Foradil Combi, 12 mcg+200 mcg 120 pcs

Foradil Combi is a drug with anti-inflammatory and bronchodilatorial action. Formoterol is a selective β 2 -adrenoreceptor agonist. It has a bronchodilator effect in patients with both reversible and irreversible airway obstruction. The action of the drug is fast (within 1-3 minutes) and lasts for 12 hours after inhalation. When the drug is used in therapeutic doses, the effect on the cardiovascular system is minimal and only rarely observed.

Inhibits the release of histamine and leukotrienes from mast cells. Some anti-inflammatory properties of formoterol have been shown in animal experiments, such as the ability to inhibit the development of edema and the accumulation of inflammatory cells.
In studies in humans, Foradyl Combi has been shown to effectively prevent 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/day allows in most cases to provide the necessary control of bronchospasm in chronic lung disease both during the day and at night.
In patients with chronic obstructive pulmonary disease (COPD) of stable course formoterol causes rapid onset of bronchodilator effect and improvement of quality of life parameters.

Budesonide is an inhaled glucocorticosteroid (GCS) with almost no systemic action. Budesonide has anti-inflammatory, anti-allergic and immunosuppressive effects. It increases production of lipocortin, which is an inhibitor of phospholipase A2, inhibits the release of arachidonic acid, inhibits the synthesis of products of arachidonic acid metabolism – cyclic endoperoxides and prostaglandins.

Prevent margin accumulation of neutrophils, decreases inflammatory exudation and cytokines production, inhibits macrophages migration, decreases intensity of infiltration and granulation processes, formation of chemotaxis substance (this explains its effectiveness at “late” allergy reactions); inhibits release of inflammatory mediators from mast cells (immediate allergy reaction). It increases quantity of “active” β-adrenoreceptors, restores patient’s response to bronchodilators, allowing reducing frequency of their use, decreases mucous membrane edema of bronchi, mucus production, sputum formation and reduces airway hyperresponsiveness.

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

Indications

Bronchial asthma:

Chronic obstructive pulmonary disease (COPD) (with proven efficacy of GCS).

Active ingredient

Composition

1 Formoterol capsule contains:

the active ingredient:

Formoterol fumarate 0.012 mg,

components:

lactose monohydrate – up to 25 mg,

capsule shell:

gelatin 100% – 79 mg,

1 capsule of Budesonide contains:

the active ingredient:

budesonide 200 mcg,

excipients:

Lactose monohydrate – 24.77,

capsule shell:

iron oxide red (E172);

titanium dioxide (E171);

water;

gelatin,

the composition of the ink:

iron oxide black (E172);

shellac;

n-butyl alcohol;

purified water;

liquid soy lecithin;

anti-foaming compound dc 1510;

Methanol 74 OR.

How to take, the dosage

Inhaled only with a special device, the Aerolyser, which is included in the package. Formoterol and budesonide are intended for inhaled use; they are capsules with powder for inhalation.

Formoterol and budesonide should be prescribed on an individual basis at the lowest effective dose.

If control of bronchial asthma symptoms is achieved with formoterol therapy, gradual reduction of the dose should be considered. Formoterol dose reduction is performed under regular medical control of the patient. Against the background of bronchial asthma exacerbation should not start formoterol treatment or change the dosage of the drug. Formoterol should not be used to relieve acute attacks of bronchial asthma.

When administering therapy to a patient with an inhalation device, the dose of the drug should be gradually adjusted (titrated) to doses sufficient to maintain the therapeutic effect.

Budesonide + Formoterol

Adults: Prior inhalation of β-adrenergic stimulants dilates the bronchi, improves the entry of Budesonide into the airways and enhances its therapeutic effect. Therefore, maintenance therapy of bronchial asthma and COPD is carried out as follows:

Formoterol is inhaled first;

Then budesonide is inhaled.

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 for adults (48 mcg/day) should not be exceeded.

As the maximum daily dose of formoterol is 48 mcg, an additional 12-24 mcg/day may be used if necessary to relieve bronchial asthma symptoms. If the need for additional doses is no longer episodic (e.g. more than 2 days/week), patients should be advised to ask their healthcare provider to review the therapy, as this may indicate a worsening of the disease.

