Foradil Combi capsules with powder d/ing set 12mcg+200mcg No. 120

Compound

Pharmacological action of Foradil Combi

Foradil Combi is a drug with anti-inflammatory and bronchodilator effects. Formoterol is a selective β 2 -adrenergic receptor agonist. It has a bronchodilator effect in patients with both reversible and irreversible airway obstruction. The effect of the drug occurs quickly (within 1-3 minutes) and persists for 12 hours after inhalation. When using the drug in therapeutic doses, the effect on the cardiovascular system is minimal and is observed only in rare cases.

Inhibits the release of histamine and leukotrienes from mast cells. Animal experiments have shown some anti-inflammatory properties of formoterol, such as the ability to inhibit the development of edema and the accumulation of inflammatory cells. In human studies, Foradil Combi has been shown to be effective in preventing bronchospasm caused by inhaled allergens, exercise, cold air, histamine or methacholine.

Since the bronchodilator effect of Foradil Combi remains pronounced for 12 hours after inhalation, maintenance therapy, in which Foradil Combi is prescribed 2 times a day, allows in most cases to provide the necessary control of bronchospasm in chronic lung diseases both during the day and at night. In patients with stable chronic obstructive pulmonary disease (COPD), formoterol causes a rapid onset of a bronchodilator effect and an improvement in quality of life parameters.

Budesonide is a glucocorticosteroid (GCS) for inhalation use with virtually no systemic effect. Budesonide has anti-inflammatory, antiallergic and immunosuppressive effects. Increases the production of lipocortin, which is an inhibitor of phospholipase A2, inhibits the release of arachidonic acid, inhibits the synthesis of arachidonic acid metabolic products - cyclic endoperoxides and prostaglandins.

Prevents the marginal accumulation of neutrophils, reduces inflammatory exudation and the production of cytokines, inhibits the migration of macrophages, reduces the severity of infiltration and granulation processes, the formation of a chemotaxis substance (which explains the effectiveness in “late” allergy reactions); inhibits the release of inflammatory mediators from mast cells (immediate allergic reaction). Increases the number of “active” β-adrenergic receptors, restores the patient’s response to bronchodilators, allowing them to reduce the frequency of their use, reduces swelling of the bronchial mucosa, mucus production, sputum formation and reduces airway hyperreactivity.

Increases mucociliary transport. The therapeutic effect of the drug in patients requiring treatment with GCS develops on average within 10 days after the start of therapy. When used regularly in patients with bronchial asthma, budesonide reduces the severity of chronic inflammation in the lungs, and thus improves pulmonary function, the course of bronchial asthma, reduces bronchial hyperreactivity and prevents exacerbations of the disease.

Directions for use and doses

Inhalation, only with the help of a special device - Aerolyzer, which is included in the package. Formoterol and budesonide are intended for inhalation use - the drugs are capsules with powder for inhalation.

Formoterol and budesonide should be prescribed individually, at the minimum effective dose.

When control of bronchial asthma symptoms is achieved during formoterol therapy, it is necessary to consider the possibility of gradually reducing the dose of the drug. Reducing the dose of formoterol is carried out under regular medical supervision.

In the event of exacerbation of bronchial asthma, do not treat with formoterol or change the dose of the drug. Formoterol should not be used to relieve acute attacks of bronchial asthma.

When conducting therapy using an inhalation device, it is necessary to gradually adjust the dose of the drug to doses sufficient to maintain the therapeutic effect.

Budesonide + formoterol

Pre-inhalation of a β-adrenergic agonist dilates the bronchi, improves the entry of budesonide into the respiratory tract and enhances its therapeutic effect, therefore maintenance therapy for bronchial asthma and COPD is carried out in the following sequence:

- inhalation of formoterol;

- budesonide inhalation.

Adults

1. The dose of formoterol for regular maintenance therapy is 12–24 mcg (contents 1–2 capsules) 2 times a day.

The maximum recommended dose of the drug for adults (48 mcg/day) should not be exceeded.

Considering that the maximum daily dose of formoterol is 48 mcg, if necessary, an additional 12–24 mcg/day can be used to relieve the symptoms of bronchial asthma. If the need for additional doses of the drug ceases to be episodic (for example, becomes more often than 2 days a week), the patient should consult a doctor to consider changing therapy, because this may indicate a worsening of the disease.

