Atimos, Oxisturbuhaler, Foradil.
Composition and form of release
Formoterol fumarate.
Capsules complete with aerolizer (12 mcg); Formoterol fumarate microionized. Dosed aerosol for inhalation (1 dose - 12 mcg); dosed powder for inhalation (1 dose - 4.5 mcg, 9 mcg).
Formoterol fumarate dihydrate.
Powder capsules for inhalation (12 μg).
pharmachologic effect
Beta-adrenomimetic. Acts primarily on beta2-adrenergic receptors. It has a bronchodilator effect, relieves and prevents bronchospasm. Inhibits the release of histamine, leukotrienes and prostaglandin D2 from mast cells, basophilic granulocytes and sensitized cells of the bronchoalveolar tree.
Pharmacokinetics
It is assumed that - after inhalation, most of the fumarate will be swallowed and then absorbed from the gastrointestinal tract. Plasma protein binding (albumin) - 31-38%. T1 / 2 of various metabolites - 13.9 and 12.3 hours. Metabolized in the liver. It is excreted in the urine unchanged and in the form of metabolites.
Indications
Prevention and treatment of bronchospasm in patients with obstructive,.
Application
The drug is administered by inhalation. To relieve acute bronchospasm, a single inhalation (12 μg) of the drug should be made, if necessary, after 1 min, inhale again. With a weakly expressed therapeutic effect, 2 more breaths can be taken after 30 minutes. The maximum daily dose is 96 mcg (8 breaths).
For the prevention of asthma attacks, one breath (12 μg) is taken in the morning and evening, and in severe cases, two breaths (24 μg) are taken 2 r / day. The interval between injections should be at least 8 hours.
With caution, the drug is prescribed to patients suffering from diabetes mellitus, as well as with uterine fibroids. When using the drug, patients are not recommended to engage in potentially hazardous activities that require increased attention and rapid mental and motor reactions. The use of aerosol in young children should only be carried out under the supervision of an adult.
Side effect
Headache, nausea, dizziness, dry mouth, nervousness, tremors, seizures, tachycardia and tachyarrhythmia.
Contraindications
Hypersensitivity to the drug or other beta-adrenergic agonists, thyrotoxicosis, tachyarrhythmias, pregnancy and lactation.
73573-87-2Characteristics of the substance Formoterol
Bronchodilator (beta 2 -adrenomimetic).
Available as 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- bronchodilating, adrenomimetic.Formoterol fumarate is a long-acting selective agonist of adrenergic beta 2 -receptors. When inhaled, formoterol fumarate acts locally on the bronchi, causing bronchodilation. In research in vitro it has been shown that its activity in relation to beta 2 -adrenergic receptors located mainly in the smooth muscles of the bronchi is more than 200 times higher than that in relation to beta 1 -adrenergic receptors located mainly in the myocardium. Beta 2 -adrenergic receptors are also found in the myocardium, making up 10-50% of the total number of beta-adrenergic receptors. The exact function of these receptors has not been established, but they increase the possibility of developing cardiac effects even with highly selective beta 2 -adrenomimetics. Formoterol fumarate stimulates intracellular adenylate cyclase, which catalyzes the transformation of ATP into cAMP. An increase in the level of cAMP causes relaxation of the smooth muscles of the bronchi and inhibits the release of immediate-type hypersensitivity mediators from cells, especially from obese cells. Research in vitro showed that formoterol fumarate inhibits the release of mediators (histamine and leukotrienes) from mast cells in human lungs. Animal studies have shown that formoterol fumarate inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and allergen-induced eosinophil influx in dogs with airway hyperresponsiveness. The relevance of these findings from animal studies and in vitro, is 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.
