Spiriva Respimat solution for inhalation 2.5 ?g / ml, 4 ml 60 dose

- for the maintenance treatment of patients with COPD, chronic bronchitis, pulmonary emphysema; maintenance therapy for persistent dyspnea; improving the quality of life impaired by COPD, and reducing the frequency of exacerbations.
- as an additional supportive therapy in patients from 6 years of age with bronchial asthma, with persisting symptoms of the disease while taking at least inhaled glucocorticosteroids; to reduce the symptoms of bronchial asthma, improve the quality of life and reduce the frequency of exacerbations.

The recommended therapeutic dose is two inhalations of the spray from the RESPIMAT inhaler (5 ?g / therapeutic dose) once a day, at the same time of day (see 'Instructions for use').

In the treatment of bronchial asthma, the full therapeutic effect occurs in a few days.

In elderly patients, patients with impaired liver function and patients with minor impaired renal function (creatinine clearance 50 - 80 ml / min), you can use the drug Spiriva Respimat at the recommended dose.

However, the use of the drug in patients with moderate or significant impairment of renal function (creatinine clearance less than 50 ml / min) should be carefully monitored. COPD does not usually occur in children. The safety and efficacy of Spiriva Respimat in children under one year of age have not been studied.

One inhalation dose contains
Active ingredient: tiotropium - 2.5 mcg (correspondingly tiotropium bromide monohydrate -3.1235 mcg).
Excipients: benzalkonium chloride - 1.105 ?g, disodium edetate - 1.105 ?g, hydrochloric acid 1M to pH 2.8 - 3.0, water - up to 11.05 mg.

Angle-closure glaucoma, prostatic hyperplasia, bladder neck obstruction.

Contraindications

The drug Spiriva Respimat is contraindicated in patients who have previously had hypersensitivity to any component of this drug, to atropine or its derivatives, for example, ipratropium bromide, oxytropium bromide.

Tradename:

SpirivaЃ RespimatЃ

International name:

tiotropium bromide

Chemical name:

(1R, 2R, 4S, 5S, 7S) -7- [2-Hydroxy-2,2-di- (2-thienyl) acetoxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02 , 4] nonane bromide monohydrate

Dosage form:

inhalation solution

Composition:

One inhalation dose contains
Active ingredient: tiotropium - 2.5 mcg (correspondingly tiotropium bromide monohydrate -3.1235 mcg).
Excipients: benzalkonium chloride - 1.105 ?g, disodium edetate - 1.105 ?g, hydrochloric acid 1M to pH 2.8 - 3.0, water - up to 11.05 mg.

Description:

a clear, colorless or almost colorless solution in a 4.5 ml cartridge placed in an aluminum cylinder.

Pharmacotherapeutic group:

M-anticholinergic

Pharmacological properties

Tiotropium bromide is a long-acting antimuscarinic drug, often referred to as an m-anticholinergic agent in clinical practice. The drug has the same affinity for the Ml - M5 subtypes of muscarinic receptors. Inhibition of M3 receptors in the airways results in smooth muscle relaxation. The bronchodilating effect depends on the dose and lasts for at least 24 hours. The long duration of action is probably related to the very slow dissociation of the drug from the M3 receptors; the half-dissociation period is significantly longer than that of ipratropium bromide. With the inhalation method of administration, tiotropium bromide, as an N-quaternary ammonium derivative, has a local selective effect (on the bronchi), while in therapeutic doses it does not cause systemic m-anticholinergic side effects.Dissociation from M2 receptors occurs faster than from M3 receptors, which indicates the predominance of selectivity for the M3 receptor subtype over M2 receptors. High affinity for receptors and slow dissociation of the drug from the connection with receptors cause a pronounced and long-term bronchodilatory effect in patients with chronic obstructive pulmonary disease (COPD).

Bronchodilation that develops after inhalation of tiotropium bromide is primarily due to local (in the respiratory tract), and not systemic action.

In clinical studies, it has been shown that the use of the drug Spiriva Respimat once a day leads to a significant improvement (compared to placebo) in lung function (forced expiratory volume in 1 second FEV1 and forced vital capacity of the lungs of FVC) within 30 minutes after using the first dose ... The improvement in lung function persists for 24 hours at equilibrium concentration.

Pharmacodynamic equilibrium was achieved within one week. Spiriva Respimat significantly improved the morning and evening peak expiratory flow rate (PEFV) measured by patients. The use of the drug Spiriva Respimat led to a decrease (compared to placebo) in the use of a bronchodilator as an ambulance. The bronchodilating effect of the drug lasts for 48 weeks of using the drug; there are no signs of addiction.

An analysis of the combined data of two randomized, placebo-controlled, crossover clinical trials showed that the bronchodilating effect of Spiriva Respimat (5 ?g) after a 4-week treatment period was quantitatively higher than the effect of SPIRIVA (18 ?g).