2. The minimum dose of the drug in one capsule is 200 mcg. The drug cannot be used if a single dose of less than 200 mcg is required. Adult patients with mild bronchial asthma may start treatment at the minimum effective dose of 200 mcg/day. The maintenance dose of budesonide for adult patients is 400-800 mcg/day in 2 doses (200-400 mcg twice daily).

In worsening bronchial asthma during conversion from oral GCS to inhaled GCS or when the dose of oral GCS is reduced, budesonide may be prescribed in a dose of 1600 mcg/day in 2-4 doses.

Children ≥6 years of age

Pre-inhalation of β-adrenergic stimulants dilates the bronchi, improves the entry of budesonide into the airways, and enhances its therapeutic effect. Therefore, maintenance therapy for bronchial asthma is as follows:

Formoterol is inhaled first;

Thereafter, budesonide is inhaled.

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

2 Because of a lack of clinical experience in children younger than 6 years of age, budesonide should not be used in this age group.

The treatment of children with mild bronchial asthma can be started with a dose of 200 mcg/day.

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

Patient special groups

Renal dysfunction. There is no evidence to support dose adjustment in patients with impaired renal function. Based on the pharmacokinetics data for oral budesonide, it is unlikely that the systemic effects of the drug may change clinically significantly in these patients.

Hepatic impairment. There is no evidence to support dose adjustment in patients with hepatic impairment. But budesonide is mainly excreted by the liver. Therefore, the drug should be used with caution in patients with severe hepatic impairment. In patients with mild to moderate hepatic impairment, the pharmacokinetic parameters for oral budesonide are unlikely to significantly change the effects of the drug.

Elderly patients (over 65 years of age). There is no evidence to support the need for a different dose in patients over 65 years of age compared to younger patients.

Inhalation instructions

In order to ensure proper use, the physician or other healthcare professional should show the patient how to use the inhaler; explain to the patient that the powder inhalation capsules should only be used with the Aerolizer; warn the patient that the capsules are for inhalation use only and are not meant to be swallowed. In children and adolescents, inhalation of budesonide and formoterol should be performed under adult supervision. It is important to ensure that the child follows the inhalation technique correctly. It is important that the patient understands that small pieces of gelatin may enter the mouth or throat as a result of inhalation due to the destruction of the gelatin capsule. In order to minimize this phenomenon, the capsule should not be pierced more than once. The capsule should be removed from the blister pack just before use (see also Aerolyser Instructions for Use).

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

There have been isolated reports of patients accidentally swallowing entire capsules of the drug. Most of these cases are not associated with adverse events. The healthcare professional should explain to the patient how to use the medication correctly, especially if the patient does not get better breathing after inhalation.

Instructions for use of the Aerosolizer

1. The Aerosolizer cap must be removed.

2. Hold the Aerosolizer firmly by its base and rotate the mouthpiece in the direction of the arrow.

3. Place the capsule into the cell at the base of the Aerosolizer (this is shaped like a capsule). Remember to remove the capsule from the blister pack just before inhalation.

4. Turn the mouthpiece and close the Aerolyser.

5. Holding the Aerolizer in an upright position, fully press the blue buttons on the sides of the Aerolizer once. Then release them.

Note. At this point, the capsule can break apart when pierced, allowing small pieces of gelatin to enter your mouth or throat. Since the gelatin is edible, there is no harm in this. To ensure that the capsule does not disintegrate completely, you should follow the following requirements: Do not puncture the capsule more than once; adhere to storage rules; remove the capsule from the blister only immediately before inhalation.

6. exhale completely.

7 Take the mouthpiece in your mouth and slightly tilt your head back. With your lips firmly around the mouthpiece, take a quick, even, maximum deep breath. There should be a characteristic rattling sound created by the rotation of the capsule and the atomization of the powder. If there is no rattling sound, open the Aerosolizer to see what has happened to the capsule. It may be stuck in the cell. In this case you should carefully remove the capsule. Under no circumstances should you try to release the capsule by repeatedly pressing the buttons on the sides of the Aerolizer.

8. If you hear a distinctive sound when you inhale, hold your breath as long as possible. At the same time, remove the mouthpiece from your mouth. Then exhale. Open the Aerosolizer and see if any powder remains in the capsule. If there is powder in the capsule, repeat steps 6-8.