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 μg 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 μg of formoterol fumarate (10 times the recommended single dose). In all subjects, the content of potassium in blood plasma decreased as much as possible by 0.55-1.52 mmol / l (the average maximum decrease was 1.01 mmol / l). There was a pronounced correlation between the concentration of formoterol fumarate and the potassium content in the blood plasma: the greatest effect on the level of potassium was observed 1-3 hours after reaching C max of formoterol fumarate. On average, the maximum increase in heart rate was noted 6 hours after taking formoterol fumarate and was 26 beats per minute. The maximum lengthening of the corrected QT interval (QTc), when calculated using Bazett's formula, averaged 25 milliseconds, and according to Fredericia's formula - 8 milliseconds. The value of the QTc interval returned to baseline 12-24 hours after taking formoterol fumarate. Plasma formoterol concentration weakly correlated with pulse rate and QTc increase. The effect on plasma potassium levels, pulse rate, QTc interval are known pharmacological effects of the class of drugs to which formoterol fumarate belongs, so their appearance in a study of very high doses of formoterol fumarate (120 μg once, 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 on patients with bronchial asthma; during the studies, long-term ECG monitoring was carried out over three 24-hour periods. There were no significant differences in ventricular or supraventricular ectopias between groups of patients (in two of these studies, the total number of patients with bronchial asthma who received any dose of formoterol fumarate and underwent continuous ECG monitoring was about 200 people). The effect of formoterol fumarate versus placebo on the ECG of patients with chronic obstructive pulmonary disease (COPD) was evaluated in a 12-month study (with no long-term ECG monitoring). Analysis of ECG intervals was performed in patients who participated in studies in the United States; 46 of them took formoterol fumarate 12 mcg twice a day and 50 patients - 24 mcg twice a day. ECG was recorded before use and after 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, during the treatment of formoterol with fumarate was not detected. Formoterol fumarate, like other beta-agonists, can cause flattening of the T wave, depression of the ST segment on the ECG; the clinical significance of these changes is unknown.
Tolerance. In clinical studies on 19 adult patients with moderate bronchial asthma, the bronchoprotective effect of formoterol fumarate was assessed by the response in a sample with methacholine after taking an initial dose of 24 μg (twice the recommended dose) and 2 weeks later when taking 24 μg twice a day ... Tolerance to the bronchoprotective effect of formoterol fumarate, as evidenced by a decrease in the bronchoprotective effect in relation to the forced expiratory volume in 1 s (FEV 1), was observed after 2 weeks of taking the drug, the loss of protective properties was noted by the end of the 12-hour period after administration. Reactions of rebound hyperreactivity of the bronchi after the termination of long-term therapy with formoterol fumarate were not observed.
Clinical researches
Studies in patients with bronchial asthma. In three large clinical studies in patients with bronchial asthma, while the efficacy of formoterol fumarate was maintained compared with placebo, there was a slight decrease in the bronchodilatory response, assessed within 12 hours, while the effect of formoterol fumarate was preserved, especially when taken at 24 μg twice a day ( twice the recommended daily dose).
In studies with single and multiple doses of formoterol fumarate at a dose of 12 mcg, the maximum improvement (indicators) in FEV 1 was usually observed between 1 and 3 hours after administration. An increase in FEV 1 in comparison with the initial value was detected within 12 hours after drug administration in most patients.
In two 12-week multicenter, randomized, comparative, double-blind, placebo studies in adults and adolescents 12 years and older with moderate to severe bronchial asthma (FEV 1 was 40-80% of normal values), it was shown that formoterol fumarate ( 12 μg 2 times a day) not only caused significant bronchodilation, assessed by FEV 1, but also improved many secondary indicators of efficacy, including improvement according to the symptom scales of combined and nocturnal asthma, as well as a decrease in the number of night awakenings and nights when patients used drugs emergency care, an increase in morning and evening peakfluometry (air flow rate).
Clinical studies in children. In a 12-month, multicenter, randomized, double-blind study of parallel groups of patients taking formoterol fumarate and placebo, 518 children aged 5-12 years with bronchial asthma, who required daily intake of bronchodilators and anti-inflammatory drugs, participated. The effectiveness of therapy was assessed on the first day, at 12 weeks and at the end of the course of treatment; according to the study, the 12-hour efficacy of formoterol fumarate (in accordance with the measurement of FEV 1) was higher than that of the placebo group at all indicated periods.
