Low hemoglobin
20.06.2020

Formoterol duration of action. Foradil - instructions for use. General characteristics. Compound

Lung problems are no joke. They not only cause discomfort and make you feel worse, but can also cause various complications. For example, asthma can even lead to The drug "Formoterol", instructions for use of which will be presented below, is precisely intended for the treatment of pathologies of the respiratory system. However, keep in mind that it is used to combat a narrow range of diseases.

Features of the drug's action

The drug is capable of expanding the bronchial lumens. At the same time, it significantly slows down the release of leukotrines and histamine from lung tissue. The main active ingredient is fumartate dihydrate.

The drug acts within 5 minutes, and its maximum effect is achieved after 2 hours. If bronchial obstruction is impaired, the medicine can remain effective for about 10 hours. This makes it possible to alleviate the patient’s condition for a long time.

A significant part of the drug after inhalation enters the stomach. There the components are absorbed. The half-life of the drug is approximately 13 hours. Its components accumulate and are metabolized in the liver. The drug is excreted in the urine. Its bioavailability is more than 40%. And it binds to blood plasma by 68%.

The most basic document that you should read before using Formoterol is the instructions for use. There is not one form of release of the drug, there are several of them: capsules with powder, dosed powder in a bottle, dosed aerosol. Regardless of which one you purchased, the medicine is for inhalation only. The product is sold in cardboard packaging.

What indications for use are there?

If you have already used Formoterol, the instructions for use (we will look at drug synonyms later) indicate a fairly narrow range of use. The following indications for use can be distinguished:

  • Treatment and prevention of sharp narrowing of the bronchial lumens - spasm.
  • Asthma. In this case, the drug is not the main one, but is used only to support the body.
  • Chronical bronchitis.
  • Pulmonary emphysema.
  • Allergic bronchial spasm. The fact is that the medicine can inhibit the release of histamine.
  • Obstructive inflammation of the upper respiratory tract, which is accompanied by impaired air flow through it.

In what cases is taking the drug prohibited?

Not everyone can take Formoterol. Instructions for use indicate the following contraindications:

  • Too high sensitivity to the main or additional components of the drug, which can cause a worsening of the condition.
  • Excessive production of thyroid hormones - thyrotoxicosis.
  • Sustained increase in blood pressure.
  • Pregnancy and lactation period. The fact is that no research has been conducted in this area. That is, it is unknown whether the main component will be excreted in milk. Therefore, if the drug still needs to be taken, then it is better to stop feeding. As for pregnancy, everything is decided by the attending doctor.
  • Heart rhythm disorder: arrhythmia, tachycardia.
  • Cardiac ischemia. Some drug interactions can cause problems with the ventricles.
  • Age up to 5 years. For small children, the drug presented is very difficult.

Possible side effects

"Formoterol" (instructions for use are in each package) can provoke some unwanted reactions, although their likelihood is low if the rules for taking the drug are followed. The following side effects may occur:

  1. From the nervous system: pain and dizziness, convulsions, sleep disturbance, nervousness, increased anxiety.
  2. From the cardiovascular system: increased or irregular heartbeat, angina pectoris, persistent decrease or increase in blood pressure.
  3. From the gastrointestinal tract: nausea and vomiting, dry oral mucosa, abdominal pain, gastroenteritis (inflammation of the stomach), dyspepsia (difficulty in digestion, which may be accompanied by pain).
  4. From the respiratory system: infectious pathologies of the bronchi, sinusitis, pharyngitis, tonsillitis, exacerbation of asthma, voice disturbance.
  5. Others: chest pain, allergic reaction in the form of a rash, itching, anaphylactic shock.

Features of the use of the medicine

If you need to take Formoterol, the instructions for use tell you about the following dosages:

  • For bronchial asthma, you need to take 12 mcg inhalations every 12 hours. Just 1-2 breaths are enough. In this way, the body is supported. If an attack can be triggered by physical activity, then it is better to take the drug 15 minutes before the start of the intended work, and the dosage is the same.
  • To support obstructive pulmonary disease, inhalations of 12 mcg should be taken twice a day.

It should be borne in mind that the presented medicine can be used no more than once every 12 hours. That is, the maximum daily dose should not exceed 24 mcg. The product is intended for inhalation only. If the doctor has prescribed the drug "Formoterol", the instructions for use (aerosol is used most often) prohibit taking it intravenously, intramuscularly or orally.

If an overdose occurs

Are you forced to take Formoterol? Instructions for use can be purchased at a pharmacy only with special permission from a doctor) is in the box for a reason. It clearly indicates the dosage of the medicine. But if for some reason you violate these instructions, an overdose may occur. It is determined by the following symptoms: tachycardia, dry mouth, headache, nausea. If the situation is not corrected in time, even death is quite possible.

In case of overdose, you must urgently call an ambulance. Treatment should be symptomatic. In this case, further use of the medicine is stopped. During treatment, it is necessary to monitor heart function using electrocardiography. During the recovery period after an overdose, the patient should be under constant supervision of specialists.

Features of drug interaction with other drugs

Are you taking Formoterol? Instructions for use (analogues have a similar composition) contain information about the features of its combination with other medications. For example, caution should be exercised when using it simultaneously with adrenergic drugs.

A pathological decrease in potassium levels in the body can be provoked by a combination of Formoterol with diuretics, steroids, and xanthine derivatives. However, kalemia is not a permanent condition. Moreover, no external replenishment of the amount of this element in the body is required.

Try not to take this drug together with tricyclic antidepressants. Combining it with beta-blockers leads to mutual blocking of the action of these drugs. That is, there will be no benefit from them, but the harm can be serious.

Combined use with drugs such as Quinidine and Disopyramide can be dangerous, as it provokes the development of cardiac ventricular arrhythmias. If there is a cardiac reaction to the medication, it must be discontinued immediately.

special instructions

"Formoterol" (you already know the instructions) has some features of use:

  • You should not use the drug to relieve an asthma attack. There are other means for this. If Formoterol is needed, the instructions for use (reviews about it are mostly good) indicate that it is only an addition to the main therapy. If during treatment you feel that your condition is worsening, you should immediately consult a doctor.
  • This medicine should not be taken in place of corticosteroids. "Formoterol" does not have a pronounced anti-inflammatory function. In this case, taking corticosteroids should be continued without reducing the dose prescribed by the doctor.
  • Women who have been diagnosed with uterine fibroids, as well as people with diabetes, should be very careful when using this product.
  • You should not immediately drive or engage in activities that require increased attention immediately after taking it.
  • Do not use the product during childbirth. The fact is that the main active ingredient can negatively affect uterine contractions.

Analogues and storage features

Most often, patients prefer an inhaler that contains 100 single doses. The product should be stored in a cool and dark place, but it is not advisable to freeze it. Direct sunlight should not fall on the bottle. Do not place the medicine near a heat source.

If this drug is not suitable for you, you can consult your doctor about analogues. Among them are the following: “Atimos”, “Oxis”, “Foradil”, “Bronkhoril”, “Shadrin”. Please note that you cannot buy or take any other medications yourself.

Formoterol is a drug that is used to treat bronchial asthma as one of the components of basic therapy. The main pharmacological effect of this drug is a bronchodilator effect, which helps eliminate shortness of breath and prevent the occurrence of asthma attacks. Unlike other bronchodilators used for symptomatic therapy, Formoterol has a prolonged effect.

Powder for inhalation Formoterol

Indications

The use of Formoterol is limited to a relatively narrow list of indications, which mainly include chronic diseases of the bronchopulmonary system with an obstructive component. In this case, the drug is usually used only for long-term continuous therapy.

Diseases for which the use of this drug is necessary:

  • bronchial asthma (as a component of basic therapy);
  • chronic obstructive pulmonary disease (COPD);
  • chronic bronchitis with severe broncho-obstructive syndrome;
  • emphysema.

