Budesonide, Formoterol

Pharmacological properties

bufomix isheiler contains formoterol and budesonide, which have a different mode of action and demonstrate additive effects to reduce the severity of exacerbations of ba.

Budesonide. Budesonide is a corticosteroids, when inhaled, has a dose-dependent anti-inflammatory effect in the respiratory tract, as a result of which the severity of AD symptoms decreases. Inhaled budesonide is characterized by less severe side effects than systemic corticosteroids. The exact mechanism of the anti-inflammatory effect of GCS is unknown.

Formoterol. Formoterol is a selective β-adrenostimulator₂-adrenoreceptors, which, when inhaled, provides fast and long-term relaxation of the smooth muscles of the bronchi in patients with reverse obstruction of the airways. The bronchodilating 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.

Pharmacokinetics

Suction. It was shown that the combination of fixed doses of budesonide and formoterol Bufomix Isheiler and the corresponding monopreparations are bioequivalent in the systemic effects of budesonide and formoterol, respectively. Despite this, after administration of a combination of fixed doses, a slight suppression of cortisol was noted compared with monopreparations. It is believed that the difference does not affect clinical efficacy.

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

The pharmacokinetic parameters of budesonide and formoterol were comparable after their administration as single drugs or as a combination of fixed doses. In budesonide, AUC and absorption rate were slightly higher, and C_max in blood plasma above after the introduction of a fixed combination. Formoterol C_max in blood plasma was similar after administration of a fixed combination. Inhaled budesonide is rapidly absorbed, and C_max in blood plasma is reached within 30 minutes after inhalation. In studies, the mean lung deposition of budesonide after inhalation with a 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, deposition in the lungs is in the same range as in adults after applying the same given dose. The resulting plasma concentrations were not determined.

Inhaled formoterol is rapidly absorbed, and C_max in blood plasma is reached within 10 minutes after inhalation. In studies, the mean lung deposition of formoterol after inhalation with a 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 about 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 as a result of conjugation reactions (active O-demethylated and deformulated metabolites are formed, however, they are mainly inactivated conjugates). Budesonide undergoes significant (about 90%) biotransformation upon first passage through the liver to metabolites with low GCS activity. GCS activity of the main metabolites - 6-β-hydroxy-budesonide and 16-α-hydroxy-prednisolone - less than 1% of the GCS activity of budesonide. There are no signs of any metabolic interactions or any substitution reactions between formoterol and budesonide.

Most of the dose of formoterol is transformed by hepatic metabolism, followed by excretion by the kidneys. After inhalation, 8–13% of the delivered dose of formoterol is excreted unchanged in the urine.Formoterol has a high systemic clearance (approximately 1.4 L / min), and the final T_½ averages 17 hours

Budesonide is excreted by metabolism, mainly under the influence of a catalyst, which is the enzyme CYP 3A4. Budesonide metabolites are excreted in the urine in pure form or in conjugated form. Only very small amounts of unchanged budesonide are detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L / min), and T_½ after the dose is 4 hours

The pharmacokinetics of formoterol in children have not been studied. The pharmacokinetics of budesonide or formoterol in patients with renal failure is unknown. The effects of budesonide and formoterol may increase in patients with liver disease.

Indications

Bufomix isheiler is indicated for the regular treatment of asthma, when the use of a combination (inhaled corticosteroids and long-acting β2-adrenergic agonists) is advisable: for patients who do not achieve adequate control with short-acting β2-adrenergic inhaled corticosteroids and agonists, used as needed ", Or for patients who have already achieved adequate control when using both inhaled corticosteroids and β2-adrenergic agonists long acting.

Application

Dosage. buffomyx isheiler is not prescribed for initial treatment of ba. doses of the components of buffomyx isheiler are selected individually and adjusted depending on 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 needs a combination of doses that differ from those in the combined inhaler, appropriate doses of β2-adrenergic receptor agonists and / or corticosteroids in separate inhalers should be prescribed.

The dose should be titrated to the minimum dose, which allows you to effectively control the symptoms of the disease. Patients need to undergo repeated examinations regularly with the doctor who prescribed the drug so that the dose of Bufomix Isheiler remains optimal. After achieving long-term symptom control with the lowest recommended dose, you should try to control your symptoms with an inhaled corticosteroid only.

The patient must be warned about the need to constantly keep with him a separate high-speed bronchodilator as a life-saving aid.

Recommended Dosage

Adults: 1-2 inhalations 2 times a day. Some patients may require up to 4 inhalations 2 times a day (maximum dose).

