Bufomix Easyhaler inhalation powder 160 mcg/dose + 4.5 mcg/dose inhaler with protective cap 120 doses

Instructions Bufomix Easyhaler inhalation powder 160 mcg/dose + 4.5 mcg/dose inhaler with protective cap 120 doses

Composition

active ingredients: 1 dose contains budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg;

excipient: lactose monohydrate.

Dosage form

Inhalation powder.

Main physicochemical properties: white or yellowish-white powder.

Pharmacotherapeutic group

Drugs used in obstructive airway diseases. Adrenergic drugs in combination with corticosteroids or other drugs, except anticholinergic drugs. Formoterol and budesonide. ATX code R03A K07.

Pharmacological properties

Pharmacodynamics

Mechanisms of action and pharmacodynamic effects

Bufomix Easyhaler contains formoterol and budesonide, which have different modes of action and demonstrate 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 therapy of bronchial asthma.

Budesonide. Budesonide is a glucocorticosteroid that, when inhaled, exerts a dose-dependent anti-inflammatory effect in the airways, resulting in a reduction in the symptoms of bronchial asthma. Inhaled budesonide is characterized by less severe adverse effects than systemic corticosteroids. The exact mechanism of the anti-inflammatory effect of glucocorticosteroids is unknown.

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

Clinical efficacy and safety

Bronchial asthma

Studies in adult patients have shown that adding formoterol to budesonide alleviated asthma symptoms and improved lung function, as well as reduced the frequency of exacerbations.

The use of budesonide/formoterol for maintenance therapy and for symptom relief provided a statistically significant and clinically meaningful reduction in the frequency of severe asthma exacerbations in all groups compared to all other types of therapy.

In patients presenting for medical attention due to acute asthma symptoms, budesonide/formoterol provided rapid and effective relief of bronchospasm symptoms similar to salbutamol and formoterol.

Chronic obstructive pulmonary disease (COPD)

Two 12-month studies evaluated the effects of the drug on lung function and exacerbation rate (as measured 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 <50% predicted. The median post-bronchodilator FEV1 at study entry was 42% predicted.

The mean number of exacerbations per year (as defined above) was significantly reduced in the budesonide/formoterol group compared with formoterol monotherapy or placebo (mean rate 1.4 compared with 1.8-1.9 in the placebo/formoterol group). The mean number of days of oral corticosteroids/patient over 12 months was slightly reduced in the budesonide/formoterol group (7-8 days/patient/year compared with 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 superior to treatment with formoterol alone.

Pharmacokinetics

Absorption

The fixed-dose combination of budesonide and formoterol and the respective monotherapy preparations were shown to be bioequivalent with respect to the systemic exposure of budesonide and formoterol, respectively. However, a slight suppression of cortisol was observed after administration of the fixed-dose combination compared to the monotherapy preparations. This difference is not considered to have an impact on clinical efficacy.

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

Inhaled formoterol is rapidly absorbed, with Cmax achieved within 10 minutes after inhalation. In studies, the mean lung deposition of formoterol after inhalation using 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 by conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are mainly observed as inactivated conjugates). Budesonide undergoes extensive (approximately 90%) first-pass biotransformation through the liver to metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the main metabolites - 6-β-hydroxy-budesonide and 16-α-hydroxy-prednisolone - is less than 1% of the glucocorticosteroid activity of budesonide. There are no signs of any metabolic interactions or any substitution reactions between formoterol and budesonide.

Breeding

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

Budesonide is eliminated by metabolism, mainly catalyzed by the enzyme CYP3A4. Budesonide metabolites are excreted in the urine in pure or conjugated form. Only very small amounts of unchanged budesonide are found in the urine. Budesonide has a high systemic clearance (approximately 1.2 l/min) and a plasma half-life of 4 hours after an intravenous dose.

The pharmacokinetics of budesonide or formoterol in patients with renal insufficiency are unknown. The exposure to budesonide and formoterol may be increased in patients with liver disease.

Linearity/nonlinearity

Systemic exposure for budesonide and formoterol is linearly correlated with the applied dose.