Restrictions

The use of the drug Formoterol is contraindicated and may be dangerous in the following cases:


 Arrhythmia
  • children under five years of age;
  • if the patient has hypersensitivity (history of allergic reactions) to any components of the pharmacological agent;
  • during pregnancy (especially in the first trimester) and lactation;
  • patients with heart rhythm and conduction disorders (arrhythmias, blockades), since in some cases the medication can affect the functional activity of the cardiovascular system;
  • people suffering from coronary heart disease and uncorrectable arterial hypertension;
  • patients with congenital and acquired lactose or galactose deficiency;
  • patients with thyrotoxicosis.

Mechanism of action

The main active ingredient that realizes all the biological effects of this medicine is formoterol fumarate. The mechanism of action of the drug is the direct stimulation of specific adrenergic receptors, which are located in the mucous lining of bronchi of various sizes.

Bronchial tree
  1. Once on the mucous membrane of the bronchial tree, Formoterol selectively binds to beta-2 adrenergic receptors, causing their activation.
  2. Due to the stimulating effect on adrenaline receptors, the intracellular enzyme adenylate cyclase is activated, which converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP).
  3. An increase in the concentration of cyclic adenosine monophosphate in the cytoplasm of cells leads to relaxation of smooth muscles, which leads to expansion of the bronchial lumen.

In addition to the main bronchodilator effect, the drug Formoterol blocks the release of biologically active substances (histamine, leukotrienes, prostaglandins) from mast cells and eosinophils, which provoke the progression of the inflammatory reaction. This effect is also important, since allergic inflammation is the basis of the pathogenesis of bronchial asthma (this effect leads to a slight decrease in the manifestations of edema and hyperreactivity).

Beta-2 adrenergic receptors, which are the molecular targets of Formoterol, are present not only in the bronchi, but are found in small quantities in the muscle fibers of the heart. Therefore, in some cases, undesirable effects on the cardiovascular system develop. The number of beta-2 adrenergic receptors in cardiomyocytes varies significantly between individuals, which is why cardiac effects develop only in a subset of patients.

https://youtu.be/q-eaMnkob0o

Medicinal composition

The main active ingredient that realizes all the biological effects of the drug is formoterol fumarate dihydrate.

In addition to the main pharmacological compound, the product contains an additional chemical substance - lactose monohydrate, which is necessary to give the medication the desired dosage form.

Release forms

There are three dosage forms of Formoterol:


 Powder for inhalation Formoterol-native
  • metered aerosol;
  • dosed powder in a bottle;
  • powder in capsules.

Please note that any form of release is intended for inhalation administration only. However, before use, you should study in detail the recommendations for taking the drug in order to become familiar with the features of using each individual dosage form.

Application Guide

All pharmacological forms of the drug that are currently offered on the official pharmaceutical market are administered only by inhalation.


 Spacer for inhalation

The frequency of use, dosage and duration of therapy are selected by the attending physician individually after assessing the severity of the disease and the characteristics of the course. This medication is not used “on demand” to relieve bronchospasm, but in combination with inhaled glucocorticosteroids is prescribed for a long time as “basic therapy”.

To facilitate the delivery of the active substance to the pathological focus, it is recommended to use a special device - a spacer.

An inhalation spacer is a special device that is a nozzle for cylinders with a drug and allows you to improve nebulization so that the pharmacological drug is able to penetrate into hard-to-reach parts of the respiratory tract.

It is forbidden to inhale the drug more often than indicated in the recommendations, as this can lead to the development of complications and undesirable effects.

Before starting treatment with Formoterol, the instructions for use of the drug must be studied, since for different dosage forms there are peculiarities in use.

Analogues of the drug

Medicines that can be used instead of Formoterol because they have a similar effect:


 Aerosol for inhalation Atimos
  • Athymos;
  • Zafiron;
  • Oxis turbuhaler;
  • Foradil;
  • Fortulin;
  • Fortix;
  • Salmeterol.

Only the attending physician can change the original drug to an analogue; it is prohibited to do this on your own due to the fact that each pharmacological agent with a similar composition has dosing features.

Side effects

Formoterol can have undesirable side effects on various organs and systems of the body. However, the most common complications arise from the cardiovascular system, because, despite the high selectivity of this medication, activation of beta-2 adrenergic receptors located in the myocardium can occur.

Side effects that may occur when taking Formoterol:


 Arterial hypertension
  • from the cardiovascular system: angina pectoris, various types of arrhythmias (often tachysystole), sudden sensations of palpitations, arterial hypertension or, conversely, a decrease in pressure;
  • from the nervous system, patients note the following symptoms: fatigue, generalized weakness, local convulsions, frequent dizziness, sleep disturbances;
  • from the respiratory system the following may appear: bronchitis, dysphonia, dyspnea (these complications aggravate the course of the underlying respiratory disease);
  • some patients develop allergy symptoms (rashes on the skin (exanthema) and mucous membranes (enanthema), itching, angioedema (Quincke's edema), urticaria);
  • in rare cases, an allergic reaction provokes an attack of suffocation (bronchospasm);
  • the development of a severe life-threatening complication – anaphylactic shock – is possible.

At the first manifestation of an allergic reaction, you should immediately stop taking this medicine and seek medical help.

Adverse reactions when taking Formoterol develop in a small percentage of patients; most patients do not experience a deterioration in their condition associated with treatment with the drug.

Formoterol is an effective drug that affects the pathogenetic mechanisms of the development of bronchial asthma and helps eliminate the main symptoms of the disease. Most patients tolerate therapy with this drug without complications and note an improvement in their well-being after a course of regular use of Formoterol.

Catad_pgroup Antiasthmatic drugs

Foradil - instructions for use

INSTRUCTIONS
on the use of a medicinal product for medical use

Registration number:

Tradename:

International Nonproprietary Name (INN):

formoterol

Dosage form:

capsules with powder for inhalation

Compound:

1 capsule contains:
active substance– formoterol fumarate 0.012 mg;
excipient– lactose up to 25 mg.

Description: transparent, colorless capsules, marked CG on the cap and FXF on the body or CG on the body and FXF on the cap in black ink. Capsule size No. 3.
Capsule contents: white, free-flowing powder.

Pharmacotherapeutic group:

selective beta2-adrenergic agonist

ATX code: R03AC13.