2. The minimum dose of budesonide in one capsule is 200 mcg. The drug should not be prescribed if a single dose of less than 200 mcg is required. In adult patients with mild bronchial asthma, treatment begins with the minimum effective dose of 200 mcg/day. The maintenance dose of budesonide for adult patients is 400–800 mcg/day in 2 divided doses (200–400 mcg 2 times a day).

In case of exacerbation of bronchial asthma during the transfer of a patient from the use of dosage forms of GCS for oral administration to inhalation or when reducing the dose of dosage forms of GCS for oral administration, budesonide can be prescribed at a dose of 1600 mcg/day in 2–4 doses.

Children ≥6 years old

1. The dose of formoterol for regular maintenance therapy is 12 mcg 2 times a day. The maximum recommended dose of the drug is 24 mcg/day.

2. Due to the lack of clinical experience in children under 6 years of age, budesonide should not be prescribed to patients in this age group.

Treatment of children with mild bronchial asthma should begin with a dose of 200 mcg/day.

The dose of budesonide for regular maintenance therapy is 100–200 mcg 2 times a day. If necessary, the dose of budesonide can be increased to a maximum of 800 mcg/day.

Special patient groups

Renal dysfunction. There is no data on the need to adjust the dose of the drug in patients with impaired renal function. Based on the pharmacokinetics of oral budesonide, it is unlikely that the systemic exposure of the drug would change in a clinically significant manner in these patients.

Liver dysfunction. There is no data on the need to adjust the dose of the drug in patients with impaired liver function, however, budesonide is eliminated mainly by the liver. In this regard, the drug should be used with caution in patients with severe liver dysfunction. In patients with mild or moderate hepatic impairment, exposure to the drug is unlikely to be significantly altered based on the pharmacokinetic parameters of oral budesonide.

Elderly patients (over 65 years old). There is no data on the need to adjust the dose of the drug in patients over 65 years of age.

Instructions for inhalation

To ensure correct use of the drug, the nurse or doctor should teach the patient the correct technique for using the inhaler; explain that capsules with powder for inhalation should only be used using an Aerolyzer; Warn the patient that the capsules are for inhalation use only and are not intended to be swallowed. In children and adolescents, inhalation of budesonide and formoterol should be carried out under adult supervision. It is necessary to ensure that the child performs the inhalation technique correctly.

It is important to warn the patient that if the gelatin capsule ruptures, small pieces of gelatin may enter the mouth or throat as a result of inhalation. In order to minimize this phenomenon, you should not pierce the capsule more than once.

The capsule should be removed from the blister pack immediately before use (see also Instructions for use of the Aerolyzer).

Rinsing the mouth with water after inhaling budesonide can prevent irritation of the oral and pharyngeal mucosa and also reduce the risk of systemic adverse events.

There are isolated reports of accidental swallowing of drug capsules whole. Most of these cases are not associated with the development of adverse events. The nurse or doctor should teach the patient the correct technique for using the drug, especially if the patient's breathing does not improve after inhalation.

Instructions for use of the Aerolyzer

1. It is necessary to remove the cap from the Aerolyzer.

2. Hold the Aerolizer firmly by the base and turn the mouthpiece in the direction of the arrow.

3. Place the capsule in the cell located at the base of the Aerolyzer (it has the shape of a capsule). It must be remembered that you need to remove the capsule from the blister pack immediately before inhalation.

4. Turn the mouthpiece to close the Aerolizer.

5. Holding the Aerolizer strictly in a vertical position, press all the way down on the blue buttons located on the sides once. Then release them.

Note. At this stage, if the capsule is pierced, it may break, causing small pieces of gelatin to enter the mouth or throat. Since gelatin is edible, it will not cause any harm. To ensure that the capsule does not collapse completely, the following requirements must be met: do not pierce the capsule more than once; follow storage rules; remove the capsule from the blister only immediately before inhalation.

6. It is necessary to exhale completely.

7. You should take the mouthpiece into your mouth and tilt your head back slightly. Holding the mouthpiece tightly with your lips, take a quick, even, as deep breath as possible. There should be a characteristic rattling sound created by the rotation of the capsule and spraying of the powder. If there is no characteristic sound, then you should open the Aerolizer and see what happened to the capsule. It may be stuck in the cell. In this case, you need to carefully remove the capsule. Under no circumstances should you try to release the capsule by repeatedly pressing the buttons on the sides of the Aerolyzer.

8. If a characteristic sound occurs when inhaling, you must hold your breath as long as possible. At the same time, remove the mouthpiece from your mouth. Then exhale. Open the Aerolyzer and see if there is any powder left in the capsule. If there is powder left in the capsule, repeat the steps described in steps 6–8.