Indication

Bronchial asthma

Bufomix Easyhaler is indicated in adults and adolescents (aged 12 years and older) for the regular treatment of bronchial asthma when the use of a combination (inhaled corticosteroids and long-acting β2-adrenoceptor agonists) is appropriate: for patients who are not adequately controlled with inhaled corticosteroids and short-acting β2-adrenoceptor agonists used "as needed", or for patients who are already adequately controlled with both inhaled corticosteroids and long-acting β2-adrenoceptor agonists.

COPD

Bufomix Easyhaler is indicated for the symptomatic treatment of adult patients aged 18 years and older with COPD with a forced expiratory volume in 1 second (FEV1) <70% predicted normal (after bronchodilator use) and a history of exacerbations despite regular bronchodilator therapy.

Contraindication

Hypersensitivity to budesonide, formoterol or lactose (which contains small amounts of milk protein).

Interaction with other medicinal products and other types of interactions

Pharmacokinetic interactions

Potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and HIV protease inhibitors) are likely to increase the plasma levels of budesonide and should therefore be avoided. If this is not possible, the time intervals between doses of these drugs should be as long as possible. Maintenance therapy is not recommended for patients taking potent CYP3A4 inhibitors.

The potent CYP3A4 inhibitor ketoconazole, 200 mg once daily, increased the plasma levels of concomitantly administered oral budesonide (single dose 3 mg) by an average of 6-fold. When ketoconazole was administered 12 hours after budesonide, the concentration increased by an average of only 3-fold, suggesting that separate administration may reduce the increase in plasma levels. Some data suggest that a significant increase in plasma levels of budesonide (average 4-fold) may occur when itraconazole 200 mg once daily is co-administered with inhaled budesonide (single dose 1000 mcg).

Concomitant treatment with cobicistat-containing products is expected to increase the risk of systemic adverse reactions. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions. In such cases, patients should be monitored for systemic corticosteroid adverse reactions.

Pharmacodynamic interactions

Beta-blockers may reduce the effect of formoterol. Therefore, Bufomix Easyhaler should not be used together with beta-blockers (including eye drops) unless there are compelling reasons for this.

In addition, levodopa, levothyroxine, oxytocin, and alcohol may impair cardiac tolerance to β2-sympathomimetics.

Concomitant treatment with monoamine oxidase inhibitors, including drugs with similar properties such as furazolidone and procarbazine, may cause hypertensive reactions.

The risk of developing arrhythmia increases during anesthesia with halogenated hydrocarbons.

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

Hypokalemia may increase the susceptibility to cardiac arrhythmias in patients treated with digitalis 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 warnings and precautions for use").

No interactions of budesonide and formoterol with any other drugs used to treat bronchial asthma have been observed.

Pediatric populations

Drug interaction studies have only been conducted in adults.

Monoamine oxidase inhibitors and tricyclic antidepressants

Bufomix Easyhaler should be used with caution in patients taking monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of stopping treatment with such agents, since the effect of formoterol (a component of Bufomix Easyhaler) on the vascular system may be enhanced by these drugs.

Diuretics

ECG changes and/or hypokalaemia caused by non-potassium-sparing diuretics (such as loop or thiazide diuretics) may be suddenly exacerbated by β-agonists, especially if the recommended dose of β-agonists is exceeded. Although the clinical significance of these effects remains unclear, caution is advised when Bufomix Easyhaler is used concomitantly with non-potassium-sparing diuretics.

Application features

It is recommended to gradually reduce the dose when discontinuing the drug and not to stop taking it abruptly. Inhaled corticosteroids should not be completely discontinued, except in cases where temporary withdrawal is necessary to confirm the diagnosis of bronchial asthma.

If patients find that treatment is ineffective or if the highest recommended dose of Bufomix Easyhaler is required, they should consult a doctor. Sudden and progressive deterioration in asthma or COPD control is potentially life-threatening and the patient should be evaluated immediately. In such cases, consideration should be given to increasing corticosteroid therapy, e.g. a course of oral corticosteroids, or antibiotic treatment if infection is present.

The patient should be advised to always carry a rescue inhaler: either Bufomix Easyhaler (for patients with bronchial asthma who use Bufomix Easyhaler as maintenance therapy and relieve symptoms), or a separate fast-acting bronchodilator (for all patients who use Bufomix Easyhaler as maintenance therapy).