Pharmacological properties

Pharmacodynamics
Formoterol is a selective beta2-adrenergic receptor agonist. It has a bronchodilator effect in patients with reversible airway obstruction. The effect of the drug occurs quickly (within 1-3 minutes) and lasts for 12 hours after inhalation. When using therapeutic doses, the effect on the cardiovascular system is minimal and is observed only in rare cases.
Foradil 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 vitro animal studies have shown that racemic formoterol and its (R,R) and (S,S) enantiomers are highly selective beta2-adrenergic receptor agonists. The (S,S) enantiomer was 800-1000 times less active than the (R,R) enantiomer and did not adversely affect the tracheal smooth muscle activity of the (R,R) enantiomer. There has been no pharmacological evidence of benefit from using one of these two enantiomers over the racemic mixture.
In human studies, formoterol has been shown to be effective in preventing bronchospasm caused by inhaled allergens, exercise, cold air, histamine, or methacholine. Since the bronchodilatory effect of formoterol remains pronounced for 12 hours after inhalation, prescribing the drug 2 times a day for long-term maintenance therapy 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, used in the form of inhalation from an Aerolyzer in doses of 12 or 24 mcg 2 times a day, causes a rapid onset of a bronchodilator effect, which lasts for at least 12 hours and is accompanied by an improvement in quality of life parameters .
Pharmacokinetics
The therapeutic dose range for formoterol is 12 mcg to 24 mcg twice daily. Data on the pharmacokinetics of formoterol were obtained in healthy volunteers after inhalation of formoterol in doses above the recommended range and in patients with COPD after inhalation of formoterol in therapeutic doses.
Suction.
After a single inhalation of formoterol fumarate at a dose of 120 mcg to healthy volunteers, formoterol was rapidly absorbed into the plasma, the maximum plasma concentration of formoterol (Cmax) was 266 pmol/L and was achieved within 5 minutes after inhalation.
In COPD patients receiving formoterol at a dose of 12 or 24 mcg twice daily for 12 weeks, plasma formoterol concentrations measured at 10 minutes, 2 hours and 6 hours after inhalation were in the ranges of 11.5-25.7 pmol/L and 23.3 -50.3 pmol/l, respectively.
In studies that examined the total urinary excretion of formoterol and its (R,R) and (S,S) enantiomers, it was shown that the amount of formoterol in the systemic circulation increases in proportion to the size of the inhaled dose (12-96 mcg).
After inhaled use of formoterol at a dose of 12 or 24 mcg 2 times a day for 12 weeks, the urinary excretion of unchanged formoterol in patients with bronchial asthma increased by 63-73%, and in patients with COPD - by 19-38%. This indicates some accumulation in the plasma after repeated inhalations. However, there was no greater accumulation of one of the enantiomers of formoterol compared to the other after repeated inhalations.
As has been reported for other inhaled medicinal products, the majority of formoterol administered by inhalation will be swallowed and then absorbed from the gastrointestinal (GI) tract. When 80 mcg of 3H-labeled formoterol was administered orally to two healthy volunteers, at least 65% of the formoterol was absorbed.
Plasma protein binding and distribution.
Formoterol binding to plasma proteins is 61-64%, binding to serum albumin is 34%.
In the concentration range observed after the use of therapeutic doses of the drug, saturation of binding sites is not achieved.
Metabolism.
The main route of metabolism of formoterol is direct conjugation with glucuronic acid. Another metabolic pathway is O-demethylation followed by conjugation with glucuronic acid (glucuronidation).
Minor metabolic pathways include conjugation of formoterol with sulfate followed by deformylation. Multiple isoenzymes are involved in the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) of formoterol, suggesting a low likelihood of drug interactions through inhibition of any or an isoenzyme involved in the metabolism of formoterol. At therapeutic concentrations, formoterol does not inhibit isoenzymes of the cytochrome P450 system.
Excretion.
In patients with bronchial asthma and COPD who received formoterol fumarate at a dose of 12 or 24 mcg 2 times a day for 12 weeks, approximately 10% and 7% of the dose, respectively, were determined in the urine as unchanged formoterol. The calculated proportions of (R,R) and (S,S) enantiomers of unchanged formoterol in urine are 40% and 60%, respectively, after a single dose of formoterol (12-120 mcg) in healthy volunteers and after single and repeated doses of formoterol in patients with bronchial asthma.
The active substance and its metabolites are completely eliminated from the body; about 2/3 of the dose administered orally is excreted in the urine, 1/3 in feces. The renal clearance of formoterol is 150 ml/min.
In healthy volunteers, the terminal half-life of formoterol from plasma after a single inhalation of formoterol fumarate at a dose of 120 mcg is 10 hours; the terminal half-lives of the (R,R) and (S,S) enantiomers, calculated from urinary excretion, were 13.9 and 12.3 hours, respectively.
Pharmacokinetics in selected patient groups
Floor
After correction for body weight, the pharmacokinetic parameters of formoterol in men and women do not differ significantly.
Elderly patients
The pharmacokinetics of formoterol in elderly patients has not been studied.
Pediatrics
In a clinical study in children aged 5-12 years with asthma who received formoterol fumarate at a dose of 12 or 24 mcg 2 times a day for 12 weeks, excretion of unchanged formoterol in urine increased by 18-84% compared with the corresponding indicator. measured after the first dose.
In clinical studies in children, about 6% unchanged formoterol was detected in the urine.
Patients with impaired liver and/or kidney function
The pharmacokinetics of formoterol in patients with impaired liver and/or renal function have not been studied.

Indications for use

Prevention and treatment of bronchial obstruction in patients with bronchial asthma as an addition to therapy with inhaled glucocorticosteroids.
Prevention of bronchospasm caused by exercise, cold air or inhaled allergens as an adjunct to inhaled corticosteroid therapy.
Prevention and treatment of bronchial obstruction in patients with chronic obstructive pulmonary disease (COPD), in the presence of both reversible and irreversible bronchial obstruction, chronic bronchitis and pulmonary emphysema.

Contraindications

Hypersensitivity to any of the components of the drug
Children under 5 years old
Lactation

Carefully

If you have one of the listed diseases, be sure to consult your doctor before using the drug.
Accompanying illnesses
Particular caution when using Foradil (especially in terms of dose reduction) and careful monitoring of patients is required in the presence of the following concomitant diseases: coronary heart disease; disturbances of heart rhythm and conduction, especially third degree atrioventricular block; severe heart failure; idiopathic hypertrophic subaortic stenosis; severe arterial hypertension; aneurysm; pheochromocytoma; hypertrophic obstructive cardiomyopathy; thyrotoxicosis; known or suspected prolongation of the QTc interval (QT corrected > 0.44 sec).
Considering the hyperglycemic effect characteristic of beta2-adrenergic agonists, additional regular monitoring of blood glucose concentrations is recommended in patients with diabetes mellitus taking Foradil.

Use during pregnancy and breastfeeding

The safety of formoterol during pregnancy and breastfeeding has not yet been established.
The use of the drug during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus. The drug Foradil, like other beta2-agonists, can slow down the process of labor due to its tocolytic effect (relaxing effect on the smooth muscles of the uterus).
It is not known whether formoterol passes into breast milk. Therefore, if it is necessary to use the drug Foradil, breastfeeding must be stopped.
There is no data on the effect of the drug on fertility. Studies in experimental animals have shown no effect on fertility with oral formoterol.

Directions for use and doses

The drug Foradil is intended for inhalation use in adults and children aged 5 years and older. The drug is not intended for oral administration. The dose of the drug is selected individually depending on the needs of the patient. The lowest dose that provides a therapeutic effect should be used. When control of bronchial asthma symptoms is achieved during therapy with Foradil, it is necessary to consider the possibility of gradually reducing the dose of the drug. Reducing the dose of Foradil is carried out under regular medical supervision of the patient’s condition.
The drug is a powder for inhalation, which should be used only with the help of a special device - an Aerolyzer, which is included in the package.
Adults
At bronchial asthma the dose of the drug for regular maintenance therapy is 12-24 mcg (contents of 1-2 capsules) 2 times a day.
The drug Foradil should be used only as additional therapy to inhaled glucocorticosteroids.
The maximum recommended dose of the drug for adults (48 mcg per day) should not be exceeded.
Considering that the maximum daily dose of Foradil is 48 mcg, if necessary, an additional 12-24 mcg per 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, it becomes more often than 2 days a week), the patient should be advised to consult with a doctor about reviewing therapy, as this may indicate a worsening of bronchial asthma.
Against the background of exacerbation of bronchial asthma, you should not start treatment with Foradil or change the dose of the drug. The drug Foradil should not be used to relieve acute attacks of bronchial asthma.
To prevent bronchospasm caused by physical activity or unavoidable exposure to a known allergen, 15 minutes before the expected contact with the allergen or before the load, 12 mcg of the drug (contents of 1 capsule) should be inhaled. Patients with a history of severe bronchospasms may require inhalation of the contents of 2 capsules (24 mcg) for prevention.
For COPD the dose of the drug for regular maintenance therapy is 12-24 mcg (contents of 1-2 capsules) 2 times a day.
Children aged 5 years and older
The maximum recommended dose of the drug is 24 mcg per day.
For bronchial asthma The dose of the drug for regular maintenance therapy is 12 mcg 2 times a day. The drug Foradil should be used only as additional therapy to inhaled glucocorticosteroids.
In children aged 5 to 12 years, it is recommended to use combination drugs containing an inhaled glucocorticosteroid and a long-acting beta2-adrenergic receptor agonist, unless it is necessary to use them separately.
With the aim of prevention of bronchospasm caused by physical activity or unavoidable exposure to a known allergen, 15 minutes before expected contact with the allergen or before exercise, the contents of 1 capsule (12 mcg) should be inhaled.
Instructions for inhalation
To ensure proper use of the drug, a doctor or other health care professional must show the patient how to use the inhaler; Explain to the patient that capsules with powder for inhalation should be used only with the help of an Aerolyzer; Warn the patient that the capsules are for inhalation use only and are not intended to be swallowed.
Children should use the drug under adult supervision.
Elderly patients (over 65 years old)
There is no evidence to support the need to use the drug at a different dose in patients over 65 years of age compared to younger patients.
It is important that the patient understands that due to the breakdown of the gelatin capsule, 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.
Remove the capsule from the blister pack immediately before use. (See also Instructions for use of the Aerolyzer).
There are isolated reports of patients accidentally swallowing capsules of the drug whole. Most of these cases are not associated with the development of adverse events. The medical professional should explain to the patient how to use the drug correctly, especially if the patient does not experience improvement in breathing after inhalation.

