Formoterol-nativ

General characteristics. Structure:

Active ingredient: 12 mkg of a formoterol of a fumarat of a dihydrate.

Excipients: Natrium benzoicum, lactoses monohydrate.

Capsule: gipromelloza, dye caramel (Е 150s).

Pharmacological properties:

Pharmacodynamics. Formoterol is the selection agonist β2–адренорецепторов (β2–адреномиметик). It has bronchodilatory effect at patients with reversible obstruction of respiratory tracts. Effect of drug comes quickly (within 1-3 minutes) and remains within 12 hours after inhalation. When using therapeutic doses influence on cardiovascular system is minimum and is noted only in rare instances.

Formoterol slows down release of a histamine and leukotrienes from mast cells. In experiments on animals some antiinflammatory properties of a formoterol, such as ability to interfere with edematization and accumulation of cells of an inflammation were shown.

In pilot studies on animal in vitro it was shown that racemic формотерол and it (R, R) and (S, S) enantiomer are the high-selection agonists β2-рецепторов. (S, S) the enantiomer by 800-1000 times was less active than (R, R) the enantiomer also did not make negative impact on activity (R, R) an enantiomer concerning influence on smooth muscles of a trachea. The pharmacological evidence of advantage of use of one of these two enantiomer, in comparison with racemic mix was not obtained.

In the researches conducted at people it is shown what формотерол effectively prevents the bronchospasm caused by the inhaled allergens, an exercise stress, cold air, a histamine or metasincaline. As the bronchodilatory effect of a formoterol remains expressed within 12 hours after inhalation, purpose of drug 2 times a day for a long maintenance therapy allows to provide in most cases necessary control of a bronchospasm at chronic diseases of lungs as during the day, and at night.

At patients with the chronic obstructive pulmonary disease (COPD) of a stable current формотерол, applied in the form of inhalations in doses on 12 or 24 mkg 2 times a day is followed by improvement of parameters of quality of life.

Pharmacokinetics. Therapeutic range of doses of a formoterol makes from 12 mkg to 24 mkg 2 times a day. Data on pharmacokinetics of a formoterol are obtained at healthy volunteers after inhalation of a formoterol in doses above the recommended range and at sick HOBL after inhalation of a formoterol in therapeutic doses.

Absorption. After single inhalation of a formoterol in a dose of 120 mkg to healthy volunteers формотерол it is quickly absorbed in a blood plasma, the maximum concentration of a formoterol in a blood plasma (Cmax) makes 266 pmol/L and is reached within 5 minutes after inhalation. At the sick HOBL receiving формотерол in a dose of 12 or 24 mkg 2 times a day within 12 weeks, the concentration of a formoterol in a blood plasma measured in 10 minutes, 2 hours and 6 hours after inhalation were in ranges of 11,5-25,7 pmol/L and 23,3-50,3 pmol/L, respectively.

In researches in which studied total excretion of a formoterol and it (R R) and (S, S) enantiomer with urine, was shown that the quantity of a formoterol in a system blood-groove increases in proportion to the size of the inhalated dose (12-96 mkg).

After inhalation use of a formoterol in a dose of 12 or 24 mkg 2 times a day within 12 weeks excretion of not changed formoterol with urine at patients with the bronchial asthma (BA) increased by 63-73%, and at sick HOBL - for 19-38%. It indicates some cumulation of a formoterol in a blood plasma after repeated inhalations. At the same time bigger cumulation of one of enantiomer of a formoterol in comparison with another after repeated inhalations was not noted.

The most part of the formoterol applied by means of an inhaler is swallowed and then soaked up from the digestive tract (DT). At purpose of 80 mkg of a 3H-marked formoterol inside to two healthy volunteers at least 65% of a formoterol were absorbed.

Distribution. Linkng of a formoterol with proteins of a blood plasma makes 61-64%, linkng with serum albumine – 34%. In the range of the concentration noted after use of therapeutic doses of drug, saturation of places of binding is not reached.

Metabolism. The main way of metabolism of a formoterol is direct conjugation with glucuronic acid. Other way of metabolism - O-demethylation with the subsequent conjugation with glucuronic acid (glyukuronidatsiy).