9 When the inhalation is complete, open the Aerosolizer, remove the empty capsule, close the mouthpiece and the Aerosolizer with the cap.

Care of the Aerolyser: Wipe the mouthpiece and cell with a dry cloth to remove any powder residue. You can also use a soft brush.

Interaction

Formoterol

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

The concomitant use of other sympathomimetic agents may aggravate the side effects of formoterol.

The concomitant use of xanthine derivatives, GCS or diuretics may increase the potential hypokalemic effects of beta2-adrenergic stimulants.

In patients who receive anesthesia with halogenated hydrocarbons, there is an increased risk of arrhythmias.

Beta-adrenoblockers can weaken the effect of formoterol. Therefore, formoterol should not be coadministered with beta-adrenoblockers (including eye drops) unless compelled to use such a combination of drugs for any extraordinary reason.

Budesonide

The use of the drug together with CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, nelfinavir, amiodarone, clarithromycin) may decrease budesonide metabolism and increase its systemic concentration. When prescribing budesonide together with CYP3A4 inhibitors, adrenal function should be monitored regularly and the dose of budesonide should be changed if necessary.

When budesonide is used with CYP3A4-inducing drugs (e.g., rifampicin, phenobarbital, phenytoin), budesonide metabolism may be increased and systemic concentrations decreased.

Methandrostenolone, estrogens increase the effect of budesonide.

Special Instructions

Formoterol

Formoterol has been shown to improve quality of life in COPD patients.

Formoterol belongs to the class of long-acting beta2-adrenomimetics. Against the background of use of another long-acting beta2-adrenomimetic, salmeterol, there was an increase in the incidence of bronchial asthma-related deaths (13 of 13,176 patients) compared to placebo (3 of 13,179 patients). There have been no clinical studies evaluating the incidence of bronchial asthma-related deaths with formoterol.

In patients with bronchial asthma, formoterol should be used only as adjunctive treatment when symptoms are not sufficiently controlled with inhaled corticosteroid monotherapy or when the disease is severe and requires inhaled corticosteroid and a long-acting β2-adrenoreceptor agonist. Formoterol should not be coadministered with other long-acting β2-adrenoreceptor agonists.

When prescribing formoterol, patients should be evaluated regarding the adequacy of the anti-inflammatory therapy they are receiving. After initiation of formoterol treatment, patients should be advised to continue anti-inflammatory therapy without change, even if improvement is noted.

Short-acting beta2-adrenoreceptor agonists should be used to control an acute attack of bronchial asthma. Patients should seek medical attention immediately if their condition suddenly worsens.

Severe exacerbations of bronchial asthma

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

In placebo-controlled clinical trials, patients who received formoterol for 4 weeks showed an increased incidence of severe exacerbations of bronchial asthma (0.9% in the 10-12 mcg 2 times/day dosing regimen, 1.9% in the 24 mcg 2 times/day group) compared to the placebo group (0.3%), especially in children 6-12 years old.

In two large controlled clinical trials involving 1,095 adult patients and children 12 years and older, severe exacerbations of bronchial asthma (requiring hospitalization) were more frequently seen in patients receiving formoterol at a dose of 24 mcg 2 times/day (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 in another large clinical trial involving 2,085 adult patients and adolescents, there was no increase in the rate of severe exacerbations of bronchial asthma depending on increasing the dose of formoterol. However, in this study, the incidence of severe exacerbations was higher in the formoterol group (2/527, 0.4% for the 24 mcg 2 times/day dosing regimen; 3/527, 0.6% for 12 mcg 2 times/day) compared with placebo (1/517, 0.2%). In the open-label phase of this study, the incidence of severe exacerbations of bronchial asthma was 1/517, 0.2% when formoterol was used at a dose of 12 mcg 2 times/day (patients could use up to two additional doses of the drug if needed).

In a 52-week, multicenter, randomized, double-blind clinical trial including 518 children aged 6 to 12 years, the incidence of severe exacerbations of bronchial asthma was higher when formoterol was used in doses of 24 mcg 2 times/day (11/171, 64%), 12 mcg 2 times/day (8/171, 4.7%) compared with placebo (0/176, 0.0%).