Side effect

Adverse reactions (AEs) 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); нечасто (≥1/1000, <1/100); редко (≥1/10000, <1/1000); очень редко (<1/10000), включая отдельные сообщения.
Immune system disorders: very rarely - hypersensitivity reactions, such as decreased blood pressure, urticaria, angioedema, itching, rash.
Mental disorders: infrequently – agitation, anxiety, increased excitability, insomnia.
Nervous system disorders: often – headache, tremor; infrequently - dizziness; very rarely - taste disturbances.
Cardiac disorders: often – a feeling of palpitations; infrequently - tachycardia; very rarely - peripheral edema.
infrequently – bronchospasm, including paradoxical.
General disorders and disorders at the injection site: uncommon – irritation of the mucous membrane of the pharynx and larynx.
Gastrointestinal disorders: uncommon – dryness of the oral mucosa; very rarely - nausea.
Musculoskeletal and connective tissue disorders: uncommon – muscle spasm, myalgia.
According to post-marketing observations, the following AEs were observed when prescribing the drug Foradil, the frequency of which, due to the small number of patients, was regarded as “frequency unknown”:
Laboratory and instrumental data: hypokalemia and hyperglycemia, prolongation of the QT interval on the electrocardiogram, increased blood pressure (including arterial hypertension).
Disorders of the respiratory system, chest and mediastinal organs: cough.
Disorders of the skin and subcutaneous tissues: rash.
Cardiac disorders: angina pectoris, cardiac arrhythmia (including atrial fibrillation, ventricular extrasystoles, tachyarrhythmia).
In clinical studies, formoterol showed a slight increase in the incidence of serious exacerbations of asthma compared to placebo. However, the results of the above clinical studies do not allow us to quantify the incidence of serious exacerbations of bronchial asthma in different groups.
If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

Symptoms. An overdose of Foradil can likely lead to the development of phenomena characteristic of an overdose of beta2-adrenergic agonists or increased manifestations of side effects: chest pain, nausea, vomiting, headache, tremor, drowsiness, palpitations, tachycardia up to 200 beats/min, ventricular arrhythmias , metabolic acidosis, hypokalemia, hyperglycemia, increased or decreased blood pressure, nervousness, convulsions, muscle cramps, dry mouth, dizziness, weakness, anxiety. As with all inhaled sympathomimetics, an overdose of Foradil can cause cardiac arrest and death.
Treatment. Maintenance and symptomatic therapy is indicated. In serious cases, hospitalization is necessary.
The use of cardioselective beta-blockers may be considered, but only under close medical supervision and extreme caution, as the use of such agents may cause bronchospasm. Monitoring of cardiac indicators is recommended.

Interaction with other drugs

Foradil, as well as other beta2-agonists, should be prescribed with caution to patients receiving drugs such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines, macrolides, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, as well as other drugs, which are known to prolong the QT interval, since in these cases the effect of agonists on the cardiovascular system may be enhanced. When using drugs that can prolong the QT interval, the risk of ventricular arrhythmias increases.
The simultaneous use of other sympathomimetic drugs may lead to worsening of the side effects of Foradil.
Concomitant use of xanthine derivatives, glucocorticosteroids 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 weaken the effect of Foradil. In this regard, Foradil should not be used in conjunction with beta-blockers (including eye drops), unless the use of such a combination of drugs is forced by any emergency reasons.

special instructions

Patients with hypersensitivity to lactose should note that the drug contains lactose.
Foradil belongs to the class of long-acting beta2-adrenergic receptor agonists. Another long-acting beta2-adrenergic 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 Foradil.
It has been shown that the use of Foradil improves the quality of life of patients with COPD.
Anti-inflammatory therapy
In patients with bronchial asthma, Foradil should be used only as an adjunctive treatment in cases of insufficient control of symptoms on monotherapy with inhaled corticosteroids or in severe forms of the disease requiring the use of a combination of an inhaled corticosteroid and a long-acting beta2-adrenergic agonist. The drug should not be used with other long-acting beta2-adrenergic receptor agonists.
When prescribing Foradil, it is necessary to assess the condition of patients regarding the adequacy of the anti-inflammatory therapy they receive. After starting treatment with Foradil, patients should be advised to continue anti-inflammatory therapy without changes, even if improvement is noted.
To relieve an acute attack of bronchial asthma, 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 5-12 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 day) compared to the placebo group (0.3%), especially in children 5-12 years old.
Hypokalemia
Therapy with beta2-agonists, including Foradil, may result in the development of potentially serious hypokalemia. Hypokalemia may increase the risk of developing arrhythmias.
Since 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/or operate machinery

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

Release form

Capsules with powder for inhalation, 12 mcg, 10 capsules in a blister. 3 or 6 blisters along with instructions for use and an inhalation device Aerolizer in a cardboard box.

Storage conditions

At a temperature not higher than 25°C. Protect from moisture.
Keep out of the reach of children.

Best before date

2 years
The drug should not be used after the expiration date.

Conditions for dispensing from pharmacies

On prescription

Manufacturer

NOVARTIS PHARMA AG, SWITZERLAND/NOVARTIS PHARMA AG, SWITZERLAND
Manufactured by:
NOVARTIS PHARMA STEIN AG, SWITZERLAND
NOVARTIS FARMACEUTICA S.A., SPAIN
Address:
Lichtstrasse 35, 4056 Basel, Switzerland
Lichtstrasse 35, 4056 Basel, Switzerland
Additional information about the drug can be obtained at:
125315, Moscow, Leningradsky prospect, building 72, building 3.

Instructions for use of the Aerolyzer

1. Remove the cap from the Aerolizer.
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 is shaped like a capsule). Remember 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 in a strictly vertical position, once Press all the way down on the blue buttons located on the sides of the Aerolizer. Then release them.
Note. At this stage, if the capsule is pierced, it may break, causing small pieces of gelatin to get into your mouth or throat. Since gelatin is edible, it will not cause you 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. Exhale completely.
7. Place the mouthpiece in your mouth and tilt your head back slightly. Cover the mouthpiece tightly with your lips and take a quick, even, as deep breath as possible.
You should hear a characteristic rattling sound created by the rotation of the capsule and spraying of the powder.
If you do not hear a characteristic sound, then you need to 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 attempt to release the capsule by repeatedly pressing the buttons on the sides of the Aerolizer.
8. If you hear a characteristic sound when inhaling, 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, open the Aerolyzer, remove the empty capsule, close the mouthpiece and close the Aerolyzer with the cap.
How to care for Arolizer
To remove any remaining powder, wipe the mouthpiece and chamber dry cloth. You can also use a soft brush.

One dose of Formoterol Easyhaler inhalation powder contains 12 mcg formoterol fumarate dihydrate .

Additional substances: lactose monohydrate .

Release form

An inhaler made of a polymer substance. A lid with a lock is put on the dosing part. On the front of the device there is the inscription “Easyhaler”. On the side of the device there is a counter for the number of remaining doses. There is a homogeneous white powder inside the inhaler.

120 doses per metered dose inhaler; one inhaler in a cardboard pack.

pharmachologic effect

Bronchodilator action.

Pharmacodynamics and pharmacokinetics

Pharmacodynamics

Drug from the group β-adrenergic agonists . Formoterol acts mainly on β2-adrenergic receptors . It has a bronchodilator effect, relieves and prevents bronchospasm. Suppresses release leukotrienes, histamine and from basophils, mast cells and sensitized bronchial cells.