Little significant ways of metabolism include conjugation of a formoterol with sulfate with the subsequent deformilirovaniye. A set of isoenzymes participate in processes of a glyukuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) of a formoterol that assumes low probability of medicinal interaction by means of inhibition of any isoenzyme which is taking part in metabolism of a formoterol. In therapeutic concentration формотерол does not inhibit isoenzymes of system of P450 cytochrome.

Removal. At reception of a formoterol in a dose of 12 or 24 mkg 2 times a day within 12 weeks in not changed view with urine are allocated 10% and 15-18% of the general dose at patients OH; Respectively, sick HOBL have 7% and 6-9% of the general dose.

The calculated shares (R, R) and (S, S) enantiomer of not changed formoterol in urine make 40% and 60%, respectively, after a single dose of a formoterol (12-120 mkg) is at healthy volunteers and after single and repeated doses of a formoterol at patients OH.

Active agent and its metabolites are completely removed from an organism; about 2/3 from the dose applied inside it is removed with urine, 1/3 - with a stake. The renal clearance of a formoterol makes 150 ml/min.

At healthy volunteers the final elimination half-life of a formoterol after single inhalation of drug of a formoterol in a dose of 120 mkg makes 10 hours of plasma; final elimination half-lives (R, R) and (S, S) enantiomer, calculated on excretion with urine, make 13,9 and 12,3 hours respectively.

Pharmacokinetics at separate groups of patients. Floor. After adjustment on body weight pharmacokinetic parameters of a formoterol at men and at women have no essential distinctions.

Elderly patients (65 years are more senior). In favor of need of change of dosing of a formoterol at patients 65 years in comparison with younger patients are more senior than data it is not received.

Patients with abnormal liver functions and/or kidneys. The pharmacokinetics of a formoterol at patients with abnormal liver functions and/or kidneys was not studied.

Indications to use:

Prevention and treatment of disturbances of bronchial passability at patients with the bronchial asthma (BA) as addition to therapy with inhalation glucocorticosteroids.

Prevention of the bronchospasm caused by inhalation of allergens, cold air or an exercise stress as addition to therapy with inhalation glucocorticosteroids.

Prevention and treatment of disturbances of bronchial passability at patients with the chronic obstructive pulmonary disease (COPD), in the presence both reversible, and irreversible bronchial obstruction, chronic bronchitis and emphysema of lungs.

Route of administration and doses:

Formoterol-nativ it is intended for inhalation use for patients aged 18 years are more senior. Drug is not intended for intake.

The dose of the drug Formoterol-nativ is selected individually depending on needs of the patient. It is necessary to use the smallest dose providing therapeutic effect. At achievement of control of symptoms of bronchial asthma against the background of therapy by the drug Formoterol-nativ, it is necessary to consider the possibility of a gradual dose decline of drug. The dose decline of the drug Formoterol-nativ is carried out under regular medical control of a condition of the patient.

Drug represents capsules with powder for inhalations which should be applied only by means of the special device - an inhaler "Inkhaler of CDM®" which is included in the packaging package.

Bronchial asthma. The drug Formoterol-nativ dose for a regular maintenance therapy makes 12-24 mkg (contents of 1-2 capsules) 2 times a day. Formoterol-nativ it is necessary to apply only as additional therapy to inhalation glucocorticosteroids (GKS). It is not necessary to exceed the maximum recommended dose of drug of 48 mkg (contents of 4 capsules) in days. Considering that the maximum daily dose of the drug Formoterol-nativ makes 48 mkg, if necessary it is in addition possible to apply 12-24 mkg a day to relief of symptoms of bronchial asthma.

If the need for use of additional doses of the drug Formoterol-nativ stops being incidental (for example, becomes more often than 2 days a week), it can indicate deterioration in a course of bronchial asthma, it is necessary to see a doctor. Against the background of an exacerbation of bronchial asthma it is not necessary to begin treatment with the drug Formoterol-nativ or to change a drug dosage. Formoterol-nativ it is not necessary to apply to stopping of bad attacks of bronchial asthma.

Prevention of the bronchospasm caused by an exercise stress or inevitable influence of the known allergen. It is necessary to apply Formoterol-nativ in a dose of 12 mkg (contents of 1 capsule) in 15 minutes prior to alleged contact with allergen or to loading. Additional inhalations of drug should not be carried out within the next 12 hours.

