Expiration date: 07/2025

The composition and form of issue:

Solution for inhalation. 1 dose contains active substance: 

tiotropiya bromide monohydrate 3,1235 mcg

(that corresponds to the content tiotropiya 2.5 ág) 

excipients: benzalkonium chloride 1,105 mcg disodium edetate — 1,105 µg 1M hydrochloric acid to a pH of 2.8–3 water — to 11.05 mg 

in the cartridge placed in aluminum cylinders, 4.5 ml cartons 1 cylinder with cartridge 1 and the inhaler.

Description pharmaceutical form:

The solution is clear, colorless or nearly colorless.

Pharmacokinetics:

Tiotropiya bromide — derived Quaternary ammonium, sparingly soluble in water. Tiotropiya bromide produced in the form of solution for inhalation, which is applied through the inhaler, Respimat. Approximately 40% of the inhaled dose deposited in the lungs, the remainder enters the gastrointestinal tract. Some pharmacokinetic data described below were obtained when using doses higher than recommended for treatment.

Suction

After inhalation of a solution in young healthy volunteers found that in systemic circulation receives about 33% of the value of inhalation dose. Eating does not affect the absorption tiotropiya bromide due to the fact that it is poorly absorbed from the gastrointestinal tract. The absolute oral bioavailability of 2-3%. Cmax in plasma observed 5 min after inhalation.

Distribution

Binding of the drug to plasma proteins is 72% Vd is 32 l/kg. At the stage of dynamic equilibrium Cmax tiotropiya bromide in plasma in patients with COPD is 10.5 and 11.7 PG/ml after 10 min of the drug at a dose of 5 ág using inhaler, Respimat. At the stage of dynamic equilibrium in plasma Cmin was 1.49 to 1.68 PG/ml. Studies have shown that tiotropiya bromide does not penetrate the GEB.

Biotransformation

The degree of biotransformation is insignificant. This is confirmed by the fact that after the on/in the introduction of the drug to young healthy volunteers found in the urine detected 74% of the substance tiotropiya bromide in an unmodified form. Tiotropiya bromide is an ester which is broken down to ethanol-N-metilskopina and ditienilglikoleva acid, these compounds do not bind to muscarinic receptors.

In vitro studies showed that some part of the drug (<20 % of the dose after I/V administration) is metabolised by oxidation by cytochrome P450 with subsequent conjugation with glutathione and the formation of various metabolites. This mechanism can be inhibited with inhibitors of isoenzymes CYP2D6 and CYP3A4 (quinidine, ketoconazole and gestodene). This implies that CYP2D6 and CYP3A4 are involved in metabolism of the drug. Tiotropiya bromide even in Sortirovochny concentrations, no inhibits the cytochrome P450 (isoenzymes CYP1A1, CYP1A2, ???2?6, CYP2C9, ???2?19, CYP2D6, ???2?1 or 3????) in human liver microsomes.

Excretion

Terminal T1/2 tiotropiya bromide after inhalation is 5-6 days. Total clearance after I/V administration of the drug to young healthy volunteers was 880 ml/min at individual variability of 22%. Tiotropiya bromide after the on/in the introduction is mainly excreted by the kidneys unchanged (74%). After inhalation of the solution renal excretion is 20.1–29.4% of the remaining neabsorbirowawrzayasa part eliminated through the intestines. Renal clearance tiotropiya bromide exceeds the Cl of creatinine, indicating tubular secretion. After a long inhalation of the drug 1 time a day by the COPD patients pharmacokinetic equilibrium is achieved at the 7th day, while no further accumulation is observed.

Tiotropiya bromide has a linear pharmacokinetics in the therapeutic range, after the on/in the application, inhalation of dry powder and inhalation solution.

Pharmacokinetics in elderly patients

In old age there is a decrease in renal clearance tiotropiya bromide (326 ml/min in patients with COPD at the age of 58 years to 163 ml/min in COPD patients older than 70 years), which is possible due to the decline in renal function. Excretion tiotropiya bromide urine after inhalation application reduced from 14% in young healthy volunteers to about 7% in patients with COPD, however, the concentration in plasma from elderly patients with COPD did not change significantly, if we consider inter - and vnutricinovialnoe variability (after inhalation of dry powder AUC increased by 43%).

Patients with impaired renal function

Minor violations kidney function (Cl creatinine 50-80 ml/min), which can occur in elderly patients, accompanied by a slight increase in the concentration tiotropiya bromide in plasma (after intravenous infusion AUC increased by 39%).