9. After completing the inhalation procedure, you must open the Aerolizer, remove the empty capsule, close the mouthpiece and the Aerolizer with the cap.

Caring for the Arolizer: to remove any remaining powder, wipe the mouthpiece and cell with a dry cloth. You can also use a soft brush.

Special instructions

Formoterol

It has been shown that the use of formoterol improves the quality of life of patients with COPD.

Formoterol belongs to the class of long-acting beta2-agonists. Another long-acting beta2-agonist, salmeterol, was associated with an increased incidence of asthma-related deaths (13 of 13,176 patients) compared with placebo (3 of 13,179 patients). Clinical studies have not been conducted to assess the incidence of deaths associated with bronchial asthma during the use of formoterol.

Anti-inflammatory therapy

In patients with asthma, formoterol should be used only as an adjunctive treatment when symptoms are insufficiently controlled on inhaled corticosteroid monotherapy or when the disease is severe and requires the use of an inhaled corticosteroid and a long-acting β2-adrenergic agonist. Formoterol should not be co-administered with other long-acting β2-adrenergic agonists.

When prescribing formoterol, it is necessary to assess the condition of patients regarding the adequacy of the anti-inflammatory therapy they receive. After starting treatment with formoterol, patients should be advised to continue anti-inflammatory therapy without changes, even if improvement is noted.

To relieve an acute attack of bronchial asthma, short-acting beta2-adrenergic receptor agonists should be used. If the condition suddenly worsens, patients should seek medical help immediately.

Severe exacerbations of bronchial asthma

In clinical studies, with the use of formoterol, there was a slight increase in the incidence of severe exacerbations of bronchial asthma compared to placebo, especially in children 6-12 years of age.

In placebo-controlled clinical studies in patients receiving formoterol for 4 weeks, there was an increase in the incidence of severe exacerbations of bronchial asthma (0.9% with a dosage regimen of 10-12 mcg 2 times a day, 1.9% with a dosage regimen of 10-12 mcg 2 times a day, 1.9% with a dosage regimen of 24 mcg 2 times a day days) compared to the placebo group (0.3%), especially in children 6-12 years old.

In two large controlled clinical trials involving 1095 adults and children 12 years of age and older, severe asthma exacerbations (requiring hospitalization) were more common in patients receiving formoterol 24 mcg twice daily (9/271, 3.3%) , compared with the groups of formoterol at a dose of 12 mcg 2 times / day (1/275, 0.4%), placebo (2/277, 0.7%) and albuterol (2/272, 0.7%).

When formoterol was used for 16 weeks, another large clinical trial of 2085 adults and adolescents did not find an increase in the incidence of severe asthma exacerbations with increasing formoterol dosage. However, in this study, the incidence of severe exacerbations was higher in the formoterol group (with a dosage regimen of 24 mcg 2 times / day - 2/527, 0.4%, with 12 mcg 2 times / day - 3/527, 0.6%) compared with placebo (1/517, 0.2%). In the open-label phase of this study, when using formoterol at a dose of 12 mcg 2 times a day (if necessary, patients could use up to two additional doses of the drug), the incidence of severe exacerbations of bronchial asthma was 1/517, 0.2%.

In a 52-week, multicenter, randomized, double-blind clinical trial that included 518 children aged 6 to 12 years, the incidence of severe asthma exacerbations was higher with formoterol 24 mcg twice daily (11/171, 6.4 %), 12 mcg 2 times / day (8/171, 4.7%) compared with placebo (0/176, 0.0%).

However, the results of the above clinical studies do not allow us to quantify the incidence of severe exacerbations of bronchial asthma in different groups.

Hypokalemia

Therapy with beta2-agonists, including formoterol, may result in potentially serious hypokalemia. Hypokalemia may increase susceptibility to the development of arrhythmias.

Because this effect of the drug can be enhanced by hypoxia and concomitant treatment; special caution should be observed in patients with severe bronchial asthma. In these cases, regular monitoring of serum potassium concentration is recommended.

Paradoxical bronchospasm

As with other inhalation therapy, the possibility of developing paradoxical bronchospasm should be taken into account. If it occurs, the drug should be discontinued immediately and alternative treatment should be prescribed.

Impact on the ability to drive vehicles and operate machinery

Patients who experience dizziness or other central nervous system disorders while using the drug formoterol should refrain from driving vehicles or operating machinery during the period of using the drug.

Budesonide

To ensure that budesonide reaches the lungs, it is important to instruct patients to correctly inhale the drug in accordance with the instructions for use.