Children aged 12-17 years: 1-2 inhalations 2 times a day.

Children under 12 years of age: Bufomix Isheiler is not recommended for children under 12 years of age.

Usually, after controlling for the symptoms of the disease when using the drug 2 times a day, the dose is titrated to the lowest effective dose, up to the use of the drug Bufomix Isheiler once a day, when, according to the doctor, the patient needs long-term bronchodilator maintenance therapy.

The need for more frequent use of a separate high-speed bronchodilator indicates a deterioration in the patients condition and the need to review the treatment of AD.

Special categories of patients. There are no specific dosage requirements for elderly patients.

There is no data on the use of the drug Bufomix Isheiler in patients with hepatic or renal failure. Since budesonide and formoterol are predominantly excreted by hepatic metabolism, increased exposure to severe liver cirrhosis can be expected.

Mode of application. For inhalation.

How to use the drug Bufomix Izheiler

The inhaler is controlled by the inhaled flow of air.This means that when the patient inhales air through the mouthpiece, the substance enters the respiratory tract along with the inhaled air.

1. Remove the protective cap from the mouth of the Izheiler.

2. Shake the inhaler 3-5 times in an upright position.

3. To release the 1st dose of the drug, place Isheiler between the thumb and forefinger and press the inhaler once. When clicked, a click will be heard.

4. Take a full breath, tightly grasp the mouthpiece with your lips and take a deep breath, holding your breath for 5-10 seconds.

5. If more than 1 dose is prescribed, repeat steps 2, 3, and 4.

6. Close the mouth of the Izheiler with a protective cap.

7. The dose counter on the inhaler helps to control the number of remaining doses of the drug. The counter switches every 5 doses. The red zone on the counter means that there are 20 doses left in Isheiler.

It is important to draw the patients attention to the following:

• It is necessary to carefully read the instructions for medical use.
• After opening the laminated bag, it is recommended to store the device in a protective container to protect it from shock and ensure reliable operation of the device.
• Shake the device and actuate it before each inhalation.
• Inhale through the mouthpiece actively and deeply enough to ensure that an optimal dose of the substance is delivered to the lungs.
• Do not exhale through the mouthpiece, as this will reduce the delivered dose. If this still happened, you need to tap the inhaler on the surface of the table or on the palm of your hand to remove the powder from the mouthpiece, and then repeat the procedure for taking the drug.
• Do not operate the device more than 1 time without inhalation of the powder. If this still happened, the patient must tap the inhaler on the surface of the table or on the palm of his hand to remove the powder from the mouthpiece, and then repeat the procedure for taking the drug.
• Always put on a dust cap and close the lid of the protective container after using the inhaler to prevent accidental spraying of powder from the device (which can lead to either an overdose or inhalation of an insufficient amount of the drug during subsequent use of the inhaler).
• Rinse the mouth with water after inhalation of the prescribed dose in order to minimize the risk of developing candidiasis of the oral cavity. If oral candidiasis occurs, patients should rinse their mouth with water after inhalation "as needed."
• Clean the mouthpiece regularly with a dry cloth. Do not use water for cleaning, since the powder is hygroscopic.
• Replace the Bufomix Isheiler inhaler when zero appears on the meter, even if some powder is still visible inside the device.

Contraindications

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

Side effects

Since bufomix isheiler contains both budesonide and formoterol, side effects characteristic of these two substances may occur in patients. after the simultaneous administration of two compounds, there was no increase in the frequency of undesirable reactions. the most common drug-related adverse events correspond to pharmacologically predicted side effects of treatment with β2-agonists. these are phenomena such as tremors and heart palpitations, which are usually insignificant and disappear after a few days.

The organ systems and the frequency of development are listed below for the undesirable reactions that are associated with formoterol. The frequency is determined by the following scale: very often (1/10), often (1/100 to 1/10), infrequently (1/1000 to 1/100), rarely (1/10 000 to 1/1000), very rarely (1/10 000), unknown (frequency cannot be set according to available data).

Infectious and parasitic diseases: often - oropharyngeal candidiasis.

On the part of the immune system: rarely - immediate or delayed hypersensitivity reactions, such as rash, urticaria, itching, dermatitis, angioedema and anaphylactic reaction.

From the endocrine system: very rarely - Cushings syndrome, inhibition of the function of the adrenal cortex, growth retardation, reduced bone mineral density.

From the side of metabolism and nutrition: rarely - hypokalemia; very rarely - hyperkalemia.

