Ипратерол®-натив

General characteristics. Structure:

Active ingredients: 0,5 mg of Fenoterolum of hydrobromide, 0,261 mg monohydrate bromide ipratropiya (0,25 mg bromide ipratropiya).

Excipients: Natrium benzoicum, sodium эдетат, citric acid monohydrate, sodium hydroxide to рН 3,2, water for injections.

Pharmacological properties:

Pharmacodynamics. Ipraterol-nativ contains two components having broncholitic activity: an ipratropiya bromide - m-holinoblokator and Fenoterolum - β2-адреномиметик.

Bronkhodilatation at inhalation introduction an ipratropiya of bromide is caused, mainly, by local, but not systemic anticholinergic action. At patients with the bronchospasm connected with chronic obstructive diseases of lungs (chronic bronchitis and emphysema of lungs), considerable improvement of function of lungs (increase in OFV1 and PSV by 15% and more) it is noted within 15 minutes, the maximum effect was reached in 1-2 hours and proceeded at most of patients till 6 o'clock after introduction.

Ipratropiya bromide does not exert negative impact on secretion of slime in respiratory tracts, mukotsiliarny clearance and gas exchange.

Fenoterolum selectively stimulates β2-адренорецепторы in a therapeutic dose. Stimulation β1-адренорецепторов happens when using high doses.

Fenoterolum relaxes smooth muscles of bronchial tubes and vessels and counteracts development of the bronkhospastichesky reactions caused by influence of a histamine, metasincaline, cold air and allergens (reaction of immediate hypersensitivity). Right after introduction Fenoterolum blocks release of mediators of an inflammation and bronkhoobstruktion from mast cells. Besides, when using Fenoterolum in higher doses, strengthening of mukotsiliarny clearance was noted.

Beta and adrenergic influence of drug on cordial activity, such as increase in frequency and force of cordial reductions, is caused by vascular action of Fenoterolum, stimulation β2-адренорецепторов hearts, and when using the doses exceeding therapeutic, stimulation β1-адренорецепторов. As well as when using other beta and adrenergic drugs lengthening of an interval of QTS when using high doses was noted. The clinical importance of this manifestation is not found out.

The tremor is the most frequent undesirable effect when using agonists of beta adrenoceptors.

At combined use of these two active agents the bronchodilatory effect is reached by impact on various pharmacological targets. The specified substances supplement each other, the spasmolytic effect on muscles of bronchial tubes as a result amplifies and the width of therapeutic action at the bronchopulmonary diseases which are followed by a konstriktion of respiratory tracts is provided. Complementary action such is that achievement of desirable effect requires lower dose of a beta and adrenergic component that allows to pick up individually an effective dose at almost total absence of side effects.

Pharmacokinetics. There are no proofs that the pharmacokinetics of the combined drug differs from that each of separate components.

Absorption. Ipratropiya bromide. At an inhalation way of introduction for an ipratropiya of bromide extremely low absorption with mucous respiratory tracts is characteristic. Concentration of active agent is in plasma on the lower bound of definition, and it is possible to measure it only at use of high doses of active agent, and also thanks to specific enrichment methods. At inhalation use in therapeutic doses of concentration a bromide ipratropiya in plasma were 1000 times lower, than after intake and intravenous administration.

Fenoterolum. Depending on a method of inhalation and the used inhalation system about 10-30% of active agent reach the lower respiratory tracts, and other part is deposited in upper respiratory tracts and swallowed. As a result a quantity of the inhalated Fenoterolum gets into digestive tract.

Absorption has two-phase character - 30% of Fenoterolum are quickly soaked up with an elimination half-life of 11 minutes, 70% are soaked up slowly with an elimination half-life of 120 minutes. There is no correlation between the concentration of Fenoterolum in a blood plasma reached after inhalation and a pharmakodinamichesky curve "time - effect". The long-term bronchodilatory effect of drug after inhalation, comparable with the corresponding effect reached after intravenous administration is not supported by high concentration of active agent in a system blood-groove. After introduction about 60% of Fenoterolum are inside soaked up. Time of achievement of the maximum concentration in a blood plasma - 2 hours.

