Spiriva® Respimat®

General characteristics. Structure:

Active ingredient: 3,1235 mkg a monohydrate bromide tiotropiya (that corresponds to 2,5 mkg a tiotropiya).

Excipients: benzalkoniya chloride, dinatrium эдетат, Acidum hydrochloricum 1M, water.

Broncholitic drug.

Pharmacological properties:

Pharmacodynamics. Tiotropiya bromide - m-holinoblokator of long action. Drug has identical affinity to M1-M5 to subtypes of muskarinovy receptors. In respiratory tracts relaxation of smooth muscles is result of M3 receptors inhibition. The Bronkhodilatiruyushchy effect depends on a dose and not less than 24 h remain. The considerable duration of action is connected probably with very slow dissociation of drug from M3 receptors; the semi-dissociation period significantly longer, than at a bromide ipratropiya.

At an inhalation way of introduction a tiotropiya bromide as N-quarternary derivative ammonium, renders local selective effect (on bronchial tubes), at the same time in therapeutic doses does not cause system m-holinoblokiruyushchikh of side effects. Dissociation from Sq.m receptors comes quicker, than from M3 receptors that testifies to dominance of selectivity concerning M3 of a subtype of receptors over Sq.m receptors. High affinity to receptors and slow dissociation of drug from communication with receptors cause the expressed and long bronkhodilatiruyushchy effect at patients with HOBL.

Bronkhodilatation developing after inhalation a bromide tiotropiya is caused, first of all, local (on respiratory tracts), but not systemic action.

In clinical trials it was shown that use of the drug Spiriva® Респимат® 1 of times/days leads to considerable improvement (in comparison with placebo) functions of lungs (the volume of the forced exhalation in 1 second of OFV1 and the forced vital capacity of easy FZhEL) within 30 min. after use of the first dose. Improvement of function of lungs remains during 24 h at equilibrium concentration.

Pharmakodinamichesky balance was reached within one week. Spiriva® Respimat® considerably improved the morning and evening peak volume expiratory rate (PVER) measured by patients. Use of the drug Spiriva® Respimat® led to reduction (in comparison with placebo) uses of bronchodilator as means of ambulance. The Bronkhodilatiruyushchy effect of drug remains for 48 weeks of use of drug; signs of accustoming are not noted.

The analysis of the combined data two randomized, placebo - controlled, cross clinical trials showed that the bronkhodilatiruyushchy effect of the drug Spiriva® Respimat® (5 mkg) after the 4 weeks period of treatment was in a quantitative sense higher, than effect of the drug Spiriva® (18 mkg).

In long-term (12-month) researches it was established that Spiriva® Respimat® considerably reduces an asthma; improves quality of life; reduces psychosocial influence of HOBL and increases activity.

The drug Spiriva® Respimat® authentically improved the general state of health (the general point) in comparison with placebo by the end of two 12-month researches, this distinction remained throughout the entire period of treatment; the drug Spiriva® Respimat® considerably reduced number of aggravations of HOBL, and increased the period until the first aggravation in comparison with placebo.

It is proved that Spiriva® Respimat® reduces risk of an aggravation of HOBL and considerably reduces quantity of cases of hospitalization.

In the retrospective analysis of separate clinical trials statistically doubtful increase, in comparison with placebo, quantities of cases of death at patients with disturbances of a heart rhythm was noticed. However these data are statistically not confirmed and can be connected with a heart disease.

In clinical trials at the patients having bronchial asthma and continuing to test disease symptoms despite a maintenance therapy inhalation GKS, including in a combination with it is long the operating agonist of beta2-adrenoceptors, it was established that addition of the drug Spiriva® Respimat® to a maintenance therapy led to reliable improvement of function of lungs in comparison with placebo, considerably reduced number of serious aggravations and the periods of deterioration in symptoms of bronchial asthma, increased the period before their first approach, led to reliable improvement of quality of life and increase in number of patients with affirmative answer at a maintenance therapy.

The Bronkhodilatiruyushchy effect of drug remained for 1 year of use, signs of accustoming were not noted.