From the psyche: infrequently - aggression, psychomotor hyperactivity, anxiety, sleep disturbances; very rarely - depression, changes in behavior (mainly in children).

From the nervous system: often - headache, tremor; infrequently - dizziness; very rarely - a violation of taste.

From the side of the organ of vision: very rarely - cataract and glaucoma.

From the cardiovascular system: often - accelerated heartbeat; infrequently - tachycardia; rarely - arrhythmia, for example, atrial fibrillation, supraventricular tachycardia, extrasystole; very rarely - angina pectoris, lengthening of the Q – Tc interval, fluctuations in blood pressure.

From the respiratory system, chest and mediastinal organs: often - moderate irritation in the throat, cough, hoarseness; rarely - bronchospasm.

From the digestive system: infrequently - nausea.

From the skin and subcutaneous tissue: infrequently - bruises.

From the side of musculoskeletal and connective tissue: infrequently - muscle cramps.

Oropharyngeal candidiasis is caused by drug deposition. Patients should be advised to rinse the oral cavity with water after each dose is applied to minimize risk. Oropharyngeal candidiasis usually responds to topical antifungal treatment and does not require withdrawal of inhaled corticosteroids.

As with other types of inhalation therapy, in rare cases, paradoxical bronchospasm may develop, which affects 1 out of 10,000 patients. In this case, the patient immediately after taking the dose increases wheezing and shortness of breath. Paradoxical bronchospasm responds to fast-acting inhaled bronchodilators, and a patient with this disorder should be treated urgently. It is necessary to immediately stop taking the drug Bufomix Isheiler, examine the patient and, if necessary, prescribe alternative therapy.

The systemic consequences of taking inhaled corticosteroids can develop, in particular, when using high doses for a long time. These effects are much less likely than the effects of oral corticosteroids. Possible systemic effects include Cushings syndrome, cushingoid appearance, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataracts, glaucoma. An increase in susceptibility to infections and a deterioration in the ability to adapt to stress may develop. These effects are likely to depend on dose, exposure time, concurrent or prior steroid use, and individual sensitivity.

Β treatment₂-agonists can lead to increased levels of insulin, free fatty acids, glycerin and ketone bodies in the blood.

Reporting suspected adverse reactions. It is important to report suspected adverse reactions after obtaining a drug registration certificate. This allows you to constantly monitor the benefit / risk ratio of the drug. Health workers are requested to report suspected adverse reactions through the national reporting system.

special instructions

It is recommended to gradually reduce the dose when you refuse the drug and do not abruptly stop taking it.

If patients find that treatment is ineffective, or if there is a need to exceed the highest recommended dose of Bufomix Isheiler, they should consult a doctor.A sudden and progressive deterioration in asthma control is potentially life-threatening, so the patient should immediately undergo a medical examination. In this case, consideration should be given to enhancing corticosteroid therapy (for example, a course of oral corticosteroids) or antibiotic treatment in the presence of infection.

Patients should be warned about the need to constantly keep their rescue inhaler with them.

Patients should be reminded that it is necessary to take a maintenance dose of Bufomix Isheiler in accordance with the prescription, even in the absence of symptoms. The prophylactic use of the drug Bufomix Isheiler, for example before exercise, has not been studied. For this purpose, an additional high-speed bronchodilator should be used.

As soon as the symptoms of AD are taken under control, a gradual reduction in the dose of Bufomix Isheiler should be considered. It is important to regularly examine patients as the dose is reduced. Use the lowest effective dose of Bufomix Isheiler.

Do not start treatment with Bufomix Isheiler with exacerbations, a significant deterioration or a sharp complication of AD.

During treatment with Bufomix Isheiler, serious adverse events and exacerbations associated with AD can occur. Patients should be informed about the need to continue treatment and seek medical attention at the same time if AD symptoms are not controlled or worsen after taking Bufomix Isheiler.

As with other types of inhalation therapy, there is a risk of developing paradoxical bronchospasm. In this case, the patient immediately after taking the dose increases wheezing and shortness of breath. If the patient has a paradoxical bronchospasm, you should immediately stop taking the drug Bufomix Isheiler, examine the patient and, if necessary, prescribe alternative therapy. Paradoxical bronchospasm responds to fast-acting inhaled bronchodilators, and a patient with this disorder should be treated urgently.