Clinical studies of the efficacy of formoterol fumarate in exercise-induced bronchospasm(the effect was estimated as a decrease in FEV 1 by more than 20%). Four randomized, double-blind, comparative studies involved 77 patients aged 4 to 41 years. The response to exercise was assessed by FEV 1 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 periods of observation. The study of the effectiveness of regular use of formoterol twice a day for the prevention of bronchial asthma attacks caused by exercise has not been conducted.
Clinical studies in patients with COPD. In clinical trials with repeated administration of formoterol fumarate at a dose of 12 μg in patients with COPD, pronounced bronchodilation (an increase in FEV 1 by 15% or more) was noted 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 peakfluometry compared with pretreatment.
Pharmacokinetics
The pharmacokinetics of formoterol fumarate was studied in healthy volunteers who used it in doses higher than recommended, and in patients with COPD who received formoterol fumarate in therapeutic doses and in excess of them. The unchanged excretion of formoterol in the urine was used as an indirect indicator of systemic exposure. Plasma distribution of formoterol corresponded to renal excretion, and T 1/2 distribution and excretion were similar. After a single inhalation of 120 μg 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 μg twice a day for 12 weeks, its mean plasma concentration ranged from 4.0-8.8 pg / ml and 8.0-17.3 pg / ml, respectively, 10 minutes, 2 and 6 hours after inhalation. After inhalation of 12-96 μg of formoterol fumarate by 10 healthy volunteers, urinary excretion of R, R- and S, S-enantiomers of formoterol increased in proportion to the dose, thus, the absorption of formoterol fumarate after inhalation is linear in the considered dose range.
In a study in patients with bronchial asthma who received 12 and 24 μg of formoterol fumarate by inhalation twice a day for 4 or 12 weeks, the cumulation index, assessed by the excretion of unchanged drug in the urine, ranged from 1.63 to 2.08 in comparison with the initial dose. For patients with COPD who used formoterol fumarate at 12 and 24 μg twice a day for 12 weeks, the cumulation index, calculated from the excretion of unchanged drug in the urine, was 1.19-1.38. This confirms some accumulation of formoterol fumarate in plasma after repeated administration. The amount of formoterol fumarate excreted against the background of equilibrium concentration was practically equal to that predicted on the basis of 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 mainly by direct glucuronidation at the phenolic or aliphatic hydroxyl group and O-demethylation followed by conjugation with glucuronide at any phenolic hydroxyl group. Another biotransformation pathway includes 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 cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6). At therapeutic concentrations, formoterol does not inhibit cytochrome P450 enzymes. Some patients may have insufficient functional activity of one or both isoenzymes CYP2D6 and CYP2C19... However, it is not known whether a deficiency of one or both isoenzymes can lead to an increase in systemic exposure or the development of systemic side effects (adequate studies have not been conducted). After ingestion of 80 μg of radioactively-labeled formoterol fumarate by two healthy volunteers, 59-62% was excreted in the urine and 32-34% in the faeces within 104 hours; their renal clearance of formoterol fumarate was about 150 ml / min. In 16 patients with bronchial asthma, who received inhalation of 12 μg or 24 μg of formoterol fumarate, 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 μg of formoterol fumarate in 12 healthy volunteers, the terminal T 1/2 (based on measurements of plasma concentrations) was 10 hours. When calculated by the level of renal excretion, the terminal T 1/2 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 μg of formoterol fumarate by healthy volunteers, a single and repeated administration of formoterol fumarate at a dose of 12 μg or 24 μg in patients with bronchial asthma, the proportion of R, R- and S, S-enantiomers of the unchanged substance found in urine was 40% and 60%, respectively (the ratio of the two enantiomers remains constant in the studied dose range 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 of formoterol fumarate, elderly patients with bronchial 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) received ... There were no pronounced differences in the safety and efficacy of formoterol fumarate in elderly and younger people; respiratory tract infections with a slightly higher frequency were observed in patients aged 75 years and older, but their relationship with the intake of formoterol fumarate has not been established. In children 5-12 years old with bronchial asthma, who received inhalation of formoterol fumarate at a dose of 12 μg or 24 μg twice a day for 12 weeks, the cumulation index, calculated from the renal excretion of unchanged formoterol fumarate, ranged within 1.18-1.84 (in adults - 1.63-2.08). In the urine of children, about 6% of formoterol fumarate was found in unchanged form and 6.5-9% in the form of conjugates. The pharmacokinetics of formoterol fumarate in people with liver or kidney damage and in elderly patients has not been studied.