Pharmacokinetics. Tiotropiya bromide - quarternary derivative ammonium, moderately soluble in water. Tiotropiya bromide is issued in the form of solution for inhalations which is applied by means of an inhaler of Respimat®. About 40% of the size of an inhalation dose are besieged in lungs, other quantity comes to a GIT. Some pharmacokinetic data described below were received when using the doses exceeding recommended for treatment.

Absorption. After solution inhalation by young healthy volunteers it is established that about 33% of the size of an inhalation dose come to system circulation. Meal does not influence absorption a bromide tiotropiya because it is badly soaked up from a GIT. Absolute bioavailability at intake makes 2-3%. Cmax in plasma is observed in 5 min. after inhalation.

Distribution. Linkng of drug with proteins of plasma makes 72%; Vd - 32 l/kg. At a stage of a dynamic equilibrium peak concentration the bromide tiotropiya in plasma at patients with HOBL makes 10.5-11.7 pg/ml in 10 min. after use of drug in a dose of 5 mkg by means of an inhaler of Respimat®. At a stage of a dynamic equilibrium of Cmax the bromide tiotropiya in plasma at patients with bronchial asthma makes 5.15 pg/ml in 5 min. after reception in the same dose by means of an inhaler of Respimat®. At a stage of a dynamic equilibrium the smallest concentration in plasma made 1.49-1.68 pg/ml. Researches showed that the tiotropiya bromide does not get through GEB.

Metabolism. Degree of biotransformation is insignificant. It is confirmed by the fact that later in/in administrations of drug to young healthy volunteers in urine 74% of substance a bromide tiotropiya in not changed look are found. Tiotropiya bromide is ether which is split on ethanol-N-metilskopin, and ditiyenilglikoliyevy acid; these connections do not contact muskarinovy receptors.

In the researches in vitro it is shown that some part of drug (<20% of a dose later in/in introductions) is metabolized by oxidation by P450 cytochrome with the subsequent conjugation with glutathione and formation of various metabolites. This mechanism can be stopped by inhibitors of isoenzymes of CYP 2D6 and 3A4 (quinidine, кетоконазол and гестоден). Thus, CYP2D6 and 3A4 participate in drug metabolism. Tiotropiya even in supertherapeutic concentration does not inhibit bromide P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A cytochrome in microsomes of a liver of the person.

Removal. Terminal T1/2 the bromide tiotropiya after inhalation makes 5-6 days at healthy volunteers and patients with HOBL. At patients with bronchial asthma effective T1/2 after inhalation makes 34 h.

The general clearance in/in administrations of drug to young healthy volunteers made later 880 ml/min., at individual variability of 22%. Tiotropiya bromide in/in introductions is generally brought later by kidneys in not changed look (74%). After inhalation of solution at healthy volunteers renal excretion makes 20.1-29.4%, the remained not absorbed part is removed through intestines. In a stage of pharmacokinetic balance at patients with asthma of 11.9% (0.595 mkg) of a dose it is removed in an invariable view with urine in 24 h after administration of drug. Renal clearance the tiotropiya of bromide exceeds KK that demonstrates its canalicular secretion. After long inhalation administration of drug of 1 times/days by patients with HOBL pharmacokinetic balance is reached for the 7th day; at the same time further we are not observed cumulation.

Tiotropiya bromide has linear pharmacokinetics in therapeutic limits later in/in uses, inhalations of dry powder and inhalation of solution.

Pharmacokinetics in special clinical cases. At advanced age the bromide tiotropiya (patients have 326 ml/min. with HOBL aged to 58 years and at patients with HOBL 70 years are more senior than 163 ml/min.) is noted decrease in renal clearance that, perhaps, is explained by depression of function of kidneys. Excretion a bromide tiotropiya with urine after inhalation use decreases from 14% at young healthy volunteers approximately to 7% at patients with HOBL, however concentration in plasma at patients of advanced age with HOBL significantly did not change if to consider boundaries - and intra individual variability (after inhalation of the dry powder AUC increased by 43%). It is established that at patients with bronchial asthma influence the tiotropiya of bromide does not depend on age of patients.

Small renal failures (KK of 50-80 ml/min.) which can be observed at patients of advanced age are followed by insignificant increase in concentration a bromide tiotropiya in plasma (later in/in infusion of AUC increased by 39%). At patients with HOBL and moderate or considerable renal failures (KK <50 ml/min.) in/in use a tiotropiya of bromide led to double increase in concentration in plasma (AUC increased by 82%), similar increase in concentration in plasma was noted also after inhalation of dry powder.