The results of the above clinical studies, however, do not quantify the incidence of severe exacerbations of bronchial asthma in the various groups.

Hypokalemia

A consequence of therapy with beta2-adrenomimetics, including formoterol, may be the development of potentially serious hypokalemia. Hypokalemia may increase the predisposition to develop arrhythmias.

To the extent to which this effect of the drug may be enhanced by hypoxia and concomitant treatment, special caution should be exercised 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 paradoxical bronchospasm should be considered. If this occurs, the drug should be discontinued immediately and alternative treatment should be prescribed.

Impact on driving and operating machinery

Patients who experience dizziness or other CNS disturbances while using formoterol should refrain from driving or operating machinery while using the drug.

Budesonide

To ensure that budesonide reaches the lungs, it is important that patients be instructed to inhale the drug correctly according to the instructions for use.

Patients should be informed that the medication is not meant to stop attacks, but for regular daily prophylactic use, even in the absence of bronchial asthma symptoms.

If paradoxical bronchospasm develops, the use of budesonide should be stopped immediately, the patient’s condition should be evaluated, and if necessary therapy with other drugs should be prescribed. Paradoxical bronchospasm should be treated immediately with a short-acting beta2-adrenomimetic. Patients should always have a short-acting beta2-adrenomimetic inhaler available to manage acute exacerbations of bronchial asthma.

Patients should be informed to consult a physician if their condition worsens (increased need for short-acting bronchodilators, increased dyspnea attacks). In these cases, the patient should be examined and the possibility of increasing the dose of inhaled or oral GCS should be considered.

To reduce the risk of oral candidiasis, patients should rinse their mouth thoroughly with water after each inhalation. If candidal infection of the mouth and throat develops, topical antifungal therapy may be given 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 GCS and/or antibiotic therapy should be administered if infection develops.

The growth dynamics of children and adolescents receiving long-term inhaled GCS therapy should be monitored regularly. In case of growth retardation it is necessary to consider the necessity of reducing the dose of inhaled GCS (administration at the minimum effective dose) and refer the child for consultation to an allergologist. The long-term effects of growth retardation (effect on final adult growth) in children receiving inhaled GCS therapy have not been studied.

An adequate study of the ability to compensate for the resulting stunting in children after withdrawal of oral GCS therapy has not been conducted.

Budesonide usually has no effect on adrenal function. However, systemic effects of budesonide may be seen in some patients with prolonged use in recommended daily doses.

. When using high doses or prolonged use of inhaled GCS, systemic adverse reactions may occur (but less frequently than with oral GCS), such as adrenal suppression and hypercorticism/Cushing’s syndrome, growth retardation in children and adolescents, decreased bone mineral 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 of starting treatment. At the start of therapy with budesonide in patients with increased bronchial secretion, a short course of oral GCS may be added to inhalation of the drug (for about 2 weeks).

Patients with hormone-dependent bronchial asthma

Patients should be relatively stable when switching from oral GCS to inhaled budesonide. For the first 10 days, high-dose budesonide should be given in combination with the same dose of oral GCS used previously. Then daily dose of oral GCS is gradually reduced (2.5 mg each month in terms of prednisolone) to the lowest possible level. Treatment with GCSs, including budesonide, should not be abruptly interrupted.

In the first months after transition, the patient should be closely monitored until his or her hypothalamic-pituitary-adrenal system has recovered sufficiently to allow an adequate response to stressful situations (e.g., trauma, surgery, or severe infection). Hypothalamic-pituitary-adrenal system function indicators should be monitored regularly.

In some cases, patients with reduced adrenal cortex function may require additional oral GCS administration during stressful situations. We recommend that this category of patients always carry a warning card stating that they require additional systemic GCS administration during stressful situations.

Reactions such as allergic rhinitis, eczema, lethargy, muscle and joint pain, and sometimes nausea and vomiting that were previously suppressed by systemic GCS may occur when patients switch from systemic GCS to inhaled budesonide therapy. These reactions should be treated with antihistamines or local GCS.

Influence on driving and operating machinery

There are no data on the effect of budesonide on driving and operating machinery. An adverse effect of the drug on the ability to drive and operate machinery is unlikely.