Experimental pharmacology
In studies on animals (minipigs, rodents, dogs), cases of arrhythmias and sudden death with histologically confirmed myocardial necrosis were noted with the simultaneous use of beta-adrenomimetics and methylxanthine derivatives. The clinical relevance of these facts to humans has not been determined.
Carcinogenicity, mutagenicity, effects on fertility
The study of carcinogenicity of formoterol fumarate was carried out on rats and mice receiving it for 2 years with food or drinking water. In rats, the incidence of ovarian leiomyoma increased at doses of formoterol fumarate of 15 mg / kg or more with drinking water and 20 mg / kg with food. When receiving 5 mg / kg of formoterol fumarate (an excess of approximately 450 times the AUC exposure in humans when taking MRDC in the form of inhalation) with food, the incidence of ovarian leiomyoma in rats did not increase. Cases of development of benign theca-cell tumors of the ovaries increased when taking formoterol fumarate with food at a dose equal to or exceeding 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 facts were not observed when formoterol fumarate was administered to rats with drinking water and in tests on mice. In male mice, the incidence of subcapsular adenomas and adrenal carcinomas increased when 69 mg / kg or more of formoterol fumarate was received in drinking water; the development of these tumors was not observed when taking formoterol fumarate with food at doses of about 50 mg / kg (AUC exposure was approximately 590 times higher than the exposure in humans with 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 leiomyomas and leiomyosarcomas of the uterus was noted when taking formoterol fumarate with food at 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 with inhalation of the maximum recommended daily dose). The increase in the incidence of leiomyomas of the reproductive system organs in female rodents was similar to the data from studies of other beta-adrenomimetics.
Formoterol fumarate did not show mutagenic or clastogenic properties in the following tests: mutagenicity study on bacterial and mammalian cells, chromosomal analysis on mammalian cells, DNA repair study on rat hepatocytes and human fibroblasts, analysis of mammalian fibroblast transformation and micronucleus tests on mice and rats.
In a reproduction study in rats receiving formoterol fumarate orally at doses of about 3 mg / kg (approximately 1000-fold excess of the maximum recommended daily inhalation dose for humans, calculated per body surface area in mg / m 2), no fertility disorders were found. In rats receiving formoterol fumarate at a dose of 6 mg / kg (2000-fold excess of the maximum recommended daily inhalation dose for humans, calculated for body surface area in mg / m2) in late pregnancy, prenatal and neonatal mortality increased. These effects were not observed when taking formoterol fumarate at a dose of 0.2 mg / kg (70-fold excess of the maximum recommended daily inhalation dose for humans, calculated for body surface area in mg / m 2). A slowdown in skeletal ossification and a decrease in body weight were observed in fetuses of rats treated with formoterol fumarate during the period of organogenesis at a rate of 0.2 mg / kg and 6 mg / kg, respectively. In studies on rats and rabbits, formoterol fumarate did not cause developmental defects.
Application of the substance Formoterol
According to Physician Desk Reference (2009), formoterol fumarate is indicated for long-term (twice a day - morning and evening) maintenance therapy for bronchial asthma and prevention (in adults and children 5 years and older) bronchospasm in reversible obstructive respiratory 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 and older for the rapid prevention of exercise-induced bronchospasm.
Formoterol fumarate is used for long-term (twice a day - morning and evening) maintenance therapy in patients with COPD, including chronic bronchitis and pulmonary emphysema.
Contraindications
Hypersensitivity.