At patients with bronchial asthma and small renal failures (KK of 50-80 ml/min.) inhalation use a tiotropiya of bromide did not lead to significant increase in influence in comparison with patients with normal function of kidneys.

It is supposed that the liver failure does not exert considerable impact on pharmacokinetics a bromide tiotropiya since the tiotropiya bromide is preferential removed by kidneys.

Indications to use:

— for the supporting treatment of patients with HOBL, chronic bronchitis, emphysema of lungs, for a maintenance therapy at the remaining asthma, for improvement of the quality of life broken owing to HOBL for decrease in frequency of aggravations;

— for an additional maintenance therapy at patients with bronchial asthma with the remaining disease symptoms against the background of reception of inhalation GKS, for reduction of symptoms of bronchial asthma, improvement of quality of life and decrease in frequency of aggravations.

Route of administration and doses:

The recommended therapeutic dose makes 2 inhalation doses of spray of an inhaler of Respimat® (5 mkg / a dose) 1 times/days, at the same time day.

At treatment of bronchial asthma the full therapeutic effect occurs in several days.

At patients of advanced age, patients with abnormal liver functions and patients with insignificant renal failures (KK of 50-80 ml/min.) it is possible to use the drug Spiriva® Respimat® in the recommended dose.

However use of drug at patients with moderate or considerable renal failures (KK <50 ml/min.) has to monitorirovatsya carefully.

HOBL usually does not occur at children. Safety and efficiency of use of the drug Spiriva® Respimat® for children are not studied.

Rules of use of an inhaler Spiriva® Respimat®. Insert of a cartridge and preparation for use. Before the first use of an inhaler it is necessary to carry out the actions given below at numbers 1-6.

1. At the closed green cap it is necessary to press the lock button and at the same time to remove a transparent sleeve, having pulled it down.

2. To take out a cartridge from packaging. To insert it the narrow end into an inhaler before fixing. To be convinced that the cartridge is completely inserted it is necessary to press strongly a cartridge on a firm surface. At the same time the bottom of a cartridge should not be flush with bottom edge of an inhaler, the lower part of a cartridge of silver color has to be visible. After the cartridge is inserted into an inhaler, it is not necessary to take out it.

3. To dress again a transparent sleeve. After that the sleeve should not be removed more.

Preparation for the first use of an inhaler of Spiriva® Respimat®

4. It is necessary to hold an inhaler of Spiriva® Respimat® vertically with a dressed green cap. It is necessary to turn a transparent sleeve in the direction of the red arrows specified on the label before click (half-turn).

5. To remove a green cap.

6. To direct an inhaler of Spiriva® Respimat® down. To press the button of giving of a dose. To close a green cap.

It is necessary to repeat stages 4, 5 and 6 before emergence of an aerosol cloudlet. Then to repeat stages 4, 5 and 6 3 more times to provide preparation of an inhaler for use.

Now the inhaler of Spiriva® Respimat® is ready to use.

Implementation of these stages does not reduce number of doses of drug. After preparation the inhaler of Spiriva® Respimat® allows to release 30 doses (60 inhalations).

Use of an inhaler of Spiriva® Respimat®. It is necessary to use this inhaler only of 1 times/days. Every time needs to be done 2 inhalations.

I. To hold an inhaler of Spiriva® Respimat® vertically with a dressed green cap to prevent accidental release of medicine. To turn a transparent sleeve in the direction of the red arrows specified on the label before click (half-turn).

II. To remove a green cap. To exhale slowly and deeply. To capture densely lips the end of a mouthpiece. The air opening of an inhaler has to be free at the same time. To direct an inhaler to a back part of a throat.

During a slow and deep breath through a mouth it is necessary to press the button of giving of a dose and to continue a breath as long as possible. To hold the breath for 10 seconds or as long as conveniently.

III. To repeat stages I-II to receive a full dose. It is necessary to use this inhaler only of 1 times/days. Every time needs to be done 2 inhalations.

To close a green cap of an inhaler before its following use.