Patients should be reminded to take the maintenance dose of Bufomix Easyhaler as prescribed, even in the absence of symptoms. Once asthma symptoms are controlled, consideration should be given to gradually reducing the dose of Bufomix Easyhaler. It is important to review patients regularly as the dose is reduced. The lowest effective dose of Bufomix Easyhaler should be used.

Treatment with the drug should not be initiated during exacerbations, significant deterioration, or sudden complication of bronchial asthma.

Serious adverse events and exacerbations of asthma may occur during treatment with Bufomix Easyhaler. Patients should be advised to continue treatment and to seek medical advice if asthma symptoms are not controlled or worsen after starting Bufomix Easyhaler.

There are no clinical trial data on the use of Bufomix Easyhaler in patients with COPD with a pre-bronchodilator FEV1 >50% predicted normal and a post-bronchodilator FEV1 <70% predicted normal.

Systemic effects of inhaled corticosteroids may occur, particularly when high doses are used for long periods of time. These effects are much less likely than those seen with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataracts, glaucoma and, much less frequently, various psychological and behavioral abnormalities, including psychomotor hyperactivity, sleep disturbances, anxiety, depression, or aggression (especially in children).

Visual disturbances may occur with systemic and topical corticosteroids. If a patient reports symptoms such as blurred vision or other visual disturbances, the patient should be referred to an ophthalmologist for evaluation of possible causes, which may include cataracts, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which have been reported following the use of systemic and topical corticosteroids.

The potential effect on bone mineral density should be considered, especially in patients taking high doses for long periods of time and who have concomitant risk factors for osteoporosis. Long-term studies of inhaled budesonide in children at average daily doses of 400 mcg (metered dose) or in adults at daily doses of 800 mcg (metered dose) have not shown any significant effect on bone mineral density. There is no information on the effect of high doses.

If there is reason to suspect deterioration of adrenal function due to previous systemic steroid therapy, caution should be exercised when transferring patients to Bufomix Easyhaler therapy.

The benefits of inhaled budesonide therapy usually minimize the need for oral steroids, but patients who are transferred from oral steroids are at risk of having reduced adrenal reserve for a long time. Recovery may take a long time after stopping oral steroid therapy, so patients who have previously used oral steroids and are transferred to inhaled budesonide may remain at risk for a significant period of time due to impaired adrenal function. In such cases, regular monitoring of hypothalamic-pituitary-adrenal function is necessary.

Prolonged treatment with high doses of inhaled corticosteroids, particularly at doses higher than recommended, may result in clinically significant suppression of adrenal function. Therefore, additional systemic corticosteroid treatment should be considered during periods of stress, such as severe infections and elective surgery. Rapid reduction of steroid doses may precipitate acute adrenal insufficiency. Symptoms that may be seen with acute adrenal insufficiency 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 should not be stopped abruptly.

When switching from oral medication to Bufomix Easyhaler, there is a general lower systemic steroid effect, which may lead to allergic or arthritic symptoms such as rhinitis, eczema, muscle and joint pain. In this case, specific treatment should be initiated. A general insufficient effect of glucocorticosteroids should be suspected if symptoms such as fatigue, headache, nausea and vomiting occur in isolated cases. In such cases, it may be necessary to temporarily increase the dose of oral glucocorticosteroids.

To reduce the risk of oropharyngeal candidiasis, patients should rinse their mouth thoroughly with water after inhalation of the maintenance dose. If oropharyngeal candidiasis occurs, patients should also rinse their mouth with water after use of the drug, if necessary.

Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided. If this is not possible, the time intervals between doses should be as long as possible. In patients taking potent CYP3A4 inhibitors, the concomitant use of Bufomix Easyhaler for maintenance therapy and symptom relief is not recommended.

Bufomix Easyhaler should be administered with caution to 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.

When treated with high doses of β2-adrenoceptor agonists, potentially life-threatening hypokalemia may develop. The hypokalemic effect of β2-adrenoceptor agonists may be enhanced by concomitant treatment with β2-adrenoceptor agonists and drugs that can cause hypokalemia or enhance the hypokalemic effect, such as xanthine derivatives, steroids and diuretics. Particular caution should be exercised in unstable bronchial asthma in the event of intermittent use of rescue bronchodilators, in acute severe bronchial asthma, since the associated risk is increased by hypoxia, as well as in other conditions where the risk of hypokalemia is increased. In these cases, it is recommended to monitor the level of potassium in the blood serum.