The systemic consequences of taking inhaled corticosteroids can develop, in particular, when using high doses for a long time. These effects are much less likely than the effects of oral corticosteroids. Possible systemic effects include Cushings syndrome, cushingoid appearance, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataracts, glaucoma, and much less commonly, various psychological and behavioral abnormalities, including psychomotor hyperactivity, sleep disturbances, anxiety, and depression or aggressiveness (especially in children).

Consideration should be given to the potential effect on bone density, especially in patients taking high doses for a long time and simultaneously having risk factors for osteoporosis. Long-term studies of inhaled budesonide in children with daily average doses of 400 mcg (metered dose) or in adults with daily doses of 800 mcg (metered dose) have not shown a significant effect on bone mineral density. No information is available on the effects of high doses.

If there is reason to believe that adrenal cortex function deteriorates due to prior systemic steroid therapy, care should be taken when transferring patients to therapy with Bufomix Isheiler.

The benefits of inhaled budesonide therapy usually minimize the need for oral steroids, but patients who switch from oral steroids have a risk of lowering the adrenal cortex reserve over time. Recovery may take a long time after stopping oral steroid therapy.In this case, you need to regularly monitor the function "hypothalamus - pituitary gland - adrenal cortex."

Long-term treatment with high-dose inhaled corticosteroids can lead to clinically significant inhibition of adrenal cortex function. Therefore, during stressful periods, such as severe infections and planned operations, additional systemic treatment with corticosteroids should be considered. A rapid decrease in the dose of steroids can provoke an acute insufficiency of the adrenal cortex. Symptoms that can be observed in acute insufficiency of adrenal cortex function include anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, decreased consciousness, seizures, hypotension, and hypoglycemia.

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

When transferring from taking oral drugs to Bufomix Isheiler, a general low systemic effect of steroids is noted, which can lead to allergic or arthritic symptoms such as rhinitis, eczema, muscle and joint pain. In this case, you need to start a specific treatment. The general insufficient effect of GCS should be suspected if, in some cases, symptoms such as fatigue, headache, nausea, and vomiting appear. In such cases, it is sometimes required to temporarily increase the dose of oral corticosteroids.

In order to reduce the risk of developing oral candidiasis, patients need to thoroughly rinse their mouth with water after inhalation of a maintenance dose. In the event of oral candidiasis, patients should rinse the oral cavity with water also after inhalation "as necessary."

Concomitant treatment with itraconazole, ritonavir, or other potent CYP 3A4 inhibitors should be avoided. If this is not possible, the intervals between doses should be as large as possible. For patients who use potent CYP 3A4 inhibitors, maintenance therapy is not recommended.

Bufomix Isheiler should be used 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 disease and cardiovascular disease and .

Caution should be exercised in treating patients with an extended Q – Tc interval. Formoterol itself can cause a prolongation of the Q – Tc interval.

In patients with an active or inactive form of pulmonary tuberculosis, fungal and viral infections in the respiratory tract, a repeated assessment of the need and dose of inhaled corticosteroids is necessary.

In treatment with β agonists₂At high doses of β-adrenoreceptors, potentially life-threatening hypokalemia may develop. Hypokalemic effect of β agonists₂-adrenoreceptors may be enhanced with simultaneous treatment with β-agonists₂-adrenoceptors and drugs that can cause hypokalemia or enhance the hypokalemia effect, for example, xanthine derivatives, steroids and diuretics. Particular caution should be exercised in case of unstable asthma in case of intermittent use of rescue bronchodilators, in acute severe asthma, since the risk associated with this is enhanced by hypoxia, as well as in other conditions where the risk of hypokalemia is increased. In these cases, it is recommended that serum potassium levels be monitored.

In patients with diabetes mellitus, it is recommended that an additional control of the concentration of glucose in the blood be carried out.

Bufomix Isheiler contains approximately 4 mg of lactose per 1 inhalation. Typically, this amount does not cause problems in individuals with lactose intolerance.The excipient lactose contains a small amount of milk proteins, which can cause allergic reactions.

Use during pregnancy and lactation

Pregnancy. There are no clinical data on the effect on pregnancy of the drug Bufomix Isheiler or the simultaneous treatment with formoterol and budesonide. Animal embryo / fetal development studies have not demonstrated any additional combination effect.

There are insufficient data on the use of formoterol in pregnant women. Formoterol caused side effects in animals during studies of the effect on the reproductive system at very high levels of systemic exposure.

Data on approximately 2000 investigated pregnancy cases did not show an increased teratogenic risk associated with the use of inhaled budesonide. Animal studies have shown that corticosteroids cause malformations. This is unlikely for people who receive recommended doses.