If the inhaler of Spiriva® Respimat® was not used more than 7 days, it is necessary to direct it before use down and to press 1 time the button of giving of a dose. If the inhaler was not used more than 21 days, to repeat stages 4-6 before receiving an aerosol cloudlet. Then to repeat stages 4-6 three more times.

Definition of the moment when it is necessary to begin to use a new inhaler. The inhaler of Spiriva® Respimat® contains 30 doses (60 inhalations). The index of doses shows how many approximately drug still remained. When the index of an inhaler shows on red area of a scale, it means what drugs remained approximately for 7 days (14 inhalations). In this period it is necessary to receive the recipe on a new inhaler of Spiriva® Respimat®.

When the index of an inhaler reaches the end of red area of a scale (i.e. when 30 doses are used), it means that the inhaler of Spiriva® Respimat® is empty. There will be an automatic blocking of an inhaler. From this point time the turn of a transparent sleeve will be impossible.

After the first use the inhaler of Spiriva® Respimat® should be utilized no later than in 3 months even if not all quantity of medicine was applied.

Care of an inhaler. The mouthpiece and a metal part of the sprayer need to be cleaned wet soft fabric towel wipes, at least, once a week.

Small decolouration of a mouthpiece does not influence functioning of an inhaler. If necessary to wipe an inhaler as well outside wet fabric towel wipes.

Features of use:

Use at pregnancy and feeding by a breast. Data on influence of the drug Spiriva® Respimat® on pregnancy are limited. When studying reproductive toxicity on animals instructions on straight lines or the mediated adverse influences of drug are not received. As a precautionary measure it is more preferable to refrain from use of the drug Spiriva® Respimat® at pregnancy. The bromide tiotropiya during breastfeeding is not present clinical data on influence. Drug should not be used at pregnant women or the nursing women if only the expected advantage for mother exceeds potential risk for a fruit and the child. For use of drug it is necessary to stop feeding by the child's breast.

Use at abnormal liver functions. At patients with abnormal liver functions it is possible to use the drug Spiriva® Respimat® in the recommended dose.

Use at renal failures. At patients with insignificant renal failures (KK of 50-80 ml/min.) it is possible to use the drug Spiriva® Respimat® in the recommended dose.

However, use of drug at patients with moderate or considerable renal failures (KK <50 ml/min.) has to monitorirovatsya carefully.

Use for children. Appointment is contraindicated to children and teenagers aged up to 18 years (in view of lack of data on efficiency and safety).

Use for elderly patients. At patients of advanced age it is possible to use the drug Spiriva® Respimat® in the recommended dose.

The drug Spiriva® Respimat® as the bronchodilator applied by 1 times/days to the supporting treatment should not be applied as initial therapy at bad attacks of a bronchospasm or to elimination of sharply arising symptoms. In case of development of a bad attack are used high-speed β2-агонисты.

The drug Spiriva® Respimat® should not be used for treatment of bronchial asthma as therapy of the first line. To patients it is necessary to recommend to continue against the background of administration of drug of Spiriva® Respimat® antiinflammatory therapy (for example, inhalation GKS) even if symptoms will decrease.

After use of drug immediate hypersensitivity reactions can develop.

Inhalation of drug can cause a bronchospasm.

At the moderated or expressed renal failure (KK of ≤50 ml/min.) administration of drug should be conducted under careful observation, as well as at reception of all medicines excreted preferential by kidneys.

Before use patients have to be informed of the application instruction.

It is not necessary to allow hits of solution or an aerosol in eyes. Pain or discomfort in eyes, indistinct sight, visual auras in combination with reddening of eyes, a chemosis and corneas can be symptoms of acute closed-angle glaucoma. At development of any combination of these symptoms it is necessary to address the specialist immediately. The eye drops possessing miotic action are not considered as effective treatment.

Spiriva® Respimat® should not be used more often than 1 times/days.

Cartridges of Spiriva® should be used only with an inhaler of Respimat®.

Influence on ability to driving of motor transport and to control of mechanisms. Researches on studying of influence on ability to manage vehicles and mechanisms were not conducted. It is necessary to be careful when performing these types of activity since development of dizziness or an illegibility of sight is possible.