Prevention of heavy bronchospasms. Single inhalation in a dose of 24 mkg (contents of 2 capsules) can be required by patients with heavy bronchospasms in the anamnesis.

HOBL. The drug Formoterol-nativ dose for a regular maintenance therapy of HOBL makes 12-24 mkg (contents of 1-2 capsules) 2 times a day.

Instruction for performing inhalations. To provide the correct use of drug, the doctor or other health worker has to:
1. to warn the patient that capsules are intended only for inhalation use and are not intended for a proglatyvaniye;
2. to explain to the patient that it is necessary to use capsules with powder to inhalations only with the help "Inkhaler of CDM®";
3. to show to the patient how to use an inhaler. It is necessary to take out the capsule from a strip packaging just before use.

Application instruction of an inhaler "Inkhaler CDM®". The inhaler powder "Inkhaler of CDM®" - the plastic device with a mobile upper part and with the moving-forward compartment for the capsule, about 6 cm high "Inkhaler of CDM®" is the one-dose inhaler allowing to dose and inhale drug in very small doses. The drug Formoterol-nativ gets into airways of the patient together with air flows when performing an active breath through a device mouthpiece. "Inkhaler is very simple CDM®" in use. It is necessary to follow the step-by-step instruction given below:
Step 1. Remove a transparent cap from the Inkhaler CDM®\device, as shown in fig. 1.
Step 2. Strong you hold the device with one hand, index and a thumb of other hand open a compartment for the capsule, as shown in fig. 2. For this purpose press an index finger PUSH in a mobile part "Inkhaler CDM®", shifting a compartment to the opposite side.
Step 3. Holding the device one hand, insert the capsule with drug into a nest of a compartment (fig. 3).
Step 4. Make sure that the capsule is correctly inserted into a nest (fig. 4).
Step 5. Holding "Inkhaler CDM®" in vertical position, close a compartment, having pressed a thumb in the opposite direction against the stop, the click (fig. 5) will not be heard yet.
Step 6. You hold the Inkhaler CDM®\device strictly vertically (fig. 6).
Step 7. Bring it to the working condition, as shown in fig. 7. For this purpose with effort press a mouthpiece so that the arrow applied on the case was behind borders of the lower part of the device to the upper line. Then release a mouthpiece for return it in initial situation. Thereby you will puncture the capsule, having opened access to medicine to a mouthpiece gleam. Attention: because of destruction of a gelatin capsule small pieces of gelatin as a result of inhalation can get into a mouth or a throat. To minimize this phenomenon, it is not necessary to puncture the capsule more than 1 time.
Step 8. Attention: before performing inhalation it is necessary to exhale (fig. 8). Do not exhale through a mouthpiece!
Step 9. Carefully squeeze a mouthpiece "Inkhaler of CDM®" teeth, densely clasp it with lips and make a deep and strong breath through a mouth (fig. 9). You will hear the vibrating sound in a compartment for the capsule made by the capsule at rotation and dispersion of drug. Attention: the mouthpiece cannot be chewed and to squeeze strongly teeth! Do not press a mouthpiece at inhalation. It can block the movement of the capsule. Hold the breath approximately for 10 seconds or longer, as far as possible. Remove an inhaler from a mouth. Make a slow exhalation. Then you breathe normally. Repeat steps 8-9 again, for the guaranteed inhalation of a dose of drug.
Step 10. After performing inhalation open a compartment for the capsule (a step 2), remove the empty capsule and then close it, as shown in fig. 5. Attention: when performing inhalation try not to close the openings located on lateral faces of a mouthpiece. It can obstruct the free traffic of air in an inhaler, dispersion of contents of the capsule thereby decreases.

Always after use densely close "Inkhaler CDM®" a cap, it will allow to keep a mouthpiece in purity. Regularly (weekly) it is necessary to clear a mouthpiece outside dry fabric. There are separate messages on an accidental proglatyvaniye patients of capsules of drug entirely, without use of the device for inhalations. The majority of such cases are not connected with development of the undesirable phenomena. The health worker has to explain to the patient as it is correct to use drug, especially, if after inhalations at the patient there does not occur breath improvement.