Restrictions on use
Cardiovascular disorders, incl. coronary insufficiency, arrhythmias, arterial hypertension, seizure disorders, thyrotoxicosis, unusual response to sympathomimetics, pregnancy, breastfeeding, age up to 5 years (safety and efficacy have not been established).
Formoterol fumarate is not recommended for patients who manage to control bronchial asthma only by non-systematic inhalation of short-acting beta 2 -adrenoreceptor agonists, as well as patients for whom therapy with inhaled corticosteroids or other drugs is completely adequate, one of which is occasionally inhaled short-acting beta 2 - adrenergic agonist.
Application during pregnancy and lactation
Adequate well-controlled studies of formoterol fumarate in pregnant women, incl. during childbirth, was not carried out. Formoterol fumarate should be used during pregnancy and childbirth (since beta-agonists can negatively affect uterine contractility) only in cases where the intended 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 used with caution in lactating women (well-controlled studies in lactating women have not been conducted).
Side effects of the substance Formoterol
Side effects of formoterol fumarate are similar to those of other selective beta 2 -adrenomimetics and include angina pectoris, arterial hypo- or hypertension, tachycardia, arrhythmia, nervousness, headache, tremors, dry mouth, palpitations, dizziness, seizures, nausea, nausea, , hypokalemia, hyperglycemia, metabolic acidosis, and insomnia.
Bronchial asthma
In controlled clinical trials, formoterol fumarate (12 mcg 2 times a day) received 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 brackets - 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 μg were studied when taken twice a day).
The safety of formoterol fumarate in comparison with placebo was studied in a multicenter, randomized, double-blind clinical trial in 518 children aged 5-12 years with bronchial asthma who needed daily intake of bronchodilators and anti-inflammatory drugs. On the background of taking 12 μg 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, which were higher in frequency than 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 trials, 405 patients with COPD received formoterol fumarate (12 μg 2 times a day). 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 greater than 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 brackets - 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%), increase in the amount of sputum 1.5% (1.2 %).
Others: back pain 4.2% (4.0%), chest pain 3.2% (2.1%), fever 2.2% (1.4%), pruritus 1.5% (1.0% ), dry mouth 1.2% (1.0%), trauma 1.2% (0%).
Overall, the incidence of all cardiovascular side effects in the two main studies was low and comparable to placebo (6.4% in patients taking 12 mcg of formoterol fumarate twice daily, and 6.0% in the placebo group). There were no specific cardiovascular side effects in the formoterol fumarate group, occurring with a frequency of 1% or more and exceeding the frequency of occurrence in the placebo group.
In two studies in patients who took 12 μg and 24 μg of formoterol fumarate twice a day, the dose-dependent nature of seven side effects (pharyngitis, fever, convulsions, increased phlegm, dysphonia, myalgia and tremor) was noted.
Post-marketing research
In the course of the widespread post-marketing use of formoterol fumarate, there have been reports of severe exacerbations of bronchial asthma, some of which ended fatally. Although most of these cases were observed in patients with severe bronchial asthma or acute decompensation of the state, several cases were observed in patients with less severe bronchial asthma. The relationship of these cases with taking formoterol fumarate has not been determined. There are rare reports of anaphylactic reactions, including severe arterial hypotension and angioedema, associated with inhalation of formoterol fumarate. Allergic reactions can manifest as urticaria and bronchospasm. There has been no evidence of the development of drug dependence when using formoterol fumarate in clinical trials.