Side effects:

Many of the listed below undesirable reactions can be caused by m-holinoblokiruyushchim properties of drug.

Side reactions were revealed on the basis of the data obtained at conduct of clinical trials and separate messages during post-registration use of drug.

From a metabolism: дегидратация*.

From a nervous system: infrequently (≥0.1% and <1%) - dizziness; бессонница*.

From an organ of sight: seldom (≥0.01% and <0.1%) - increase in intraocular pressure, glaucoma, indistinct sight.

From cardiovascular system: infrequently (> 0.1% and <1%) - a ciliary arrhythmia, tachycardia (including supraventricular tachycardia), a heart consciousness.

From a respiratory organs: infrequently (≥0.1% and <1%) - cough, nasal bleeding, pharyngitis, a dysphonia; seldom (≥0.01% and <0.1%) - a paradoxical bronchospasm, laryngitis; синусит*.

From the alimentary system: often (≥1% and <10%) - insignificant passing dryness of a mucous membrane of a throat; infrequently (> 0.1% and <1%) - a lock, oral cavity candidiasis, a dysphagy; seldom (≥0.01% and <0.1%) - a gastroesophageal reflux, an ulitis, a glossitis, stomatitis; intestinal impassability, including paralytic intestinal непроходимость*.

From integuments: seldom (≥0.01% and <0.1%) - skin infections and skin ulcers, a xeroderma.

Allergic reactions: infrequently (> 0.1% and <1%) - rash, an itch; seldom (≥0.01% and <0.1%) - a Quincke's disease, a small tortoiseshell; hypersensitivity, including reactions immediate типа*.

From a musculoskeletal system and connecting fabric: swelling суставов*.

From an urinary system: infrequently (> 0.1% and <1%) - a dysuria, an ischuria (is more often at men with existence of the contributing factors); seldom (≥0.01% and <0.1%) - an infection of urinary tract.

* in the joint base of clinical trials these side reactions were not revealed; only single messages on these side reactions at broad use of drug are noted, however communication with m-holinoblokiruyushchim effect of drug is not proved; it is difficult to estimate the frequency of these unusual occurrences.

Interaction with other medicines:

Though special researches of medicinal interaction were not conducted, a tiotropiya bromide was applied together with other drugs which are applied for treatment of HOBL including sympathomimetic bronchodilators, methylxanthines, GKS to intake and inhalation use, antihistaminic drugs, Mucolyticums, modifiers of leukotrienes, kromona, anti-IgE drugs; at the same time clinical signs of medicinal interaction were not noted.

Prolonged combined use a bromide tiotropiya with other m-holinoblokiruyushchimi drugs was not studied. Therefore long-term combined use of the drug Spiriva® Respimat® with other m-holinoblokiruyushchimi drugs is not recommended.

Contraindications:

— children's and teenage age up to 18 years (in view of lack of data on efficiency and safety);

— hypersensitivity to atropine or its derivatives, for example, an ipratropiya to bromide, an oksitropiya to bromide or to any component of drug.

With care drug should be used at closed-angle glaucoma, a hyperplasia of a prostate, obstruction of a neck of a bladder.

Overdose:

At use of drug in high doses manifestations of m-holinoblokiruyushchego of action are possible. After 14-day inhalation use a bromide tiotropiya in the doses reaching 40 mkg at healthy faces the significant adverse phenomena, except feeling of dryness of mucous membranes of a nose and a stomatopharynx which frequency depended on the dose size (10-40 mkg/days) were not observed. The exception made clear decrease in a sialosis, since 7 in the afternoon drug use. In six long-term researches at patients with HOBL at inhalation use of solution a bromide tiotropiya in a daily dose of 10 mkg within 4-48 weeks the essential undesirable phenomena were not observed.

Owing to low peroral bioavailability developing of acute intoxication in case of an inadvertent proglatyvaniye of solution a bromide tiotropiya for inhalations from a cartridge is improbable.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 25 °C. Drug needs to be used within 3 months after the first inhalation. Period of validity 3 years.

Issue conditions:

According to the recipe

Packaging:

60 doses (4 ml) - cartridges with a capacity of 4.5 ml (1) - cylinders aluminum (1) complete with an inhaler of Respimat® - packs cardboard.