Features of use:

Use at pregnancy and during breastfeeding. Safety of use of a formoterol at pregnancy and during breastfeeding is not established so far.

Use at pregnancy is possible only if the estimated advantage for mother exceeds potential risk for a fruit. Formoterol, as well as others β2–адреномиметики, can slow down process of childbirth owing to the tokolitichesky action (which is running down actions on smooth muscles of a uterus).

It is unknown whether gets формотерол into breast milk. Therefore, in need of use of a formoterol, breastfeeding needs to be stopped.

There are no data on influence of drug on fertility. Researches on experimental animals did not reveal influence on fertility at oral administration of a formoterol.

Antiinflammatory therapy. At patients with bronchial asthma of Formoterol-nativ it is necessary to use only as additional treatment at insufficient control of symptoms against the background of monotherapy by inhalation GKS or at the severe form of a disease demanding use of a combination of inhalation GKS and an agonist β2-адренорецепторов long action. It is impossible to apply Formoterol-nativ with other agonists β2-адренорецепторов long action.

At purpose of the drug Formoterol-nativ it is necessary to estimate a condition of patients concerning adequacy of that of antiinflammatory therapy which they receive.

After an initiation of treatment patients should recommend to continue by the drug Formoterol-nativ antiinflammatory therapy without changes, even if improvement is noted.

It is necessary to apply agonists to stopping of a bad attack of bronchial asthma β2-адренорецепторов. At a sudden aggravation of symptoms patients have to ask for medical care immediately.

Hypopotassemia. Development of potentially serious hypopotassemia can be a consequence of therapy β2-адреномиметиками, including Formoterol-nativ. The hypopotassemia can increase risk of development of arrhythmias. As this effect of the drug Formoterol-nativ can be strengthened by a hypoxia and the accompanying treatment, extra care should be observed at patients with bronchial asthma of a heavy current. In these cases regular control of potassium concentration in blood serum is recommended.

Paradoxical bronchospasm. As well as the paradoxical bronchospasm can cause other inhalation drugs, Formoterol-nativ. In this case, it is necessary to cancel immediately drug and to appoint alternative treatment.

Use of a formoterol in the dose exceeding 54 mkg/days (over 4 inhalations) can lead to positive takes of doping tests.

Influence on ability to manage motor transport and other vehicles, for work with moving mechanisms. Data on influence of the drug Formoterol-nativ on ability to driving of motor transport and to control of mechanisms are absent. In case of development of such side reactions as dizziness, a tremor, spasms or a muscular spasm it is necessary to refrain from driving of motor transport and control of mechanisms, and also from occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Undesirable reactions are distributed according to emergence frequency. For assessment of frequency the following criteria are used: very often (> 1/10), it is frequent (from 1/100 to 1/10), infrequently (from 1/1000 to 1/100), is rare (from 1/10000 to 1/1000), is very rare (<1/10000), (including separate messages).

Infectious and parasitic diseases: often - pharyngitis, an acute respiratory viral infection.

Disturbances from immune system: very seldom – anaphylactic reactions, a small tortoiseshell, a Quincke's disease (Quincke's edema), an itch, rash.

Disturbances from a metabolism and food: very seldom - a metabolic acidosis.

Disturbances of mentality: infrequently - agitation, alarm, a hyperexcitability, sleeplessness; very seldom - increased fatigue.

Disturbances from a nervous system: often - a headache, a tremor; infrequently - dizziness; very seldom – change of flavoring feelings.

Disturbances from heart: often - a heart consciousness, a stethalgia; infrequently – tachycardia; very seldom - peripheral hypostases; stenocardia, disturbance of a cordial rhythm (including fibrillation of auricles, ventricular extrasystoles, tachyarrhythmia).

Disturbances from vessels: very seldom - a lowering of arterial pressure (hypotension), increase in arterial pressure (hypertensia).

Disturbances from respiratory system, bodies of a thorax and a mediastinum: often – sinusitis, increase in products of a phlegm; infrequently - a bronchospasm, including paradoxical, a dysphonia; very seldom - cough.