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

Pneumonia and other lower respiratory tract infections

Physicians should be aware of the possibility of pneumonia in patients with COPD, given the frequent overlap of clinical features of pneumonia and exacerbation of the underlying disease. Lower respiratory tract infections, including pneumonia, have been reported following the use of inhaled corticosteroids.

Immunosuppression

Patients taking drugs that suppress the immune system are more susceptible to infection than healthy people.

Pneumonia in patients with COPD

An increased incidence of pneumonia, including pneumonia requiring hospitalization, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid doses, but this has not been demonstrated reliably in all studies.

There is no convincing clinical evidence of intraclass differences in the risk of pneumonia between inhaled corticosteroid preparations.

Physicians should remain alert to the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with symptoms of COPD exacerbation.

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

Bufomix Easyhaler contains approximately 4 mg of lactose per inhalation. This amount is not usually a problem for patients with lactose intolerance. The excipient lactose contains small amounts of milk proteins which may cause allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy: There are no clinical data on the effects of Bufomix Easyhaler or concomitant treatment with formoterol and budesonide on pregnancy. Animal embryo-fetal development studies have not shown any additive effect of the combination.

There are no adequate data from the use of formoterol in pregnant women. Formoterol has caused adverse effects in animal reproductive studies at very high systemic exposure levels.

Data on approximately 2000 exposed pregnancies have not shown an increased teratogenic risk associated with inhaled budesonide. Animal studies have shown that glucocorticosteroids cause malformations. This is unlikely in humans given recommended doses.

Animal studies have also found 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.

During pregnancy, Bufomix Easyhaler should be used 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.

Breastfeeding. Budesonide is excreted in breast milk. However, at therapeutic doses, no effects on the breastfed infant are expected. It is not known whether formoterol is excreted in human milk. Small amounts of formoterol have been detected in animal breast milk. The use of Budesonide Easyhaler in breast-feeding women should only be considered if the expected benefit to the mother outweighs any possible risk to the foetus.

Fertility: There are no data on the potential effects of budesonide on fertility. In animal reproductive studies, formoterol showed a slightly reduced fertility in male rats at high systemic exposure.

Ability to influence reaction speed when driving vehicles or other mechanisms

Bufomix Easyhaler has no or negligible influence on the ability to drive and use machines.

If dizziness, tremors, or seizures occur during treatment, you should not drive or operate machinery.

Method of administration and doses

Dosage

Bufomix Easyhaler is not prescribed for the initial treatment of bronchial asthma. The doses of the components of the drug Bufomix Easyhaler are selected individually and adjusted according to the severity of the disease. This should be taken into account not only at the beginning of the use of combination drugs, but also when adjusting the maintenance dose. If the patient requires a combination of doses that differs from those available in the combination inhaler, appropriate doses of β2-adrenoceptor agonists and/or corticosteroids in separate inhalers should be prescribed.

The dose should be titrated to the lowest dose that effectively controls symptoms. Patients should be re-evaluated regularly by their prescriber to ensure that the dose of Bufomix Easyhaler remains optimal. Once long-term symptom control is achieved with the lowest recommended dose, symptoms should be controlled with an inhaled corticosteroid alone.

There are two options for using the Bufomix Easyhaler drug.

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

B. maintenance therapy and symptom relief: Bufomix Easyhaler is used for regular maintenance therapy, as well as, if necessary, for symptom relief.

A. supportive therapy

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

Recommended doses:

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

Adolescents (12-17 years): 1-2 inhalations 2 times a day.

Typically, after achieving control of the symptoms of the disease with the use of the drug twice a day, the dose is titrated to the lowest effective dose, including the use of the drug Bufomix Easyhaler 1 time a day, in cases where, in the opinion of the physician, the patient requires maintenance therapy with a long-acting bronchodilator in combination with an inhaled corticosteroid.

More frequent use of an additional rapid-acting bronchodilator indicates a worsening of the patient's condition and the need to review asthma treatment.