Animal studies also found that excessive amounts of perinatal 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 Isheiler should only be used if the expected benefit outweighs the potential risk. It is necessary to apply the lowest effective dose of budesonide necessary to maintain adequate control of AD.

Lactation. Budesonide passes into breast milk. However, at therapeutic doses, no effect is expected on the breastfed baby. It is not known whether formoterol passes into breast milk. A small amount of formoterol has been detected in animal milk. The use of the drug Bufomix Isheiler in women who are breastfeeding should be considered only if the expected benefit to the mother outweighs the possible risk to the fetus.

Children. Bufomix Izheiler is not recommended for children under the age of 12 years.

In children receiving long-term therapy with inhaled corticosteroids, it is recommended to regularly measure growth. If growth slows down, the treatment regimen should be reviewed in order to reduce the dose of the inhaled corticosteroid to the minimum, ensuring the preservation of effective control over the course of AD. The benefits of corticosteroid treatment and the risk of growth inhibition should be carefully weighed. In addition, it is necessary to refer the patient to a pediatric pulmonologist.

Some evidence from long-term studies suggests that most children and adolescents treated with inhaled budesonide eventually achieve their target growth as they grow older. At the same time, an initially small temporary decrease in growth was noted (about 1 cm). In general, it happens during the 1st year of treatment.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms.

In case of dizziness, tremor, convulsions during treatment, you should not drive vehicles or work with mechanisms.

Interactions

Pharmacokinetic interactions

Powerful CYP 3A4 inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and HIV protease inhibitors) are likely to increase plasma levels of budesonide, so their simultaneous use should be avoided. If this is not possible, the intervals between doses of these drugs should be as large as possible. For patients who use potent CYP 3A4 inhibitors, maintenance therapy is not recommended.

A potent inhibitor of CYP 3A4 ketoconazole at a dose of 200 mg once a day raises blood plasma levels of budesonide used simultaneously orally (a single dose of 3 mg), an average of 6 times. When ketoconazole was taken 12 hours after budesonide, the concentration increased on average only 3 times, which indicates that separate administration can reduce the increase in blood plasma levels. Some data indicate that a significant increase in plasma levels of budesonide can occur (on average 4 times) while taking itraconazole at a dose of 200 mg once daily with inhaled budesonide (a single dose of 1000 μg).

Pharmacodynamic interactions. Β-adrenergic blockers can weaken the effect of formoterol. Therefore, Bufomix Isheiler should not be used together with β-adrenergic blockers (including eye drops), unless there are good reasons for this.

Simultaneous treatment with quinidine, disopyramide, procainamide, phenothiazine, antihistamines (terfenadine) and tricyclic antidepressants can extend the Q – Tc interval and increase the risk of ventricular arrhythmia.

In addition, levodopa, levothyroxine, oxytocin, and alcohol may impair β-cardiac tolerance.₂sympathomimetics.

Simultaneous treatment with monoamine oxidase inhibitors, including agents with similar properties, such as furazolidone and procarbazine, can cause hypertensive reactions.

The risk of developing arrhythmias is increased against the background of anesthesia with halogenated bicarbonates.

The simultaneous use of other β-adrenergic drugs or anticholinergics can enhance the bronchodilating effect.

Hypokalemia may increase the tendency to cardiac arrhythmias in patients who are treated with digitalis glycosides.

No interaction of budesonide and formoterol with any other drugs that are used to treat AD is noted.

Overdose

Symptoms an overdose of formoterol may be accompanied by symptoms that usually occur with an overdose of β2-adrenergic agonists: tremor, headache, heart palpitations. in some cases, symptoms such as tachycardia, hyperglycemia, hypokalemia, lengthening of the q – tc interval, arrhythmia, nausea, and vomiting have been reported. supportive and symptomatic treatment is indicated. the dose of 90 mcg taken over 3 hours was safe in patients with acute bronchial obstruction.

With an acute overdose of budesonide, even with excessive doses, clinical problems are not expected. In chronic use of excessive doses, corticosteroids may appear, such as hypercorticism and suppression of adrenal cortex function.

If therapy with Bufomix Isheiler must be discontinued due to an overdose of formoterol, the provision of appropriate therapy with inhaled corticosteroids should be considered.

Storage conditions

Before opening the laminated package, the drug does not require special storage conditions.

After opening the laminated bag, store at a temperature not exceeding 25 ° C in a place protected from moisture.