Pharmacokinetics

Ingestion of up to 90% of the active substance during inhalation is acceptable. Rapidly absorbed from the intestines. Absorption reaches 65%. The time for maximum concentration to occur is 30-60 minutes. Plasma protein binding is approximately 62-64%. Half-life is 2.5-3 hours. Transformed mainly by glucuronidation . It is evacuated from the body by the kidneys and feces.

When used inhalation, it is quickly absorbed, the highest concentration occurs after 15 minutes. Bioavailability is 46%. Reacts with proteins by 50%. The half-life is approximately 8 hours.

Indications for use

Prevention and treatment of bronchospasm in persons suffering from and obstructive.

Contraindications

  • to the components of the drug.
  • Children under 6 years of age.
  • Intolerance lactose, glucose-galactose malabsorption , flaw lactase .

Side effects

The most common symptoms are nausea and dry mouth.

In more rare cases, muscle cramps are detected, tachycardia, myalgia , dizziness, anxiety, agitation, sleep disturbances, increased bronchospasm and nervousness. Even less often - hypersensitivity reactions ( , heavy hypotension , itching, , exanthema ), changes in the sense of taste, peripheral edema.

Instructions for use Formoterol Easyhaler (Method and dosage)

Formoterol Easyhaler is used for inhalation only.

Bronchial asthma

For continuous maintenance therapy, 1 inhalation of the drug is prescribed twice a day; Some patients may require 2 inhalations twice a day. The highest daily dose for regular use is 4 inhalations.
If necessary, the use of additional inhalations, in addition to those prescribed, is allowed to relieve symptoms, but not more than 6 inhalations per day in total.
Do not carry out more than 3 inhalations at a time. Frequent (more than 2 times a day or more than 2 days a week) use of the drug or its use in dosages exceeding those recommended for maintenance treatment is a sign of insufficient control of bronchial asthma. In this case, it is necessary to reconsider the treatment regimen.

Prevention of bronchospasm provoked by physical activity

In such cases, take 1 inhalation approximately 15 minutes before the expected physical activity. In severe cases of the disease, the need for 2 inhalations cannot be ruled out, but the maximum daily dose of 6 inhalations should not be exceeded.

Overdose

To date, not enough clinical experience has been accumulated in the treatment of overdose, but it is assumed that an overdose of Formoterol Easyhaler is accompanied by nausea, headaches, vomiting, palpitations, ventricular arrhythmias, tachycardia , pressure change, metabolic acidosis, hyperglycemia, hypokalemia , prolongation of the QT interval.

Supportive and symptomatic treatment and concentration monitoring are indicated. potassium in blood. If the process is severe, the patient must be hospitalized. Cautious use is allowed (since it may provoke bronchospasm) cardioselective β-blockers .

Interaction

It is not recommended to combine formoterol With MAO inhibitors, adrenomimetic drugs, tricyclic antidepressants , since the risk of adverse reactions from the circulatory system increases.

When used together glucocorticosteroids, xanthine derivatives, diuretics increase the likelihood of a hypokalemic effect from taking the drug.

Beta blockers (including eye drops) are capable of partially or completely stopping the action formoterol .

When used together Quinidine, Procainamide, Disopyramide, phenothiazines, tricyclic antidepressants, antihistamines the likelihood of occurrence increases ventricular arrhythmias .

Terms of sale

On prescription.

Storage conditions

Store at temperatures below 30°C in a dry place. Keep away from children.

Best before date

Two years. After opening the package, the product is allowed to be used for 4 months.

special instructions

Careful observation and special caution are required if it is necessary to use the drug in patients with coronary heart disease , cardiac rhythm and conduction disturbances, severe cardiac failure, subvalvular idiopathic aortic stenosis, uterine fibroids, obstructive hypertrophic cardiomyopathy, thyrotoxicosis, prolongation of the QT interval by ECG .

Formoterol Easyhaler may affect the ability to drive vehicles, so such activities are not recommended when using the drug.

Analogs

Level 4 ATX code matches:

The most famous analogues of Formoterol Easyhaler: Atimos, Zafiron, Oxis Turbuhaler, .

For children

The drug is not used in children under 6 years of age

Children aged 6 years or more for ongoing maintenance treatment bronchial asthma 1 inhalation is prescribed twice a day. More than 2 inhalations per day are not recommended.

During pregnancy and lactation

It is possible to use the drug during these periods only according to strict indications and taking into account all risks.

73573-87-2

Characteristics of the substance Formoterol

Bronchodilator (beta 2 adrenergic agonist).

Available in the form of formoterol fumarate and formoterol fumarate dihydrate. Formoterol fumarate is a white or yellowish crystalline powder. Easily soluble in glacial acetic acid, soluble in methanol, to a lesser extent in ethanol and isopropanol, slightly soluble in water, practically insoluble in acetone, ethyl acetate and diethyl ether. Molecular weight 840.9.

Pharmacology

pharmachologic effect- bronchodilator, adrenomimetic.

Formoterol fumarate is a long-acting selective adrenergic beta 2 receptor agonist. When inhaled, formoterol fumarate acts locally on the bronchi, causing bronchodilation. In research in vitro it has been shown that its activity against beta 2 adrenoreceptors, located mainly in the smooth muscles of the bronchi, is more than 200 times higher than that against beta 1 adrenoreceptors, located mainly in the myocardium. Beta 2 adrenergic receptors are also found in the myocardium, constituting up to 10-50% of the total number of beta adrenergic receptors. The exact function of these receptors has not been established, but they increase the potential for cardiac effects of even highly selective beta 2-agonists. Formoterol fumarate stimulates intracellular adenylate cyclase, which catalyzes the transformation of ATP into cAMP. An increase in cAMP levels causes relaxation of bronchial smooth muscle and inhibits the release of immediate hypersensitivity mediators from cells, especially from mast cells. Research in vitro showed that formoterol fumarate inhibits the release of mediators (histamine and leukotrienes) from mast cells in the human lung. In animal studies, formoterol fumarate was found to inhibit histamine-induced plasma albumin extravasation in anesthetized guinea pigs and allergen-induced eosinophil influx in dogs with airway hyperresponsiveness. The significance of these facts obtained from animal studies and in vitro, unclear to humans.

The main side effects of inhaled beta 2 -adrenergic agonists are the result of excessive activation of systemic beta adrenergic receptors. The most common side effects in adults and adolescents include skeletal muscle tremors and seizures, insomnia, tachycardia, hypokalemia and hyperglycemia.

The pharmacokinetic and pharmacodynamic relationships between heart rate, ECG parameters, plasma potassium levels and renal excretion of formoterol fumarate were studied in 10 healthy male volunteers aged 25 to 45 years after a single inhalation of 12, 24, 48 or 96 mcg of formoterol fumarate. A linear relationship was found between renal excretion of formoterol fumarate and a decrease in plasma potassium, an increase in plasma glucose and an increase in heart rate. In another study, 12 volunteers received a single dose of 120 mcg of formoterol fumarate (10 times the recommended single dose). In all subjects, the potassium content in the blood plasma decreased as much as possible by 0.55-1.52 mmol/l (the average maximum decrease was 1.01 mmol/l). A strong correlation was noted between the concentration of formoterol fumarate and the potassium content in the blood plasma: the greatest effect on potassium levels was observed 1-3 hours after the Cmax of formoterol fumarate was reached. On average, the maximum increase in heart rate was observed 6 hours after taking formoterol fumarate and was 26 beats per minute. The maximum prolongation of the corrected QT interval (QTc) when calculated using the Bazett formula averaged 25 milliseconds, and according to the Fredericia formula - 8 milliseconds. The QTc interval returned to baseline 12-24 hours after taking formoterol fumarate. Plasma formoterol concentrations were weakly correlated with heart rate and QTc increase. Effects on plasma potassium levels, pulse rate, and QTc interval are known pharmacological effects of the drug class to which formoterol fumarate belongs, so their appearance in a study of very high doses of formoterol fumarate (120 mcg single dose, 10 times the recommended single dose) was not unexpected . These phenomena were well tolerated by healthy volunteers.

