. The hypokalemic effect of β2-adrenergic agonists may be enhanced when used concomitantly with other medicinal products that may cause hypokalemia or potentiate its effect, such as xanthine derivatives, steroids, and diuretics. Particular caution is required in patients with unstable bronchial asthma who frequently use rescue bronchodilators, in acute severe bronchial asthma, due to the increased risk associated with hypoxia, and in other conditions where the risk of hypokalemia is elevated. In these cases, monitoring of serum potassium levels is recommended.

In patients with diabetes mellitus, additional monitoring of blood glucose concentration is recommended.

Bufomix Iziheiler contains approximately 4 mg of lactose per inhalation. This amount usually does not cause problems in patients with lactose intolerance. This excipient contains a small amount of milk proteins, which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy. There are no clinical data on the effects of Bufomix Iziheiler or combined treatment with formoterol and budesonide during pregnancy. Animal studies on embryofetal development did not demonstrate any additional effects of the combination.

There is insufficient data on the use of formoterol in pregnant women. Formoterol caused adverse effects in animals during reproductive toxicity studies at very high systemic exposure levels.

Data from approximately 2000 studied pregnancies did not show an increased teratogenic risk associated with inhaled budesonide. Animal studies have shown that glucocorticoids can cause developmental abnormalities. This is unlikely in humans using the drug at the recommended dose.

Animal studies have also shown that excessive prenatal glucocorticoids increase the risk of intrauterine growth retardation, adult cardiovascular disease, irreversible changes in glucocorticoid receptor density, neurotransmitter turnover, and behavior at concentrations below the teratogenic dose range.

Bufomix Iziheiler should be used during pregnancy only if the expected benefit outweighs the potential risk. The lowest effective dose of budesonide necessary to maintain adequate control of bronchial asthma should be used.

Lactation. Budesonide is excreted in breast milk. However, no effects on the breastfed infant are expected at therapeutic doses. It is unknown whether formoterol is excreted in human breast milk. A small amount of formoterol has been detected in the milk of animals. The use of Bufomix Iziheiler 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. In animal studies on the effects of formoterol on reproductive function, a slightly reduced fertility level was observed in male rats at high systemic exposure.

Ability to affect reaction speed when driving vehicles or operating machinery.

Bufomix Iziheiler has no or negligible influence on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Dosing

Bronchial Asthma

The medicinal product Bufomix Easyhaler is not intended for initial treatment of bronchial asthma. The doses of the components of the medicinal product should be individually selected and adjusted according to the severity of the disease. This should be taken into account not only at the beginning of treatment with combined preparations but also during adjustment of the maintenance dose. If a patient requires a combination of doses different from those available in the combined inhaler, appropriate doses of β2-adrenoceptor agonists and/or corticosteroids should be prescribed using separate inhalers.

The dose should be titrated to the lowest dose that effectively controls symptoms. Patients must undergo regular follow-up examinations by the physician who prescribed Bufomix Easyhaler to ensure that the dose remains optimal. After achieving long-term symptom control with the lowest recommended dose, an attempt should be made to control symptoms using only an inhaled corticosteroid.

There are two regimens for using Bufomix Easyhaler:

A. Maintenance therapy: Bufomix Easyhaler is used for regular maintenance therapy in combination with a separate short-acting bronchodilator used as a rescue medication.

B. Maintenance therapy and symptom relief: Bufomix Easyhaler is used for regular maintenance therapy and, as needed, for symptom relief.

A. Maintenance Therapy

Patients should be advised to always carry a separate short-acting bronchodilator for use as a rescue medication.

Recommended Doses:

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

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

Children (aged 6 years and older): 2 inhalations twice daily.

After achieving symptom control with twice-daily administration, the dose should generally be titrated down to the lowest effective dose, including reducing to once-daily use of Bufomix Easyhaler, when, in the physician’s opinion, the patient requires maintenance therapy with a long-acting bronchodilator in combination with an inhaled corticosteroid.