Interaction
Other adrenergic drugs should be used with caution while taking formoterol, as there is a risk of potentiating the predictable sympathomimetic effects of formoterol. With the simultaneous administration of xanthine derivatives, steroids or diuretics, the hypokalemic effect of adrenergic receptor agonists may increase. ECG changes and / or hypokalemia due to non-potassium-sparing diuretics, such as loop or thiazide diuretics, can suddenly be aggravated by beta-adrenergic agonists, especially when the dose of the latter is exceeded (although the clinical significance of these effects is unclear, caution is required when concomitant administration of drugs of these groups ). Formoterol, like other beta 2 -agonists, should be prescribed with special care while taking MAO inhibitors, tricyclic antidepressants or other drugs that can prolong the QTc interval, since this can potentiate the effect of adrenergic agonists on the cardiovascular system (the risk of developing ventricular arrhythmias increases ). Formoterol and beta-blockers can mutually suppress the effects of each other when administered simultaneously. Beta-blockers can not only interfere with the pharmacological action of beta-agonists, but can also cause severe bronchospasm in patients with bronchial asthma.
Overdose
Symptoms: angina attack, 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 inhalation of formoterol fumarate was 156 mg / kg (approximately 53,000 and 25,000 times higher than the inhalation MRDC for adults and children, respectively, based on body surface area in mg / m 2).
Treatment: cancellation of formoterol fumarate, symptomatic and supportive therapy, ECG monitoring. The use of cardioselective beta-blockers should be carried out taking into account the possible risk of developing bronchospasm. Data on the effectiveness of dialysis in case of overdose of formoterol fumarate are insufficient.
Route of administration
Inhalation
Precautions for the substance Formoterol
Long-acting agonists of beta 2 -adrenergic receptors may increase the risk of death from bronchial asthma. In this regard, when treating 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 medium doses of inhaled glucocorticoids) or in cases where the severity of the disease requires two types of therapy, including formoterol fumarate. Data from a large placebo-controlled study conducted in the United States comparing the safety of another long-acting beta 2 -adrenergic agonist (salmeterol) and placebo when added to conventional asthma therapy showed that salmeterol led to an increased risk of death compared to placebo. These findings can be extended to formoterol fumarate, which is a long-acting beta 2 -adrenergic receptor agonist.
Formoterol fumarate is not intended to relieve an attack of bronchial asthma. If, against the background of taking formoterol fumarate in a previously effective dosage, attacks of bronchial asthma begin to occur or the patient needs more than usual, the number of inhalations of short-acting beta 2 -agonists, urgent medical advice is needed, since these are frequent signs of destabilization of the condition. In this case, the therapy should be reviewed and additional treatments should be prescribed (anti-inflammatory therapy, such as corticosteroids); an increase in the daily dose of formoterol fumarate is unacceptable. The frequency of inhalation should not be increased (more than 2 times a day). You should not use formoterol fumarate in patients with visible worsening or acute decompensation of bronchial asthma, as these can be life-threatening situations.
Like other inhaled beta 2 -adrenergic agonists, formoterol fumarate can cause paradoxical bronchospasm; in this case, the intake of formoterol fumarate should be stopped immediately and an alternative treatment should be prescribed. In many patients, monotherapy with beta 2 -adrenomimetics does not provide adequate control of the symptoms of bronchial asthma; these patients require early administration of anti-inflammatory drugs such as corticosteroids.
No data have been obtained on the clinically significant anti-inflammatory activity of formoterol fumarate, therefore, it cannot be considered as an alternative to corticosteroids. Formoterol fumarate is not intended as a substitute for inhaled or oral corticosteroids; you should not stop taking or reduce the dose of corticosteroids. Treatment with corticosteroids in patients who have previously taken these drugs by mouth or by inhalation should be continued, even if the patients' well-being has improved as a result of taking formoterol fumarate. Any changes in the dose of corticosteroids, in particular a decrease, should be based only on data from a clinical assessment of the patient's condition.
Like other agonists of beta 2 -adrenergic receptors, formoterol fumarate in some patients can cause clinically significant cardiovascular effects (increased heart rate, increased blood pressure, etc.); in such cases, taking formoterol fumarate should be discontinued. Similar to other beta 2 -adrenomimetics, 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 are usually transient and do not require replenishment.
In patients with bronchial asthma, the use of beta-blockers, incl. for secondary prevention of myocardial infarction is undesirable. In such cases, the question of the appointment of cardioselective beta-blockers should be considered, although they should be used with caution.