The electrocardiographic and cardiovascular effects of formoterol fumarate were compared with the effects of albuterol (not registered in Russia) and placebo in two 12-week double-blind studies in patients with bronchial asthma; The studies involved long-term ECG monitoring over three 24-hour periods. There were no significant differences in ventricular or supraventricular ectopia between patient groups (in these two studies, the total number of patients with bronchial asthma who received any dose of formoterol fumarate and underwent long-term ECG monitoring was about 200 people). The effect of formoterol fumarate compared with placebo on the ECG of patients with chronic obstructive pulmonary disease (COPD) was assessed in a 12-month study (without long-term ECG monitoring). ECG interval analysis was performed on patients participating in US studies; of these, 46 people took formoterol fumarate 12 mcg 2 times a day and 50 patients took 24 mcg twice a day. ECG was recorded before use and 5-15 minutes and 2 hours after the first use of the drug, then after 3, 6 and 12 months of treatment. According to the results of the study, clinically significant acute or chronic effects on ECG intervals, incl. QTc was not detected during treatment with formoterol fumarate. Formoterol fumarate, like other beta-agonists, can cause flattening of the T wave and ST segment depression on the ECG; the clinical significance of these changes is unknown.

Tolerance. In a clinical study on 19 adult patients with moderate bronchial asthma, the bronchoprotective effect of formoterol fumarate was assessed by the response in a methacholine test after taking an initial dose of 24 mcg (twice the recommended dose) and after 2 weeks when taking 24 mcg twice a day . Tolerance to the bronchoprotective effect of formoterol fumarate, as evidenced by a decrease in the bronchoprotective effect in relation to forced expiratory volume in 1 s (FEV 1), was observed after 2 weeks of taking the drug, loss of protective properties was noted by the end of the 12-hour period after administration. No rebound bronchial hyperreactivity reactions were observed after discontinuation of long-term therapy with formoterol fumarate.

Clinical researches

Studies in patients with bronchial asthma. In three large clinical trials in patients with asthma, while the effectiveness of formoterol fumarate compared with placebo was maintained, there was a slight decrease in the bronchodilator response assessed over 12 hours, while the effect of formoterol fumarate was maintained, especially when taking 24 mcg twice daily ( twice the recommended daily dose).

In studies with single and multiple doses of formoterol fumarate at a dose of 12 mcg, the maximum improvement in FEV 1 was usually observed between 1 and 3 hours after dosing. An increase in FEV 1 compared to the initial value was detected within 12 hours after administration of the drug in most patients.

Two 12-week multicenter, randomized, comparative, double-blind, placebo studies in adults and adolescents 12 years of age and older with moderate to severe asthma (FEV 1 was 40-80% of normal values) showed that formoterol fumarate ( 12 mcg twice a day) not only caused significant bronchodilation, assessed by FEV 1, but also improved many secondary efficacy indicators, including improvements in combined and nocturnal asthma symptom scales, as well as a decrease in the number of night awakenings and nights when patients used drugs emergency care, increasing morning and evening peak flow measurements (air flow rate).

Clinical studies in children. A 12-month, multicenter, randomized, double-blind, parallel-group study of formoterol fumarate and placebo included 518 children 5–12 years of age with asthma who required daily bronchodilators and anti-inflammatory drugs. The effectiveness of therapy was assessed on the first day, on the 12th week and at the end of the course of treatment; According to the study results, the 12-hour effectiveness of formoterol fumarate (as measured by FEV 1) exceeded that of the placebo group at all specified times.

Clinical studies of the effectiveness of formoterol fumarate in exercise-induced bronchospasm(the effect was assessed as a decrease in FEV 1 by more than 20%). Four randomized, double-blind comparative studies included 77 patients aged 4 to 41 years. The response to exercise was assessed by FEV 1 after 15 minutes, 4, 8 and 12 hours after a single dose of 12 μg of formoterol fumarate and placebo. The indicators in the formoterol fumarate group were significantly higher than those in the placebo group at all follow-up periods. The effectiveness of regular twice-daily use of formoterol in preventing exercise-induced asthma attacks has not been studied.

Clinical studies in patients with COPD. In clinical trials with repeated administration of formoterol fumarate at a dose of 12 mcg in patients with COPD, pronounced bronchodilation was noted (increase in FEV 1 by 15% or more) 5 minutes after inhalation of the initial dose, lasting for 12 hours. According to two comparative studies using placebo formoterol fumarate (12 mcg) improved morning peak flow measurements compared with the pre-treatment period.

Pharmacokinetics

The pharmacokinetics of formoterol fumarate were studied in healthy volunteers who used it in doses higher than recommended, and in patients with COPD who received formoterol fumarate in therapeutic and higher doses. Urinary excretion of unchanged formoterol was used as an indirect indicator of systemic exposure. The distribution of formoterol from blood plasma corresponded to renal excretion, and T1/2 of distribution and elimination were similar. After a single inhalation of 120 mcg of formoterol fumarate in 12 healthy volunteers, it was rapidly absorbed into the plasma, reaching C max (92 pg/ml) within 5 minutes. In patients with COPD who received formoterol fumarate at a dose of 12 or 24 mcg twice daily for 12 weeks, its average plasma concentration ranged from 4.0-8.8 pg/ml and 8.0-17.3 pg/ml ml, respectively, 10 minutes, 2 and 6 hours after inhalation. After inhalation of 12-96 mcg of formoterol fumarate by 10 healthy volunteers, the urinary excretion of the R,R- and S,S-enantiomers of formoterol increased proportionally to the dose, i.e., the absorption of formoterol fumarate after inhalation is linear over the dose range considered.

In a study in patients with bronchial asthma who received 12 and 24 mcg of formoterol fumarate inhaled twice a day for 4 or 12 weeks, the accumulation index, assessed by excretion of unchanged drug in urine, ranged from 1.63-2.08 compared with initial dose. For patients with COPD who used formoterol fumarate 12 and 24 mcg twice a day for 12 weeks, the accumulation index, calculated from the excretion of unchanged drug in urine, was 1.19-1.38. This confirms some accumulation of formoterol fumarate in plasma with repeated dosing. The amount of formoterol fumarate eliminated at steady state was almost equal to that predicted based on pharmacokinetics after a single dose. Presumably, most of formoterol fumarate (similar to other inhaled drugs) will be swallowed and then absorbed from the gastrointestinal tract. Binding in vitro with plasma proteins is 61-64% at a concentration of 0.1-100 ng/ml, with albumin - 31-38% at a plasma concentration of 5-500 ng/ml (these plasma concentrations exceed those after inhalation of 120 mg of formoterol fumarate). Formoterol fumarate is metabolized primarily by direct glucuronidation at a phenolic or aliphatic hydroxyl group and O-demethylation followed by conjugation with a glucuronide at any phenolic hydroxyl group. Another biotransformation pathway involves sulfation and deformylation, accompanied by sulfation. The predominant route is direct conjugation at the phenolic hydroxyl group, the second most important route is O-demethylation, accompanied by conjugation at the phenolic 2"-hydroxyl group. Four isoenzymes of cytochrome P450 (CYP2D6, CYP2C19, CYP2C9 and CYP2A6). At therapeutic concentrations, formoterol does not inhibit cytochrome P450 enzymes. Some patients may experience insufficient functional activity of one or both isoenzymes CYP2D6 And CYP2C19. However, whether deficiency of one or both isoenzymes may lead to increased systemic exposure or the development of systemic side effects is unknown (no adequate studies have been conducted). Following oral administration of 80 mcg of radiolabeled formoterol fumarate to two healthy volunteers, 59-62% was excreted in urine and 32-34% in feces within 104 hours; their renal clearance of formoterol fumarate was about 150 ml/min. In 16 patients with bronchial asthma who received 12 mcg or 24 mcg of formoterol fumarate by inhalation, about 10% of the drug was excreted in the urine unchanged and 15-18% in the form of conjugates. In 18 patients with COPD who received formoterol fumarate in the same doses, these figures were 7% and 6-9%, respectively. After a single inhalation of 120 mcg of formoterol fumarate in 12 healthy volunteers, the terminal T1/2 (based on plasma concentration measurements) was 10 hours. When calculated based on the level of renal excretion, the terminal T1/2 for the R,R- and S,S-enantiomers of formoterol fumarate was 13.9 and 12.3 hours, respectively. After a single inhalation of 12-120 mcg of formoterol fumarate by healthy volunteers, a single and repeated dose of formoterol fumarate at a dose of 12 mcg or 24 mcg by patients with bronchial asthma, the proportion of R, R- and S, S-enantiomers of the unchanged substance found in the urine was 40% and 60%, respectively (the ratio of the two enantiomers remains constant over the dose range studied and there is no evidence of accumulation of one of them relative to the other with repeated doses).