Increased use of a short-acting bronchodilator indicates worsening of the patient’s condition and the need to reassess the treatment of bronchial asthma.

Children under 6 years of age: Due to limited data available, Bufomix Easyhaler is not recommended for children under 6 years of age.

B. Maintenance Therapy and Symptom Relief

Patients take the daily maintenance dose of Bufomix Easyhaler and additionally use Bufomix Easyhaler as needed for symptom relief. Patients should be advised to always carry Bufomix Easyhaler for immediate use as a rescue medication.

Use of Bufomix Easyhaler for maintenance therapy and symptom relief should be considered particularly for patients:

• with inadequate control of bronchial asthma who frequently require medications for symptom relief;

• with a history of asthma exacerbations requiring medical intervention.

Patients who frequently and in large quantities use Bufomix Easyhaler on an as-needed basis should be closely monitored for the development of dose-dependent adverse effects.

Recommended Doses:

Adults and adolescents (aged 12 years and older): The recommended maintenance dose is 2 inhalations per day – either 1 inhalation in the morning and 1 in the evening, or 2 inhalations either in the morning or in the evening. As needed, when symptoms occur, 1 additional inhalation should be taken. If symptoms do not resolve within a few minutes, another inhalation may be administered. In any single episode, no more than 6 inhalations should be used.

Generally, no more than 8 inhalations per day are 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 reassessment and review of their maintenance therapy.

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

General Information

Special Patient Groups

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

Method of Administration

For inhalation use.

How to Use Bufomix Easyhaler Correctly

The inhaler is activated by the airflow during inhalation. This means that when the patient inhales through the mouthpiece, the medication is delivered into the airways along with the inhaled air.

Important points to emphasize to the patient:

• Carefully read the instructions for medical use.
• Shake the device and activate it before each inhalation.
• Inhale through the mouthpiece sufficiently actively and deeply to ensure optimal delivery of the medication to the lungs.
• Do not exhale through the mouthpiece, as this may reduce the delivered dose. If this occurs, the patient should tap the inhaler gently on a hard surface or the palm of the hand to dislodge any powder from the mouthpiece, then repeat the inhalation procedure.
• Do not activate the device more than once without inhaling the powder. If this occurs, the patient should tap the inhaler gently on a hard surface or the palm of the hand to clear the mouthpiece, then repeat the inhalation procedure.
• Always replace the dust cap after using the inhaler to prevent accidental dispersion of powder (which could lead to either overdose or insufficient medication delivery during the next use).
• Rinse the mouth with water after inhaling the prescribed dose to minimize the risk of developing oral candidiasis. If oral candidiasis occurs, patients should rinse their mouth with water after inhalations as needed.
• Clean the mouthpiece regularly with a dry cloth. Water should not be used for cleaning, as the powder is hygroscopic.
• Replace the Bufomix Easyhaler when the dose counter reaches zero, even if some powder remains visible inside the device.

Children

Bufomix Easyhaler is not recommended for children under 6 years of age. It may be used in children aged 6 years and older as indicated, according to the doses specified in the section "Method of Administration and Dosage."

In children receiving long-term inhaled corticosteroids, regular monitoring of growth is recommended. If growth slows, the treatment regimen should be reassessed with the aim of reducing the inhaled corticosteroid dose to the lowest level that maintains effective control of bronchial asthma. The benefits of corticosteroid therapy should be carefully weighed against the risk of growth suppression. Additionally, the patient should be referred to a pediatric pulmonologist.

Some long-term study data indicate that most children and adolescents treated with inhaled budesonide eventually achieve their target adult height. However, an initial small, transient reduction in growth (approximately 1 cm) has been observed, typically during the first year of treatment.