Distribution. Ipratropiya bromide. Being derivatives of quarternary nitrogen, it is badly dissolved in fats in and poorly gets through biological membranes. Does not kumulirut.

Fenoterolum. Communication with proteins of plasma of 40-55%. Fenoterolum in not changed look gets through a placental barrier and is allocated with breast milk.

Metabolism. Ipratropiya bromide. It is metabolized in a liver. About 8 metabolites an ipratropiya which poorly contact muskarinovy receptors are known.

Fenoterolum. It is metabolized in a liver. In 24 hours of 60% of the dose entered intravenously and 35% of peroral it is excreted with urine. This share of active agent is exposed to biotransformation owing to "effect of primary passing" through a liver therefore bioavailability of drug after introduction inside falls approximately to 1,5%. The fact that the swallowed amount of drug practically does not affect the level of active agent in a blood plasma reached after inhalation in any way is explained by it. Fenoterolum biotransformation at the person proceeds only by conjugation with sulfates preferential in an intestines wall.

Removal. Ipratropiya bromide. It is removed preferential through intestines. About 25% are removed in not changed look, other part - in the form of numerous metabolites.

Fenoterolum. It is removed by kidneys and with bile in the form of inactive sulphatic conjugates. At parenteral administration Fenoterolum is removed according to three-phase model with elimination half-lives - 0,42 minutes, 14,3 minutes and 3,2 hours.

The combination pharmacokinetics an ipratropiya of bromide and Fenoterolum in population of persons of advanced and children's age, and also at patients with the broken functions of a liver and kidneys is not studied.

Indications to use:

Prevention and symptomatic treatment of chronic obstructive respiratory diseases with reversible obstruction of respiratory tracts, such as bronchial asthma and, especially, a chronic obstructive pulmonary disease, chronic obstructive bronchitis with existence of emphysema of lungs or without it.

Route of administration and doses:

The dose has to be selected individually. During performing therapy medical observation is required. The following doses are recommended:

At adults (including elderly people) and teenagers 12 years are more senior: bad attacks of bronchial asthma. At easy and moderate attacks in many cases 1 ml (20 drops) is recommended.

In especially hard cases, for example at the patients who are in intensive care units at inefficiency of the doses stated above higher doses, to 2,5 ml (50 drops) can be required. The maximum dose, can reach 4,0 ml (80 drops). The maximum daily dose - 8,0 ml (160 drops).

Course and prolonged treatment. In need of repeated use for each introduction use 1-2 ml (20-40 drops) to 4 times a day. In case of a moderate bronchospasm or as supportive application at implementation of ventilation of the lungs the dose which lower level makes 0,5 ml (10 drops) is recommended.

At children at the age of 6-12 years: bad attacks of bronchial asthma. In many cases for bystry stopping of symptoms 0,5 - 1 ml (10 - 20 drops) are recommended.

In hard cases if the dose of 1 ml (20 drops) is inefficient, higher doses, to 2 ml (40 drops) can be required. In especially hard cases if the dose to 2,0 ml (40 drops) is inefficient, use (on condition of medical observation) the maximum dose reaching 3,0 ml (60 drops) is possible. The maximum daily dose can reach 4,0 ml (80 drops).

Course and prolonged treatment. In need of repeated use use for each introduction 0,5 - 1 ml (10 - 20 drops) to 4 times a day. In cases of a moderate bronchospasm or as supportive application at implementation of ventilation of the lungs the recommended dose - 0,5 ml (10 drops).

At children 6 years are aged younger (which body weight makes less than 22 kg): because information on use of drug in this age group is limited, use of the following dose is recommended (only on condition of medical observation): about 25 mkg an ipratropiya of bromide and 50 mkg of Fenoterolum of hydrobromide = 0,1 ml (2 drops) on body weight kg (on one dose), but no more than 0,5 ml (10 drops) (on one dose). The maximum daily dose - 1,5 ml. Solution for inhalations should be used only for inhalations (with the suitable nebulizer) and not to apply orally.

Treatment should be begun with the smallest recommended dose usually. The recommended dose has to get divorced 0,9% chloride sodium solution up to the final volume making 3-4 ml and to be applied (completely) by means of the nebulizer. Ipraterola-nativ solution for inhalations should not get divorced the distilled water.