After correction for body weight, there were no significant differences in pharmacokinetic parameters depending on gender. In clinical trials, formoterol fumarate was administered to elderly patients with asthma (318 people aged 65 years and older, 39 people aged 75 years and older) and COPD (395 and 62 people aged 65 years and older and 75 years and older, respectively) . There were no significant differences in the safety and effectiveness of formoterol fumarate in elderly and younger people; Respiratory tract infections were observed with a slightly higher frequency in patients aged 75 years and older, but their relationship with formoterol fumarate was not established. In children 5-12 years old with bronchial asthma who received inhaled formoterol fumarate at a dose of 12 mcg or 24 mcg twice daily for 12 weeks, the accumulation index, calculated from the renal excretion of unchanged formoterol fumarate, ranged from 1.18-1.84 (in adults - 1.63-2.08). About 6% of formoterol fumarate in unchanged form and 6.5-9% in the form of conjugates were found in the urine of children. The pharmacokinetics of formoterol fumarate in people with liver or kidney damage and in elderly patients has not been studied.

Experimental pharmacology

In animal studies (mini-pigs, rodents, dogs), cases of arrhythmias and sudden death with histologically confirmed myocardial necrosis were reported with the simultaneous use of beta-agonists and methylxanthine derivatives. The clinical significance of these facts for humans has not been determined.

Carcinogenicity, mutagenicity, effect on fertility

A study of the carcinogenicity of formoterol fumarate was carried out on rats and mice receiving it for 2 years through food or drinking water. In rats, the incidence of ovarian leiomyomas increased at doses of formoterol fumarate of 15 mg/kg or more in drinking water and 20 mg/kg in food. When 5 mg/kg formoterol fumarate (approximately 450 times the AUC of human exposure from inhaled MRDC) was administered in food, the incidence of ovarian leiomyoma in rats was not increased. The incidence of benign theca cell tumors of the ovary was increased when formoterol fumarate was taken with food at a dose equal to or greater than 0.5 mg/kg (AUC exposure of a dose of 0.5 mg/kg is approximately 45 times higher than the exposure of inhaled MRDC). These findings were not observed when formoterol fumarate was administered to rats through drinking water or in tests in mice. In male mice, the incidence of subcapsular adenomas and adrenal carcinomas increased when receiving 69 mg/kg or more of formoterol fumarate in drinking water; the development of these tumors was not observed when formoterol fumarate was taken with food in doses of about 50 mg/kg (AUC exposure is approximately 590 times higher than the exposure in humans when taken by inhalation of the maximum recommended daily dose). The development of hepatocarcinomas in mice was observed when 20 and 50 mg/kg of formoterol fumarate (females) and 50 mg/kg (males) were taken with food. The development of uterine leiomyomas and leiomyosarcomas has been observed when formoterol fumarate was taken with food in doses of 2 mg/kg or more (AUC exposure at a dose of 2 mg/kg is approximately 25 times higher than the exposure in humans after inhalation of the maximum recommended daily dose). The increase in the incidence of leiomyomas of the reproductive system in female rodents was similar to data from studies of other beta-agonists.

Formoterol fumarate did not exhibit mutagenic or clastogenic properties in the following tests: mutagenicity studies on bacterial and mammalian cells, chromosomal analysis on mammalian cells, DNA repair studies on rat hepatocytes and human fibroblasts, mammalian fibroblast transformation assays, and micronucleus tests on mice and rats.

In a reproduction study in rats treated with oral formoterol fumarate at doses of approximately 3 mg/kg (approximately 1000 times the maximum recommended daily inhalation dose for humans based on body surface area in mg/m2), no impairment of fertility was observed. Rats treated with formoterol fumarate at a dose of 6 mg/kg (2000 times the maximum recommended daily human inhalation dose based on body surface area in mg/m2) during late pregnancy had increased prenatal and neonatal mortality. These effects were not observed with formoterol fumarate at a dose of 0.2 mg/kg (70 times the maximum recommended daily inhalation dose for humans based on body surface area in mg/m2). A slowdown in skeletal ossification and a decrease in body weight were observed in fetuses of rats that received formoterol fumarate at a rate of 0.2 mg/kg and 6 mg/kg, respectively, during the period of organogenesis. In studies in rats and rabbits, formoterol fumarate did not cause malformations.

Use of the substance Formoterol

According to Physician Desk Reference (2009), formoterol fumarate is indicated for long-term (twice daily - morning and evening) maintenance therapy for bronchial asthma and prevention (in adults and children 5 years and older) of bronchospasm in reversible obstructive airway diseases, incl. in patients with symptoms of nocturnal asthma.

The use of formoterol fumarate "on demand" (if necessary) is indicated for adults and children 5 years of age and older for the rapid prevention of bronchospasm caused by exercise.

Formoterol fumarate is used for long-term (twice daily - morning and evening) maintenance therapy in patients with COPD, including chronic bronchitis and emphysema.

Contraindications

Hypersensitivity.

Restrictions on use

Cardiovascular disorders, incl. coronary insufficiency, arrhythmias, arterial hypertension, convulsive disorders, thyrotoxicosis, unusual response to sympathomimetics, pregnancy, breastfeeding, age under 5 years (safety and effectiveness have not been established).

Formoterol fumarate is not recommended for patients whose asthma can be controlled only by non-systematic inhalation of short-acting beta 2-adrenergic agonists, as well as for patients for whom therapy with inhaled corticosteroids or other drugs is completely adequate, one of which is an inhaled short-acting beta 2-adrenergic agonist from time to time. adrenomimetic.

Use during pregnancy and breastfeeding

Adequate controlled studies of formoterol fumarate in pregnant women, incl. during childbirth, was not carried out. Formoterol fumarate should be used during pregnancy and childbirth (as beta-agonists may adversely affect uterine contractility) only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

Formoterol fumarate is excreted in rat milk. It is not known whether it is excreted in breast milk in women, but since many drugs are excreted in human milk, formoterol fumarate should be administered with caution to nursing women (well-controlled studies have not been conducted in nursing women).

Side effects of the substance Formoterol

Side effects of formoterol fumarate are similar to the side effects of other selective beta 2 -agonists and include angina pectoris, arterial hypo- or hypertension, tachycardia, arrhythmia, nervousness, headache, tremor, dry mouth, palpitations, dizziness, convulsions, nausea, fatigue, weakness , hypokalemia, hyperglycemia, metabolic acidosis and insomnia.

Bronchial asthma

During controlled clinical trials, formoterol fumarate (12 mcg 2 times a day) was administered to 1985 patients (children 5 years and older, adolescents and adults) with bronchial asthma. Among the identified side effects of formoterol fumarate with a frequency of 1% or more exceeding the frequency of side effects in the placebo group, the following were noted (next to the name is the percentage of occurrence of this side effect in the formoterol fumarate group, in parentheses - in the placebo group):

tremor 1.9% (0.4%), dizziness 1.6% (1.5%), insomnia 1.5% (0.8%).

bronchitis 4.6% (4.3%), chest infections 2.7% (0.4%), dyspnea 2.1% (1.7%), tonsillitis 1.2% (0.7%) , dysphonia 1.0% (0.9%).