In long-term (12-month) studies, Spiriva Respimat was found to significantly reduce shortness of breath; improves the quality of life; reduces the psychosocial impact of COPD and increases activity.

Spiriva Respimat significantly improved overall health (overall score) compared to placebo at the end of the two 12-month studies, and this difference persisted throughout the treatment period; the drug Spiriva Respimat significantly reduced the number of exacerbations of COPD, and increased the period until the first exacerbation compared with placebo.

It has been proven that Spiriva Respimat reduces the risk of exacerbation of COPD and significantly reduces the number of hospitalizations.

In a retrospective analysis of individual clinical trials, a statistically insignificant increase was observed, compared with placebo, in the number of deaths in patients with cardiac arrhythmias. However, these data are not statistically confirmed and may be associated with heart disease.

In clinical studies in patients suffering from bronchial asthma and continuing to experience symptoms of the disease, despite maintenance therapy with an inhaled corticosteroid, including in combination with a long-acting agonist of beta2-adrenergic receptors, it was found that the addition of the drug Spiriva Respimat to maintenance therapy led to a significant improved lung function compared with placebo, significantly reduced the number of serious exacerbations and periods of worsening of bronchial asthma symptoms, and increased the period to their first onset, led to a significant improvement in the quality of life and an increase in the number of patients with a positive response to maintenance therapy. The bronchodilating effect of the drug persisted for 1 year of use, there were no signs of addiction.

Pharmacokinetics
Tiotropium bromide is a quaternary ammonium derivative, moderately soluble in water. Tiotropium bromide is available in the form of a solution for inhalation, which is applied using the RESPIMAT inhaler. Approximately 40% of the inhalation dose is deposited in the lungs, the rest enters the gastrointestinal tract. Some of the pharmacokinetic data described below have been obtained using doses higher than those recommended for treatment.

Suction
After inhalation of the solution by young healthy volunteers, it was found that about 33% of the inhalation dose enters the systemic circulation. Food intake does not affect the absorption of tiotropium bromide, due to the fact that it is poorly absorbed from the gastrointestinal tract. Absolute oral bioavailability is 2-3%. The maximum plasma concentration is observed 5-7 minutes after inhalation. At the stage of dynamic equilibrium, the peak plasma concentration of tiotropium in patients with COPD is 10.5 pg / ml and decreases rapidly. This indicates a multi-compartment distribution of the drug. At the stage of dynamic equilibrium, the basal concentration of tiotropium in the blood plasma is 1.6 pg / ml. At the stage of dynamic equilibrium, the peak concentration of tiotropium in the blood plasma in patients with bronchial asthma was 5,15 pg / ml and reached after 5 min.

Distribution
Plasma protein binding of the drug is 72%; the volume of distribution is 32 l / kg. Studies have shown that tiotropium bromide does not cross the blood-brain barrier.

Biotransformation The
degree of biotransformation is negligible. This is confirmed by the fact that after intravenous administration of the drug to young healthy volunteers, 74% of the substance of tiotropium bromide in unchanged form is found in the urine. Tiotropium bromide is an ester that is cleaved into ethanol-N-methylscopine and dithienyl glycolic acid; these compounds do not bind to muscarinic receptors.

In vitro studies have shown that some part of the drug (<20% of the dose after intravenous administration) is metabolized by oxidation with cytochrome P450, followed by conjugation with glutathione and the formation of various metabolites. This mechanism can be inhibited by inhibitors of isoenzymes CYP450 2D6 and 3A4, quinidine, ketoconazole and gestodene. Thus, CYP450 2D6 and 3A4 are involved in drug metabolism. Tiotropium bromide, even at supertherapeutic concentrations, does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.

Withdrawal The
terminal half-life of tiotropium bromide after inhalation is 27 to 45 hours in patients with COPD. In patients with asthma, the effective half-life after inhalation is 34 hours.

The total clearance after intravenous administration of the drug to young healthy volunteers was 880 ml / min. Tiotropium bromide after intravenous administration is mainly excreted by the kidneys unchanged (74%). After inhalation of the solution in patients with COPD, renal excretion is 18.6% (0.93 ?g), the remaining unabsorbed part is excreted through the intestine. At the stage of pharmacokinetic equilibrium in patients with asthma, 11.9% (0.595 ?g) of the dose is excreted unchanged in the urine 24 hours after taking the drug. The renal clearance of tiotropium bromide exceeds the clearance of creatinine, which indicates its tubular secretion. After long-term inhalation of the drug once a day in patients with COPD, pharmacokinetic equilibrium is achieved on day 7; in this case, no further accumulation is observed.

Tiotropium bromide has linear pharmacokinetics within therapeutic limits following intravenous administration, dry powder inhalation, and solution inhalation.