Composition and release form of the drug
Powder capsules for inhalation hard, transparent, size 3, light brown; the contents of the capsules are white or almost white powder.
Excipients: sodium benzoate - 0.02 mg, lactose monohydrate - up to 12 mg.
Capsule shell composition: caramel dye (E150c) - 1.4388%, hypromellose - up to 100%.
10 pieces. - blister packs (3) in a set. with a device for inhalation. or without it - cardboard packs.
10 pieces. - blister packs (6) in a set. with a device for inhalation. or without it - cardboard packs.
pharmachologic effect
Beta-adrenomimetic. Acts mainly on β 2 -adrenergic receptors. It has a bronchodilator effect, relieves and prevents bronchospasm. Inhibits the release of histamine, leukotrienes and prostaglandin D 2 from mast cells, basophils and sensitized cells of the bronchoalveolar tree.
Pharmacokinetics
When administered by inhalation, it is possible to swallow about 90% of the active substance. When taken orally, it is rapidly absorbed from the gastrointestinal tract. The absorption is 65%. C max is achieved in 0.5-1 hours. Plasma protein binding is 61-64%. T 1/2 - 2-3 hours Metabolized mainly by glucuronidation. It is excreted by the kidneys (70%) and through the intestines (30%). Renal clearance - 150 ml / min.
When inhaled, it is rapidly absorbed, C max is reached after 15 minutes, the concentration of the active substance in the lungs after inhalation with turbuhaler is 21-37%. Bioavailability - 46%. Protein binding 50%. T 1/2 - 8 h.
Indications
Prevention and treatment of bronchospasm in patients with obstructive bronchitis, bronchial asthma.
Contraindications
Hypersensitivity to formoterol or other beta-adrenergic agonists, children under 5 years of age.
Dosage
Applied by inhalation. The dose depends on the dosage form used and the age of the patient.
Side effects
Perhaps:, nausea, dry mouth, tremors.
Rarely: muscle cramps, myalgia, tachycardia, dizziness, agitation, anxiety, sleep disturbances, nervousness, increased bronchospasm.
In some cases: hypersensitivity reactions (severe arterial hypotension, urticaria, angioedema, pruritus, exanthema), peripheral edema, change in taste.
Drug interactions
You should not combine formoterol with adrenergic agonists, MAO inhibitors, tricyclic antidepressants (the risk of side effects from the cardiovascular system increases).
With the simultaneous use of xanthine derivatives, GCS, diuretics increase the likelihood of hypokalemic action of the drug.
With the simultaneous use of quinidine, disopyramide, procainamide, phenothiazines, antihistamines, tricyclic antidepressants increase the risk of ventricular arrhythmias.
(including in the form of eye drops) partially or completely block the effect of formoterol.
special instructions
Special care and careful observation is required if it is necessary to use formoterol in patients with the following concomitant diseases: IHD; rhythm and conduction disturbances, especially AV block III degree; severe heart failure; idiopathic subvalvular aortic stenosis; hypertrophic obstructive cardiomyopathy; thyrotoxicosis; known or suspected prolongation of the QT interval (QT corrected> 0.44 sec).
Use with caution in patients with diabetes mellitus, uterine myoma.
Influence on the ability to drive vehicles and control mechanisms
Tremor or anxiety that occurs during treatment with beta-adrenostimulants can affect the patient's ability to drive, therefore, when using formoterol, it is not recommended to engage in potentially hazardous activities that require increased attention, rapid psychomotor reactions.
Pregnancy and lactation
During and during lactation, formoterol is used with caution, only in cases where the expected therapeutic effect for the mother outweighs the potential risk of side effects for the fetus or child.
Name: Formoterol (Formoterol)
Pharmacological effects:
Beta-adrenomimetic agent that stimulates mainly beta-adrenergic receptors. It has a bronchodilator (expanding the lumen of the bronchi) effect. Inhibits (suppresses) the release of histamine and leukotrienes (biologically active substances produced in the body) from the lung tissue. The onset of action of the drug after 5 minutes, maximum - after 2 hours, the duration of action with reversible bronchial obstruction (violation of air permeability through the bronchi) up to 10 hours.