Cultivation of solution has to be carried out every time before use, the remains of divorced solution should be destroyed. Divorced solution should be used right after preparation. Dosing can depend on a method of inhalation and a type of the nebulizer. Duration of inhalation can be controlled on an expenditure of divorced volume.

Ipraterola-nativ solution can be applied to inhalations with use of various commercial models of nebulizers. When there is a wall oxygen, solution is the best of all to apply at a flow rate 6 - 8 liters a minute. It is necessary to follow the application instruction, service and the cleaning of the device delivered together with the nebulizer.

Features of use:

Use at pregnancy and during breastfeeding. Data of preclinical trials and experience of use of a combination the ipratropiya of bromide and Fenoterolum show that components of medicine do not exert a negative impact at pregnancy. It is necessary to consider a possibility of the inhibiting effect of Fenoterolum on a sokratitelny uterine activity. Drug is contraindicated in I and III trimesters of pregnancy (a possibility of weakening of patrimonial activity by Fenoterolum). It is necessary to apply with care of drug in the II trimester of pregnancy. Fenoterolum gets into breast milk. This, confirmatory that the ipratropiya bromide gets into breast milk, it is not received. However nursing mothers should appoint the drug Ipraterol-nativ with care.

In case of unexpected bystry strengthening of an asthma (breath difficulties) it is necessary to see a doctor immediately.

Prolonged use:
- at the patients having bronchial asthma or the easy and medium-weight HOBL forms, the symptomatic treatment can be more preferable than regular use;
- at patients with bronchial asthma or severe forms of HOBL it is necessary to remember need of carrying out or strengthening of antiinflammatory therapy for control of inflammatory process of respiratory tracts and the course of a disease.

Regular use of the increasing doses of the drugs containing β2-адреномиметики such as drug Ipraterol-nativ, for stopping of bronchial obstruction can cause uncontrollable deterioration in a course of a disease. In case of strengthening of bronchial obstruction increase in a dose β2-агонистов, including the drug Ipraterol-nativ, more recommended for a long time not only is not justified, but also it is dangerous. For prevention of life-threatening deterioration in a course of a disease it is necessary to consider a question of review of treatment planning of the patient and adequate antiinflammatory therapy by inhalation glucocorticosteroids. At the patients having a mucoviscidosis in the anamnesis disturbances of motility of digestive tract are possible.

It is necessary to appoint other sympathomimetic bronchodilators along with the drug Ipraterol-nativ only under medical observation.

Patients have to be instructed about the correct use of inhalation solution of the drug Ipraterol-nativ. For the prevention of hit of solution in eyes it is recommended that the solution used by means of the nebulizer was inhaled through a mouthpiece. In the absence of a mouthpiece the mask, skintight to the person, has to be used. Especially carefully the patients predisposed to development of glaucoma have to care for protection of eyes.

Influence on ability to driving of motor transport and to control of mechanisms. Researches on studying of influence of drug on ability to driving of motor transport and control of mechanisms were not conducted. Cases of dizziness and an illegibility of sight at use of drug can exert a negative impact on above-mentioned ability.

Side effects:

Determination of frequency: 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 1/000), is very rare (<1/10000).

From a nervous system: often - a small tremor of skeletal muscles, nervousness; seldom - a headache, dizziness, it is very rare - change of mentality.

From cardiovascular system: often - tachycardia, including supraventricular tachycardia; a heart consciousness (especially at patients with the burdening factors); seldom (when using in high doses) - decrease in diastolic arterial pressure, increase in systolic arterial pressure, arrhythmia (including fibrillation of auricles).

From respiratory system: seldom - cough, local irritation of respiratory tracts, pharyngitis; very seldom - a paradoxical bronchospasm, a laryngospasm.

From digestive tract: often – dryness in a mouth; infrequently - disturbance of motility of digestive tract, vomiting, a lock, diarrhea (especially at patients with a mucoviscidosis).

From an organ of sight: at hit of drug in an eye - a mydriasis, increase in intraocular pressure, glaucoma, pain in an eyeglobe; sometimes at treatment drug notes reversible disturbances of accommodation and glaucoma. Pain in an eyeglobe or the discomfort, indistinct sight, feeling of emergence of an aura or color spots before eyes, in combination with a hyperemia of a conjunctiva and corneal hypostasis can be symptoms of acute glaucoma. It is necessary to use the drops narrowing a pupil and to address immediately the ophthalmologist.