Patients should be informed that the drug is not intended to relieve attacks, but for regular daily preventive use even in the absence of symptoms of bronchial asthma.

If paradoxical bronchospasm develops, you should immediately stop using budesonide, assess the patient's condition and, if necessary, prescribe therapy with other drugs. Paradoxical bronchospasm must be immediately relieved with a short-acting beta2-agonist. Patients should always have a short-acting beta2-agonist inhaler available to relieve acute exacerbations of bronchial asthma.

Patients should be informed about the need to consult a doctor if their condition worsens (increased need for short-acting bronchodilators, increased attacks of shortness of breath). In such cases, it is necessary to examine the patient and consider the possibility of increasing the dose of inhaled or oral GCS.

To reduce the risk of developing candidal infections of the oral cavity and pharynx, the patient should thoroughly rinse his mouth with water after each inhalation of the drug. With the development of candidal infection of the oral cavity and pharynx, local antifungal therapy can be performed without stopping treatment with budesonide.

In case of exacerbation of bronchial asthma, the dose of budesonide should be increased or, if necessary, a short course of systemic corticosteroids should be administered and/or antibiotic therapy should be prescribed if infection develops.

It is necessary to regularly monitor the growth dynamics of children and adolescents receiving long-term therapy with inhaled corticosteroids. If growth is delayed, the need to reduce the dose of inhaled corticosteroids (prescribed in the minimum effective dose) and refer the child for consultation to an allergist should be considered. The long-term consequences of growth retardation (impact on final adult height) in children receiving therapy with inhaled corticosteroids have not been studied.

There has been no adequate study of the possibility of compensating for growth retardation in children after discontinuation of therapy with oral corticosteroids.

Budesonide usually has no effect on adrenal function. However, in some patients, with long-term use at recommended daily doses, systemic effects of budesonide may be observed.

When prescribing inhaled corticosteroids in high doses or over a long period of time, systemic adverse reactions may develop (however less frequently than when using oral corticosteroids), such as suppression of adrenal function, hypercortisolism/Cushing's syndrome, growth retardation in children and adolescents, decreased mineral bone density, hypersensitivity reactions, cataracts, glaucoma and, less commonly, a number of behavioral disorders, including psychomotor hyperactivity, sleep disturbances, agitation, depression or aggression (especially in children).

Patients with hormone-independent bronchial asthma

In patients with hormone-independent bronchial asthma, the therapeutic effect of budesonide develops on average within 10 days after the start of treatment. At the beginning of budesonide therapy in patients with increased bronchial secretion, oral corticosteroids can be added to the drug inhalations in a short course (lasting about 2 weeks).

Patients with hormone-dependent bronchial asthma

When switching from oral corticosteroids to inhaled budesonide, patients should be in a relatively stable condition. During the first 10 days, high doses of budesonide are prescribed in combination with previously used oral corticosteroids at the same dose. Then the daily dose of oral corticosteroids begins to be gradually reduced (2.5 mg every month in terms of prednisolone) to the minimum possible level. Treatment with corticosteroids, including budesonide, should not be abruptly interrupted.

The patient's condition should be carefully monitored in the first months after transition until the hypothalamic-pituitary-adrenal axis has recovered sufficiently to provide an adequate response to stressful situations (for example, trauma, surgery, or severe infection). The function of the hypothalamic-pituitary-adrenal system should be regularly monitored.

In some cases, patients with reduced adrenal cortex function may need additional administration of GCS for oral administration during stressful situations. This category of patients is recommended to always carry a warning card with them, which should indicate that in stressful situations they need additional systemic administration of GCS.

When transferring patients from systemic corticosteroids to inhaled budesonide therapy, reactions such as allergic rhinitis, eczema, lethargy, pain in muscles and joints, and sometimes nausea and vomiting, which were previously suppressed by taking systemic corticosteroids, may occur. Treatment of these reactions should be carried out with antihistamines or local corticosteroids.

Impact on the ability to drive vehicles and operate machinery

There is no data on the effect of budesonide on the ability to drive vehicles and operate machinery. A negative effect of the drug on the ability to drive vehicles and operate machinery is unlikely.

Interaction

Formoterol

Formoterol (as well as other beta2-agonists) should be prescribed with caution to patients receiving drugs such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines, macrolides, MAO inhibitors, tricyclic antidepressants, and other drugs known to cause they prolong the QT interval because in these cases, the effect of adrenergic stimulants on the cardiovascular system may be enhanced. When using drugs that can prolong the QT interval, the risk of ventricular arrhythmias increases.