Contraindications

Side effects

The adverse reactions reported in clinical trials are categorized according to the frequency of occurrence. The following criteria were used to assess frequency: very common (≥1/10); common (≥1/100, <1/10); infrequent (≥1/1000, <1/100); rare (≥1/10 000, <1/1000); very rare (<1/10 000), including individual reports. Within each group, adverse reactions are distributed in decreasing order of significance.

Formoterol

Allergic reactions: very rare – hypersensitivity reactions such as arterial hypotension, urticaria, angioedema, pruritus, rash.

Psychiatric disorders: infrequent – agitation, anxiety, increased excitability, insomnia.

Nervous system disorders: often – headache, tremor; infrequent – dizziness; very rare – taste disorders.

The cardiovascular system: often – palpitations; infrequent – tachycardia; very rare – peripheral edema.

Respiratory system: infrequent – bronchospasm, including paradoxical, irritation of the mucous membranes of the pharynx and larynx.

Gastrointestinal system disorders: infrequent dryness of the oral mucosa; very rare – nausea.

Muscular system: infrequent – muscle spasm, myalgia.

Unwanted reactions according to post-marketing observations while prescribing formoterol (Foradil)

Laboratory and instrumental data: hypokalemia, hyperglycemia, prolongation of QT interval (during ECG), increase of BP (including arterial hypertension).

Respiratory system disorders: cough.

Skin and subcutaneous tissue disorders: rash.

Cardiovascular system: angina pectoris, heart rhythm disorders, including atrial fibrillation, ventricular extrasystoles, tachyarrhythmia.

Budesonide

Endocrine system disorders: rarely – suppression of adrenal cortex function, Cushing’s syndrome, hypercorticism, growth retardation in children and adolescents.

An organ of vision: rarely – cataracts, glaucoma.

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

Psychiatric disorders: post-marketing observations – psychomotor hyperactivity, sleep disorders, anxiety, depression, aggressive behavior, behavioral disorders (especially in children).

Skeletal and muscular system: rarely – decreased bone mineral density.

The respiratory system: often – cough; rarely – paradoxical bronchospasm, candidiasis of the mucous membranes of the oral cavity and larynx, pharyngeal irritation, dysphonia which disappears after discontinuation of therapy with budesonide or reduction of the drug dose.

In a three-year clinical trial, use of budesonide in patients with COPD showed an increased incidence of subcutaneous hematoma (10%) and pneumonia (6%) compared with the placebo group (4% and 3%, at p<0.001 and p<0.01, respectively).

Overdose

Formoterol

Symptoms: Formoterol overdose is suspected to cause phenomena characteristic of the excessive action of other beta2-adrenomimetics, such as nausea, vomiting, headache, tremor, somnolence, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalemia, hyperglycemia, arterial hypertension.

Treatment: supportive and symptomatic therapy is indicated. In severe cases hospitalization is necessary. Beta-adrenoblockers may be considered, but only with extreme caution and under close medical supervision, as they may cause bronchospasm.

Budesonide

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

Pregnancy use

Formoterol

The safety of Foradil Combi during pregnancy and lactation has not yet been established.

The use in pregnancy is possible only if the expected benefit to the mother exceeds the potential risk to the fetus. Formoterol, as well as other beta2-adrenomimetics, may delay the process of labor due to its tocolytic action (relaxing action on the uterine smooth muscle).

It is not known whether formoterol is excreted with breast milk in humans. Breast-feeding should be stopped while taking Foradil Combi.

Budesonide

Possible teratogenic effect of GCS on the fetus has been found in experimental studies in animals. There is no data about teratogenic action of budesonide or about the presence of reproductive toxicity in humans.

The use during pregnancy is possible only if the expected benefits to the mother exceed the potential risk to the fetus. If therapy with GCS during pregnancy is necessary, it is preferable to use them by inhalation, because GCS for inhaled use have less systemic effect compared to oral GCS.

It is not known whether budesonide is excreted with breast milk in humans.

Fertility

There are no data on the effect of the drug on fertility. No effect of oral formoterol and p/c budesonide administration on fertility was found in experimental animal studies.

Similarities