Allergic reactions: seldom - skin rash, a Quincke's disease of language, lips and the person, a small tortoiseshell.

Others: an ischuria, the increased sweating, a hypopotassemia, feeling of the general weakness, a mialgiya.

Interaction with other medicines:

Simultaneous use of others beta адреномиметических means, anticholinergic drugs of systemic action and ksantinovy derivatives (for example, theophylline) can strengthen bronchodilatory effect of the drug Ipraterol-nativ.

Perhaps considerable weakening of bronchodilatory effect of drug at co-administration of beta adrenoblockers.

The hypopotassemia connected using beta-adrenergic agonists can be strengthened by co-administration of ksantinovy derivatives, glucocorticosteroids and diuretics. This fact should pay special attention at treatment of patients with severe forms of obstructive respiratory diseases. The hypopotassemia can lead to increase in risk of developing of arrhythmias at the patients receiving digoxin. Besides, the hypoxia can strengthen a negative impact of a hypopotassemia on a cordial rhythm. In similar cases it is recommended to carry out monitoring of level of potassium in blood serum.

It is necessary to appoint with care β2-адренергические means to the patients receiving inhibitors of a monoaminooxidase and tricyclic antidepressants as these drugs are capable to strengthen action of beta and adrenergic means.

Inhalation of means for the general anesthesia of the halogenated hydrocarbon anesthetics, for example, of a halothane, trichloroethylene or an enfluran, can strengthen influence of beta and adrenergic funds for cardiovascular system.

Combined use of the drug Ipraterol-nativ with kromoglitsiyevy acid and/or glucocorticosteroids increases efficiency of therapy.

Contraindications:

• Hypersensitivity to Fenoterolum or atropinopodobny drugs or other components of the drug Ipraterol-nativ.
• Hypertrophic subaortic stenosis
• Tachyarrhythmia.
• I and III trimesters of pregnancy.

With care. Closed-angle glaucoma, arterial hypertension, a diabetes mellitus, recently postponed myocardial infarction (within the last 3 months), a heart disease and vessels, such as chronic heart failure, coronary heart disease, aortal stenosis, expressed damages of cerebral and peripheral arteries, a hyperthyroidism, a pheochromocytoma, a prostate hyperplasia, obstruction of a neck of a bladder, a mucoviscidosis, the II trimester of pregnancy, breastfeeding, children's age up to 6 years.

Overdose:

Symptoms of overdose are usually connected with action of Fenoterolum. Emergence of the symptoms connected with excess stimulation of beta adrenoceptors is possible. Emergence of tachycardia, heartbeat, a tremor, increase in arterial pressure, increase in distinction between systolic and diastolic arterial pressure, stenocardias, arrhythmias and feelings of "inflows" of blood to the person, feeling of weight behind a breast, strengthening of a bronkhoobstruktion, metabolic acidosis is the most probable. The possible symptoms of overdose caused an ipratropiya by bromide (such as, dryness in a mouth, accommodation disturbance), are expressed poorly and tranzitorno that is explained by its topical administration.

Treatment: purpose of sedatives, anxiolytic medicines (tranquilizers), in hard cases - an intensive care is recommended.

As a specific antidote use of beta adrenoblockers is possible, it is more preferable than the selection β1-адреноблокаторов. However at patients with bronchial asthma or HOBL it is necessary to consider a possibility of strengthening of bronchial obstruction which can lead to a lethal outcome under the influence of beta adrenoblockers and carefully select their dose.

Storage conditions:

In the dry, protected from light place, at a temperature not above 25 °C. Not to freeze. To store in the place, unavailable to children. A period of validity - 2 years. Not to use drug after expiry date.

Issue conditions:

According to the recipe

Packaging:

Solution for inhalations of 0,25 mg +0,5 mg/ml. On 20 ml of drug in bottles from dark glass with a polyethylene dropper and the screwing-up polypropylene cover. On 1 bottle with the application instruction place in a cardboard pack.