Concomitant use of other sympathomimetic agents may result in increased side effects of formoterol.

The simultaneous use of xanthine derivatives, corticosteroids or diuretics may enhance the potential hypokalemic effect of beta2-agonists.

Patients receiving anesthesia using halogenated hydrocarbons are at increased risk of developing arrhythmias.

Beta blockers may reduce the effect of formoterol. In this regard, formoterol should not be prescribed together with beta-blockers (including eye drops), unless the use of such a combination of drugs is forced by any emergency reasons.

Budesonide

Use of the drug together with inhibitors of CYP3A4 (for example, itraconazole, ketoconazole, ritonavir, nelfinavir, amiodarone, clarithromycin) may lead to a decrease in the metabolism of budesonide and an increase in its systemic concentration. When prescribing budesonide together with CYP3A4 inhibitors, adrenal function should be regularly monitored and the dose of budesonide adjusted if necessary.

When budesonide is used together with drugs that induce CYP3A4 (for example, rifampicin, phenobarbital, phenytoin), it is possible to increase the metabolism of budesonide and reduce its systemic concentration.

Methandrostenolone and estrogens enhance the effect of budesonide.

Side effects of Foradil Combi

Adverse reactions observed in clinical studies are distributed according to frequency of occurrence. The following criteria were used to assess frequency: very often (≥1/10); often (from ≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports. Within each group, adverse reactions are distributed in order of decreasing importance.

Formoterol

Allergic reactions: very rarely - hypersensitivity reactions, such as arterial hypotension, urticaria, angioedema, itching, rash.

From the mental side: infrequently - agitation, anxiety, increased excitability, insomnia.

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

From the cardiovascular system: often - palpitations; infrequently - tachycardia; very rarely - peripheral edema.

From the respiratory system: infrequently - bronchospasm, including paradoxical, irritation of the mucous membrane of the pharynx and larynx.

From the digestive system: infrequently - dryness of the oral mucosa; very rarely - nausea.

From the musculoskeletal system: infrequently - muscle spasm, myalgia.

Adverse reactions according to post-marketing observations when prescribing formoterol (Foradil)

Laboratory and instrumental data: hypokalemia, hyperglycemia, prolongation of the QT interval (during ECG), increased blood pressure (including arterial hypertension).

From the respiratory system: cough.

From the skin and subcutaneous tissues: rash.

From the cardiovascular system: angina pectoris, heart rhythm disturbances, incl. atrial fibrillation, ventricular extrasystoles, tachyarrhythmia.

Budesonide

From the endocrine system: rarely - suppression of adrenal cortex function, Cushing's syndrome, hypercortisolism, growth retardation in children and adolescents.

From the side of the organ of vision: rarely - cataracts, glaucoma.

Allergic reactions: rarely - hypersensitivity reactions, rash, urticaria, angioedema, itching, contact dermatitis (delayed hypersensitivity reaction type IV).

From the psyche: post-marketing observations - psychomotor hyperactivity, sleep disturbances, anxiety, depression, aggressive behavior, behavioral disorders (especially in children).

From the musculoskeletal system: rarely - decrease in bone mineral density.

From the respiratory system: often - cough; rarely - paradoxical bronchospasm, candidiasis of the oral mucosa and larynx, pharyngeal irritation, dysphonia, which disappears after stopping budesonide therapy or reducing the dose of the drug.

In a three-year clinical study, when using budesonide in patients with COPD, there was an increase in the incidence of subcutaneous hematomas (10%) and pneumonia (6%) compared with the placebo group (4% and 3%, with p <0.001 and p <0.01, respectively).

Overdose of Foradil Combi

Formoterol

Symptoms: an overdose of formoterol can presumably lead to phenomena characteristic of the excessive action of other beta2-agonists, such as nausea, vomiting, headache, tremor, drowsiness, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalemia, hyperglycemia, arterial hypertension.

Treatment: maintenance and symptomatic therapy is indicated. In serious cases, hospitalization is necessary. The use of beta blockers may be considered, but only with extreme caution and under close medical supervision, as the use of such drugs may cause bronchospasm.

Budesonide

Budesonide has low acute toxicity. A single inhalation of a large amount of the drug can lead to temporary suppression of the function of the hypothalamic-pituitary-adrenal system, which does not require emergency treatment. In case of budesonide overdose, treatment can be continued in doses sufficient to maintain the therapeutic effect.