Others: viral infections 17.2% (17.1%), chest pain 1.9% (1.3%), rash 1.1% (0.7%).

Three side effects—tremor, dizziness, and dysphonia—were dose-dependent (doses of 6, 12, and 24 mcg administered twice daily were studied).

The safety of formoterol fumarate compared with placebo was studied in a multicenter, randomized, double-blind clinical trial in 518 children aged 5-12 years with asthma who required daily bronchodilators and anti-inflammatory drugs. When taking 12 mcg of formoterol fumarate 2 times a day, the frequency of side effects was comparable to that in the placebo group. The nature of the side effects detected in children differed from the side effects of formoterol fumarate noted in adults. Side effects in the formoterol fumarate group in children that exceeded the incidence of side effects in the placebo group included infections/inflammation (viral infections, rhinitis, tonsillitis, gastroenteritis) or gastrointestinal complaints (abdominal pain, nausea, dyspepsia).

COPD

In two controlled studies, 405 patients with COPD received formoterol fumarate (12 mcg twice daily). The incidence of adverse events was comparable in the formoterol fumarate and placebo groups. Among the side effects in the formoterol fumarate group with a frequency equal to or exceeding 1% and exceeding that in the placebo group, the following were noted (next to the name is the percentage of occurrence in the formoterol fumarate group, in parentheses - in the placebo group):

From the nervous system and sensory organs: cramps 1.7% (0%), calf muscle cramps 1.7% (0.5%), anxiety 1.5% (1.2%).

From the respiratory system: upper respiratory tract infections 7.4% (5.7%), pharyngitis 3.5% (2.4%), sinusitis 2.7% (1.7%), increased sputum 1.5% (1.2 %).

Others: back pain 4.2% (4.0%), chest pain 3.2% (2.1%), fever 2.2% (1.4%), itching 1.5% (1.0% ), dry mouth 1.2% (1.0%), injuries 1.2% (0%).

Overall, the incidence of all cardiovascular adverse events in the two main studies was low and comparable to placebo (6.4% in patients taking formoterol fumarate 12 mcg twice daily and 6.0% in the placebo group). No specific cardiovascular side effects were observed in the formoterol fumarate group, which occurred with a frequency of 1% or more and exceeded the frequency of occurrence in the placebo group.

In two studies in patients taking 12 mcg and 24 mcg of formoterol fumarate twice daily, seven side effects (pharyngitis, fever, convulsions, increased sputum production, dysphonia, myalgia and tremor) were noted to be dose-dependent.

Post-marketing studies

During widespread post-marketing use of formoterol fumarate, there were reports of severe exacerbations of asthma, some of which were fatal. Although most of these cases were observed in patients with severe bronchial asthma or acute decompensation of the condition, a few cases were observed in patients with less severe bronchial asthma. The relationship of these cases to the use of formoterol fumarate has not been determined. There are rare reports of anaphylactic reactions, including severe hypotension and angioedema, associated with inhaled formoterol fumarate. Allergic reactions can manifest themselves in the form of urticaria and bronchospasm. There was no evidence of the development of drug dependence with the use of formoterol fumarate in clinical trials.

Interaction

Other adrenergic agents should be used with caution while taking formoterol, as there is a risk of potentiating the predictable sympathomimetic effects of formoterol. When taking xanthine derivatives, steroids or diuretics simultaneously, the hypokalemic effect of adrenergic receptor agonists may be enhanced. ECG changes and/or hypokalemia caused by non-potassium sparing diuretics, such as loop or thiazide diuretics, may be suddenly exacerbated by beta-agonists, especially when the dose is exceeded (although the clinical significance of these effects is unclear, caution is required when co-prescribing drugs of these groups ). Formoterol, like other beta 2-agonists, should be prescribed with special attention when taking MAO inhibitors, tricyclic antidepressants or other drugs that can prolong the QTc interval, as this may potentiate the effect of adrenergic agonists on the cardiovascular system (increases the risk of developing ventricular arrhythmias ). Formoterol and beta-blockers may mutually suppress each other's effects when administered simultaneously. Beta blockers may not only antagonize the pharmacological action of beta agonists, but may also cause severe bronchospasm in patients with asthma.

Overdose

Symptoms: angina pectoris, arterial hyper- or hypotension, tachycardia (more than 200 beats/min), arrhythmia, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitations, nausea, dizziness, fatigue, weakness, hypokalemia, hyperglycemia, insomnia, metabolic acidosis. Cardiac arrest and death are possible (as with all inhaled sympathomimetics). The minimum lethal dose for rats receiving formoterol fumarate by inhalation was 156 mg/kg (approximately 53,000 and 25,000 times the inhalation MDV for adults and children, respectively, based on body surface area in mg/m2).

Treatment: withdrawal of formoterol fumarate, symptomatic and supportive therapy, ECG monitoring. The use of cardioselective beta-blockers should take into account the possible risk of bronchospasm. Data on the effectiveness of dialysis for formoterol fumarate overdose are insufficient.

Routes of administration

Inhalation.

Precautions for the substance Formoterol

Long-acting beta2-adrenergic agonists may increase the risk of death from asthma. In this regard, in the treatment of bronchial asthma, formoterol fumarate should be used only in addition to treatment in patients who do not achieve an adequate effect when prescribing other drugs for the treatment of bronchial asthma (for example, when prescribing low or moderate doses of inhaled glucocorticoids) or in cases where the severity of the disease requires the use of two types of therapy, including formoterol fumarate. Data from a large placebo-controlled study in the United States comparing the safety of another long-acting beta 2 -adrenergic agonist (salmeterol) with placebo when added to conventional asthma therapy showed that salmeterol resulted in an increased risk of death compared with placebo. These findings may also apply to formoterol fumarate, which is a long-acting beta2-adrenergic receptor agonist.

Formoterol fumarate is not intended to relieve an attack of bronchial asthma. If, while taking formoterol fumarate at a previously effective dosage, attacks of bronchial asthma begin to occur or the patient requires a greater than usual number of inhalations of short-acting beta 2 agonists, urgent consultation with a doctor is necessary, since these are frequent signs of destabilization of the condition. In this case, therapy should be reviewed and additional treatments prescribed (anti-inflammatory therapy, such as corticosteroids); An increase in the daily dose of formoterol fumarate is unacceptable. The frequency of inhalations should not be increased (more than 2 times a day). Formoterol fumarate should not be used in patients with visible worsening or acute decompensation of asthma, as this may be a life-threatening situation.

Like other inhaled beta 2 -agonists, formoterol fumarate can cause paradoxical bronchospasm; in this case, formoterol fumarate should be discontinued immediately and alternative treatment should be prescribed. In many patients, monotherapy with beta 2-agonists does not provide adequate control of asthma symptoms; such patients require early administration of anti-inflammatory drugs, such as corticosteroids.

There is no evidence of clinically significant anti-inflammatory activity of formoterol fumarate; therefore, it cannot be considered as an alternative to corticosteroids. Formoterol fumarate is not intended to replace corticosteroids taken by inhalation or by mouth; You should not stop taking or reduce the dose of corticosteroids. Treatment with corticosteroids in patients who have previously taken these drugs orally or inhaled should be continued, even if the patient's well-being has improved as a result of taking formoterol fumarate. Any changes in the dose of corticosteroids, in particular reductions, should be based only on clinical assessment of the patient's condition.

Like other beta 2-adrenergic receptor agonists, formoterol fumarate can cause clinically significant cardiovascular effects (increased heart rate, increased blood pressure, etc.) in some patients; in such cases, formoterol fumarate should be discontinued. Similar to other beta 2 -agonists, formoterol can cause clinically significant hypokalemia (possibly due to intracellular ion redistribution), which contributes to the development of cardiovascular side effects. Decreases in serum potassium levels are usually transient and do not require replacement.

In patients with bronchial asthma, the use of beta-blockers, incl. for secondary prevention of myocardial infarction, is undesirable. In such cases, the use of cardioselective beta-blockers should be considered, although they should be used with caution.



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