Disturbances from digestive tract: infrequently – dryness of a mucous membrane of an oral cavity; very seldom - nausea.

Disturbances from skeletal and muscular and connecting fabric: often - dorsodynias, spasms of legs; infrequently – a muscular spasm, mialgiya.

The general frustration and disturbances in an injection site: often - fever; infrequently - irritation of a mucous membrane of a throat and throat.

Laboratory and tool data: infrequently - flattening or inversion of a tooth T, ST segment depression, lengthening of an interval of QT on the electrocardiogram; very seldom - a hypopotassemia, a hyperglycemia.

If any of the side reactions specified in the instruction are aggravated, or you noticed any other side reactions which are not specified in the instruction, report about it to the doctor.

Interaction with other medicines:

The drug Formoterol-nativ as well as others β2-адреномиметики, should appoint with care the patients receiving such medicines as: quinidine, Disopyramidum, procaineamide, fenotiazina, macroleads, inhibitors of a monoaminooxidase (MAO), tricyclic antidepressants, antihistaminic drugs, and also other drugs who are known that they extend QT interval as in these cases action of adrenostimulyator on cardiovascular system can amplify and raises risk of developing of ventricular arrhythmias.

Simultaneous use of other sympathomimetic means can lead to aggravation of side reactions of the drug Formoterol-nativ.

Simultaneous use of derivatives of xanthine, glucocorticosteroids or diuretics can strengthen potential gipokaliyemichesky effect of the drug Formoterol-nativ.

At the patients receiving anesthesia with use of halogenated hydrocarbons the risk of development of arrhythmias increases.

The drugs relating to β2-адреноблокаторам can weaken effect of the drug Formoterol-nativ and lead to a serious bronchospasm at patients with bronchial asthma. In this regard it is not necessary to use the drug Formoterol-nativ together with β2-адреноблокаторами (including eye drops) if only to use of such combination of drugs do not force any extraordinary reasons.

Contraindications:

• Hypersensitivity and/or intolerance of any of drug components.
• Age up to 18 years.
• Feeding by a breast.
• Rare hereditary diseases, such as lactose intolerance, deficit of lactase or glyukozo-galaktozny malabsorption.

With care. If you have one of the listed diseases, before drug use surely consult with the doctor. Respect for extra care at drug Formoterol-nativ use (especially from the point of view of a dose decline) and careful observation of patients is required in the presence of the following associated diseases: coronary heart disease; disturbances of a cordial rhythm and conductivity, especially atrioventricular block of the III degree; heavy heart failure; idiopathic hypertrophic subaortal stenosis; heavy degree of arterial hypertension; aneurism of any localization; pheochromocytoma; ketoacidosis; hypertrophic subaortic stenosis; thyrotoxicosis; the known or suspected lengthening of an interval of QTc (QT korrigirovanny> 0,44 sec.); considering the hyper glycemic effect inherent β2-адреномиметикам, at patients with the diabetes mellitus accepting Formoterol-nativ additional regular control of concentration of glucose in blood is recommended.

Overdose:

Symptoms. The overdose formoteroly can probably lead to development of the phenomena characteristic of overdose β2–адреномиметиками or to strengthening of manifestation of side effects: pain behind a breast, a heart consciousness, tachycardia to 200 удмин, ventricular arrhythmias, increase or lowering of arterial pressure, dryness in a mouth, nausea, vomiting, a headache, dizziness, a tremor, nervousness, weakness, alarm, drowsiness, a metabolic acidosis, a hypopotassemia, a hyperglycemia, spasms. As well as for all inhalation β2–адреномиметиков, at overdose formoteroly, the cardiac standstill and death is possible.

Treatment. Performing the supporting and symptomatic therapy is shown. In serious cases hospitalization is necessary. Use cardioselective β2-адреноблокаторов, but only under careful medical observation on condition of respect for extreme care as use of such means can cause a bronchospasm can be considered. Control of indicators of cordial activity is recommended.

Storage conditions:

In the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Capsules with powder for inhalations, 12 mkg. On 10 capsules in a blister strip packaging from multilayer aluminum foil and printing aluminum foil. On 3 or 6 blister strip packagings together with the device for inhalations or without it, the application instruction place in a cardboard pack.