Pharmacokinetics in elderly patients
In old age, there is a decrease in renal clearance of tiotropium (347 ml / min in patients with COPD under the age of 65 years and 275 ml / min in patients with COPD and asthma over 65 years old). It was found that in patients with bronchial asthma, the effect of tiotropium bromide does not depend on the age of the patients.

Patients with impaired renal function
After inhalation of tiotropium once a day during the period of steady state pharmacokinetics in patients with COPD and minor renal impairment (creatinine clearance 50-80 ml / min), there was a slight increase in AUCo-6, ss by 1.8-30% and Cmax , ss compared with patients with normal renal function (creatinine clearance> 80 ml / min). In patients with COPD and moderate or significant renal impairment (creatinine clearance <50 ml / min), intravenous administration of tiotropium bromide led to a twofold increase in the total exposure (the area under the concentration / time curve AUC0-4h increased by 82%, and the Cmax increased by 52%) compared with patients with COPD and normal renal function. A similar increase in plasma concentration was observed after inhalation of dry powder.

In patients with bronchial asthma and mild renal impairment (creatinine clearance 50-80 ml / min), inhalation of tiotropium bromide did not lead to a significant increase in exposure compared to patients with normal renal function.

Patients with impaired liver function
It is assumed that liver failure does not significantly affect the pharmacokinetics of tiotropium bromide, since tiotropium bromide is predominantly excreted by the kidneys and by non-enzymatic cleavage of the ether bond to form derivatives that do not have pharmacological activity.

Indications

Spiriva Respimat is indicated for:

- for the maintenance treatment of patients with COPD, chronic bronchitis, pulmonary emphysema; maintenance therapy for persistent dyspnea; improving the quality of life impaired by COPD, and reducing the frequency of exacerbations.
- as an additional supportive therapy in patients from 6 years of age with bronchial asthma, with persisting symptoms of the disease while taking at least inhaled glucocorticosteroids; to reduce the symptoms of bronchial asthma, improve the quality of life and reduce the frequency of exacerbations.

Carefully

Angle-closure glaucoma, prostatic hyperplasia, bladder neck obstruction.

Contraindications

The drug Spiriva Respimat is contraindicated in patients who have previously had hypersensitivity to any component of this drug, to atropine or its derivatives, for example, ipratropium bromide, oxytropium bromide.

Application during pregnancy and during breastfeeding

Data on the effect of Spiriva Respimat on pregnancy are limited. In preclinical studies in the study of reproductive toxicity, there were no indications of direct or indirect adverse effects of the drug. As a precautionary measure, it is preferable to refrain from using the drug Spiriva Respimat during pregnancy.

There are no clinical data on the effect of tiotropium bromide in women who are breastfeeding. The drug should not be used in pregnant or breastfeeding women if the potential benefit to the mother does not outweigh the potential risk to the fetus and baby. For the period of using the drug, it is necessary to stop breastfeeding the child.

Method of administration and dosage

The recommended therapeutic dose is two inhalations of the spray from the RESPIMAT inhaler (5 ?g / therapeutic dose) once a day, at the same time of day (see 'Instructions for use').

In the treatment of bronchial asthma, the full therapeutic effect occurs in a few days.

In elderly patients, patients with impaired liver function and patients with minor impaired renal function (creatinine clearance 50 - 80 ml / min), you can use the drug Spiriva Respimat at the recommended dose.

However, the use of the drug in patients with moderate or significant impairment of renal function (creatinine clearance less than 50 ml / min) should be carefully monitored. COPD does not usually occur in children. The safety and efficacy of Spiriva Respimat in children under one year of age have not been studied.

Side effect

Many of the adverse reactions listed below may be due to the m-anticholinergic properties of the drug.

Adverse reactions were identified on the basis of data obtained during clinical trials and individual reports during post-marketing use of the drug.

The frequency of adverse reactions that may occur during therapy is given in the form of the following gradation: very often (? 1/10); often (? 1/100, <1/10); infrequently (? 1/1000, <1/100); rarely (? 1/10 000, <1/1 000); very rare (<1/10 000); unspecified frequency (frequency cannot be estimated from available data).

Metabolic and nutritional
disorders Unspecified frequency: dehydration.

Nervous system disorders
Uncommon: dizziness.
Rarely: insomnia.

Violations of the organ of vision
Rarely: increased intraocular pressure, glaucoma; blurred vision.

Cardiovascular system disorders
Rarely: atrial fibrillation; tachycardia (including supraventricular tachycardia), palpitations.

Respiratory, chest and mediastinal
disorders Uncommon: cough, pharyngitis, dysphonia.
Rarely: epistaxis, bronchospasm, laryngitis.
Unspecified frequency: sinusitis.