Overdose

Symptoms. Overdose of formoterol may be associated with symptoms typically seen with β2-adrenoceptor agonist overdose: tremor, headache, tachycardia. In isolated cases, symptoms such as tachycardia, hyperglycemia, hypokalemia, prolonged QTc interval, arrhythmia, nausea, and vomiting have been reported. Supportive and symptomatic treatment is indicated. A dose of 90 mcg administered over three hours in patients with acute bronchial obstruction was found to be safe.

Acute overdose of budesonide, even after administration of excessive doses, is not expected to cause clinical problems. However, chronic use of excessive doses may lead to glucocorticosteroid effects such as hypercorticism and adrenal suppression.

If treatment with Bufomix Easyhaler must be discontinued due to formoterol overdose, appropriate therapy with inhaled corticosteroids should be considered.

Side effects

Since the medicinal product Bufomix Easyhaler contains both budesonide and formoterol, patients may experience adverse reactions characteristic of these two substances. No increase in the frequency of adverse reactions has been observed following the concomitant use of these two substances. The most common treatment-related adverse reactions correspond to the pharmacologically predictable side effects of β2-agonist therapy. These include tremor and palpitations, which are usually mild and resolve within a few days.

The adverse reactions associated with budesonide or formoterol are listed below by system organ class and frequency of occurrence. Frequency is defined according to the following scale: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000).

Infections and infestations

Common: Oropharyngeal candidiasis.

Immune system disorders

Rare: Immediate or delayed hypersensitivity reactions such as rash, urticaria, pruritus, dermatitis, angioedema, and anaphylactic reaction.

Endocrine disorders

Very rare: Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density.

Metabolism and nutrition disorders

Rare: Hypokalaemia.

Very rare: Hyperglycaemia.

Psychiatric disorders

Uncommon: Aggression, psychomotor hyperactivity, anxiety, sleep disorders.

Very rare: Depression, behavioural changes (mainly in children).

Nervous system disorders

Common: Headache, tremor.

Uncommon: Dizziness.

Very rare: Taste disturbance.

Eye disorders

Uncommon: Blurred vision.

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, blood pressure fluctuations.

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: Bruising.

Musculoskeletal and connective tissue disorders

Uncommon: Muscle cramps.

Oropharyngeal candidiasis is caused by deposition of the drug in the oropharynx. Patients should be advised to rinse the mouth with water after each dose to minimize the risk. Oropharyngeal candidiasis usually responds to local antifungal treatment and does not require discontinuation of inhaled corticosteroids. In case of oropharyngeal candidiasis, rinsing the mouth with water after administration of the drug should also be considered.

As with other forms of inhaled therapy, paradoxical bronchospasm may occur in rare cases, affecting 1 in 10,000 patients. In such cases, wheezing and breathlessness increase immediately after dosing. Paradoxical bronchospasm responds to fast-acting inhaled bronchodilators and must be treated immediately. Bufomix Easyhaler should be discontinued immediately, the patient should be examined, and alternative therapy initiated if necessary.

Systemic effects of inhaled corticosteroids may occur, particularly with long-term use of high doses. These effects are much less likely than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid appearance, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, and glaucoma. Increased susceptibility to infections and impaired ability to respond to stress may develop. These effects are likely dose-, duration-, and individual-sensitivity-dependent and may be influenced by concomitant or prior steroid use.

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

Paediatric populations

Regular monitoring of growth is recommended in children receiving long-term inhaled corticosteroid therapy.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life: 2 years in the laminated pouch.

Use within 4 months after opening the laminated pouch.

Storage conditions.

Prior to opening the laminated pouch, the product does not require special storage conditions. After opening the laminated pouch, store at a temperature not exceeding 25°C in a dry place. Keep out of the reach of children.

Packaging.

120 doses per inhaler with a protective cap in a laminated pouch.

1 laminated pouch per cardboard box.

Prescription status. Prescription only.

Manufacturer. Orion Corporation.

Manufacturer's address.

Orionintie 1, 02200 Espoo, Finland.