Formoterol - indications for use:
Prevention and treatment of bronchospasm (a sharp narrowing of the lumen of the bronchi) in patients with obstructive bronchitis (inflammation of the bronchi, combined with impaired air permeability through them); bronchial asthma; bronchospasm caused by an allergen or exercise.Formoterol - method of administration:
The drug is administered by inhalation. To stop (relieve) acute bronchospasm, a single inhalation (12 μg) of the drug should be made, if necessary, a second breath should be made after a minute. The highest daily dosage is 96 mcg (8 breaths). To prevent asthma attacks, 12 μg is administered (1 inhalation) 2 times a day every 12 hours, in severe cases - 24 μg 2 times a day at least 8 hours later.Formoterol - side effects:
Headache, dizziness, dry mouth, nervousness, small-amplitude muscle tremors, tachycardia (heart palpitations), nausea.Formoterol - contraindications:
Pregnancy, breastfeeding, hypersensitivity to the drug or beta-adrenergic agonists.When using the medication, patients are not encouraged to engage in activities that require increased attention or coordination of movements. It is not necessary to combine formoterol with other adrenergic agonists, MAO inhibitors, triiclic antidepressants. With caution, the drug is prescribed to patients with diabetes mellitus, with myoma (benign tumor of the muscle layer) of the uterus.
Formoterol - release form:
Dosed aerosol for inhalation in an inhaler of 100 doses. One dosage contains 12 mcg of formoterol fumarate.Formoterol - storage conditions:
List B. In a cool place, avoiding freezing. Protect from direct sunlight and heat sources.Formoterol - synonyms:
Foradil.Important!
Before using the medicine Formoterol you should consult your doctor. This manual is for informational purposes only.
Name:
Formoterol (Formoterol)
Pharmachologic effect:
Beta-adrenomimetic agent that stimulates mainly beta-adrenergic receptors. It has a bronchodilator (expanding the lumen of the bronchi) effect. Inhibits (suppresses) the release of histamine and leukotrienes (biologically active substances produced in the body) from the lung tissue. The onset of action of the drug after 5 minutes, maximum - after 2 hours, the duration of action in case of reversible bronchial obstruction (violation of air permeability through the bronchi) up to 10 hours.
Indications for use:
Prevention and treatment of bronchospasm (a sharp narrowing of the lumen of the bronchi) in patients with obstructive bronchitis (inflammation of the bronchi, combined with impaired air permeability), bronchial asthma, bronchospasm caused by an allergen or exercise.
Application method:
The drug is administered by inhalation. To stop (relieve) acute bronchospasm, a single inhalation (12 μg) of the drug should be made, if necessary, a second inhalation should be made after a minute. The maximum daily dose is 96 mcg (8 breaths). For the prevention of asthma attacks, 12 μg (1 inhalation) is administered 2 times a day after 12 hours, in severe cases - 24 μg 2 times a day at least 8 hours later.
Adverse events:
Headache, dizziness, dry mouth, nervousness, small-amplitude muscle tremors, tachycardia (heart palpitations), nausea.
Contraindications:
Pregnancy, breastfeeding, hypersensitivity to the drug or beta-adrenergic agonists.
When using the drug, patients are not recommended to engage in activities requiring increased attention or coordination of movements. Do not combine formoterol with other adrenomimetic drugs, MAO inhibitors, triiclic antidepressants. With caution, the drug is prescribed to patients with diabetes mellitus, with myoma (benign tumor of the muscle layer) of the uterus.
Release form of the drug:
Dosed aerosol for inhalation in an inhaler of 100 doses. One dose contains 12 mcg of formoterol fumarate.
Storage conditions:
Drug from list B. In a cool place, avoiding freezing. Protect from direct sunlight and heat sources.
Synonyms:
Foradil.
Drugs with a similar action:
Bronchoryl Theo-Asthalin forte Theo-Asthalin Shadrinum Isadrinum Gambaran
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