Disorders from the gastrointestinal tract
Often: slight transient dryness of the pharyngeal mucosa.
Uncommon: constipation, oral candidiasis.
Rarely: dysphagia, gastroesophageal reflux, gingivitis, glossitis.
Unspecified frequency: stomatitis, intestinal obstruction, including paralytic intestinal obstruction.

Skin and subcutaneous tissue disorders
Rarely: skin infections and skin ulcers, dry skin.

Allergic reactions
Uncommon: rash, itching.
Rarely: angioedema, urticaria.
Unspecified frequency: hypersensitivity, including immediate reactions.

Musculoskeletal and connective tissue
disorders Unspecified frequency: joint swelling.

Disorders from the kidneys and urinary system
Uncommon: dysuria, urinary retention (more often in men with predisposing factors).
Rare: urinary tract infections.

Overdose

When using high doses of the drug, manifestations of m-anticholinergic action are possible. After 14 days of inhalation of tiotropium bromide in doses up to 40 mcg, no significant adverse events were observed in healthy individuals, except for a feeling of dryness of the mucous membranes of the nose and oropharynx, the frequency of which depended on the dose (10-40 mcg per day). The exception was a distinct decrease in salivation starting from the 7th day of the drug administration. In six long-term studies in patients with COPD, when inhaled solution of tiotropium bromide at a daily dose of 10 mcg for 4 to 48 weeks, no significant adverse events were observed.

Interaction with other medicinal products

Although no specific drug interaction studies have been conducted, tiotropium bromide has been used in conjunction with other drugs for the treatment of COPD, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, antihistamines, mucolytics, leukotriene modifiers, cromones, anti-IgE drugs, while there were no clinical signs of drug interactions.

Concomitant use with long-acting beta2-agonists, inhaled glucocorticosteroids and their combinations does not affect the effect of tiotropium.

Long-term combined use of tiotropium bromide with other m-anticholinergic drugs has not been studied. Therefore, long-term concomitant use of Spiriva Respimat with other m-anticholinergic drugs is not recommended.

special instructions

ѕрепарат —пирива –еспимат, как бронходилататор, примен¤емый один раз в день дл¤ поддерживающего лечени¤, не должен примен¤тьс¤ в качестве начальной терапии при острых приступах бронхоспазма или дл¤ устранени¤ остро возникающих симптомов. ¬ случае развити¤ острого приступа используютс¤ быстродействующие –2-агонисты.

ѕрепарат —пирива –еспимат не должен использоватьс¤ дл¤ лечени¤ бронхиальной астмы в качестве терапии первой линии. ѕациентам следует рекомендовать на фоне приема препарата —пирива –еспимат продолжать противовоспалительную терапию (например, ингал¤ционными глюкокортикостероидами), даже если симптомы уменьшатс¤.

ѕосле применени¤ препарата могут развиватьс¤ немедленные реакции повышенной чувствительности.

»нгал¤ци¤ препарата может вызывать бронхоспазм.

ѕри умеренной или выраженной почечной недостаточности (клиренс креатинина ? 50 мл/мин) прием препарата следует вести под тщательным наблюдением, как и при приеме всех лекарственных препаратов, экскретируемых преимущественно почками.

ѕациенты должны быть ознакомлены с инструкцией по применению. Ќе следует допускать попадани¤ раствора или аэрозол¤ в глаза. Ѕоль или дискомфорт в глазах, нечеткое зрение, зрительные ореолы в сочетании с покраснением глаз, отек конъюнктивы и роговицы могут быть симптомами острой закрытоугольной глаукомы. ѕри развитии любой комбинации этих симптомов следует немедленно обратитьс¤ к специалисту. vлазные капли, обладающие миотическим действием, не считаютс¤ эффективным лечением.

ѕрепарат —пирива –еспимат не должен использоватьс¤ чаще, чем один раз в день.

 артриджи —пиривы должны использоватьс¤ только с ингал¤тором –еспимат.

¬ли¤ние препарата на способность управл¤ть транспортными средствами и механизмами

»сследовани¤ по изучению вли¤ни¤ на способность управл¤ть транспортными средствами и механизмами не проводились. —ледует соблюдать осторожность при выполнении данных видов де¤тельности, так как возможно развитие головокружени¤ или нечеткости зрени¤.

‘орма выпуска

–аствор дл¤ ингал¤ций 2,5 мкг/доза
»нгал¤тор –еспиматЃ в комплекте с картриджем вместимостью 4,5 мл, помещенным в алюминиевый цилиндр. »нгал¤тор и цилиндр с картриджем с инструкцией по применению в картонную пачку.

”слови¤ хранени¤

ѕри температуре не выше 25 ?—. Ќе замораживать.
»спользовать в течение 3 мес¤цев после первой ингал¤ции.
’ранить в недоступном дл¤ детей месте.

—рок годности

3 years.
Do not use after the expiration date printed on the package.

Conditions of dispensing from pharmacies

Prescribed by a doctor.