B. supportive care and symptom relief

A daily maintenance dose of Bufomix Easyhaler is taken, and Bufomix Easyhaler is used additionally when symptom relief is needed. Patients should be advised to always carry Bufomix Easyhaler for immediate use as a rescue medication.

Physicians and patients using Bufomix Easyhaler for reliever symptoms should discuss the prophylactic use of Bufomix Easyhaler for allergen- or exercise-induced bronchospasm; the frequency of dosing should also be considered when recommending the drug. In cases of frequent need for bronchodilation without a corresponding need for increased doses of inhaled corticosteroids, alternative therapy should be considered.

The use of Bufomix Easyhaler for maintenance therapy and symptom relief should be considered in particular in patients:

with insufficiently controlled bronchial asthma, who often need medications to relieve symptoms;

with exacerbation of bronchial asthma in the past, which required medical intervention.

Patients who use Bufomix Easyhaler inhalations frequently and in large quantities as needed should be closely monitored for the development of dose-related adverse events.

Recommended doses:

Adults and adolescents (12 years of age and older): The recommended maintenance dose is 2 inhalations per day – 1 inhalation in the morning and evening or 2 inhalations in the morning or evening only. Some patients may require a maintenance dose of 2 inhalations twice a day. If necessary, 1 additional inhalation should be used in case of symptoms. If symptoms do not disappear after a few minutes, an additional inhalation should be used. In any individual case, no more than 6 inhalations should be used.

Usually, a total of no more than 8 inhalations are required per day; however, for a limited period, the total daily dose may be up to 12 inhalations. Patients who use more than 8 inhalations per day are strongly advised to consult a doctor. They should be re-examined and their maintenance therapy reviewed.

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

COPD

Recommended doses:

Adults: 2 inhalations 2 times a day.

General information

Special patient groups

There are no special dosage requirements for elderly patients. There are no data on the use of Bufomix Easyhaler in patients with impaired renal or hepatic function. Since budesonide and formoterol are eliminated primarily by hepatic metabolism, increased exposure can be expected in patients with severe cirrhosis of the liver.

Method of application

For inhalation.

How to use Bufomix Easyhaler correctly

The inhaler is flow-controlled. This means that when the patient inhales air through the mouthpiece, the substance enters the airways along with the inhaled air.

It is important to draw the patient's attention to the following:

Carefully read the instructions for medical use.

After opening the laminated package, it is recommended to store the device in a protective container to protect it from shocks and ensure reliable operation of the device.

Shake the device and prime it before each inhalation.

Inhale through the mouthpiece actively and deeply enough to ensure the optimal dose of the substance enters the lungs.

Do not exhale through the mouthpiece as this will reduce the dose delivered. If this does happen, tap the inhaler on a table or in the palm of your hand to remove the powder from the mouthpiece and then repeat the dosing procedure.

Do not actuate the device more than once without inhaling the powder. If this does happen, the patient should tap the inhaler on a table or the palm of their hand to remove the powder from the mouthpiece, and then repeat the dosing procedure.

Always put on the dust cap and close the protective container lid after using the inhaler to prevent accidental spraying of the powder from the device (which could lead to either an overdose or inhalation of an insufficient amount of the drug the next time you use the inhaler).

Rinse mouth with water after inhalation of the prescribed dose to minimize the risk of developing oral candidiasis. If oral candidiasis occurs, patients should rinse mouth with water after inhalations “as needed.”

Clean the mouthpiece regularly with a dry cloth. Do not use water for cleaning as the powder is hygroscopic.

Replace the Bufomix Easyhaler inhaler when the counter shows zero, even if some powder is still visible inside the device.

Children.

Bufomix Easyhaler is not recommended for children under 12 years of age for the treatment of bronchial asthma.

In children receiving long-term therapy with inhaled corticosteroids, it is recommended to measure height regularly. If growth is slowed, the treatment regimen should be reviewed with the aim of reducing the dose of inhaled corticosteroid to the minimum that ensures effective control of bronchial asthma. The benefits of corticosteroid treatment should be carefully weighed against the risk of growth suppression. In addition, the patient should be referred to a pediatric pulmonologist.

Some evidence from long-term studies suggests that most children and adolescents treated with inhaled budesonide eventually reach their target adult height. However, there has been an initial small temporary reduction in height (approximately 1 cm). This generally occurs during the first year of treatment.