In patients with COPD and moderate or significant renal impairment (creatinine Cl <50 ml/min) in/in tiotropiya bromide use led to a twofold increase in plasma concentrations (AUC increased by 82%), a similar increase in plasma concentrations was observed after inhalation of dry powder.

Patients with impaired liver function

It is assumed that hepatic impairment has no significant effect on the pharmacokinetics of tiotropiya bromide, because tiotropiya bromide is mainly excreted by the kidneys.

Description pharmacological action:

Tiotropiya bromide is antimuscarinic drug with prolonged action, in clinical practice often called m-holinoblokirutuyu means. The drug has equal affinity for subtypes of the muscarinic M1–M5 receptors. The result of inhibition of m3 receptors in the Airways is relaxation of smooth muscles. Bronhodilatiruty the effect is dose-dependent and persists for at least 24 h. a Significant duration of action is probably connected with a very slow dissociation of the drug from m3-receptors period of predissociative significantly longer than ipratropium bromide. The inhalation method of introduction tiotropy bromide, N-Quaternary ammonium derivative, has a local election effect (bronchi) in therapeutic doses does not cause systemic m-holinoblokirutmi side effects. Dissociation from m2-receptors is faster than from m3-receptors, which confirms the prevalence of selectivity in respect of subtype m3 receptors over m2 receptors. High affinity receptors and slow dissociation of the drug from the receptors cause a pronounced and long-lasting bronchodilatory effect in patients with COPD.

Bronhodilatace that develops after inhalation tiotropiya bromide, primarily due to the local (respiratory tract) and not a systemic effect.

In clinical studies, it has been shown that the drug Spiriva, Respimat once a day leads to significant improvements (compared with placebo) lung function (forced expiratory volume in 1 s and forced vital capacity) within 30 minutes after using the first dose. Improvement in lung function is maintained for 24 h at Css.

Pharmacodynamic equilibrium is reached within one week. Respimat, Spiriva significantly improved morning and evening peak volume exhalation rate, measured patients. The use of the drug Spiriva, Respimat resulted in a decrease (compared with placebo) the use of the bronchodilator as a means of first aid.

Bronhodilatiruty effect of the drug persists for 48 weeks of the drug signs of addiction are not marked.

Analysis of the combined data of 2 randomized, placebo-controlled, cross clinical studies have shown that bronhodilatiruty effect of the drug Spiriva, Respimat (5 µg) after 4-week treatment period was quantitatively higher than the effect of the drug Spiriva (18 mcg).

In the long term (12-month) studies, it was found that Spiriva, Respimat significantly reduces breathlessness, improves quality of life, reduces psycho-social impact of COPD and increases activity.

Drug Spiriva, Respimat significantly improved the overall health (total score) compared with placebo by the end of the two 12-month studies, this difference persisted throughout the treatment period, the drug Spiriva, Respimat considerably reduced the number of exacerbations of COPD and increases the period until the first deterioration compared to placebo.

It is proved that Spiriva, Respimat reduces the risk of COPD exacerbation and significantly reduces the number of hospital admissions.

The retrospective analysis of separate clinical studies, it was observed statistically significant increase in the number of deaths in patients with arrhythmias compared to placebo. However, these data are not statistically confirmed and can be associated with heart disease.

Indications:

Maintenance treatment, a reduction in the frequency of exacerbations and improve the quality of life in diseases of the broncho-pulmonary system:

- COPD

- chronic bronchitis

- emphysema

persistent shortness of breath.

Contraindications:

a history of hypersensitivity to atropine, its derivatives (including ipratropium bromide, oxytrope bromide) or to any component of these drugs

children up to 18 years (the lack of data on efficacy and safety).

Application of pregnancy and breast-feeding:

Clinical data on the effects of the drug Spiriva, Respimat pregnancy no. In preclinical studies is not received guidance on direct or indirect adverse effects on pregnancy, development of the embryo/fetus, childbirth or postnatal development.

Clinical data on the impact tiotropiya bromide in women who are breastfeeding, no. The drug should not be used in pregnant or breastfeeding women unless the potential benefit to the mother outweighs the potential risk to the fetus and child. For the period of use of the drug should discontinue breast-feeding a baby.

Side effects:

Many of the following adverse reactions can be attributed to m-holinoblokirutmi properties of the drug.

Adverse reactions have been identified on the basis of data obtained when conducting clinical studies and individual reports during post-approval use of the drug.

Classification of frequency of side effects (according to who): very often (>10%) often (>1%, <10%) uncommon (>0,1%, <1%) rare (>0,01%, <0,1%) very rare (<0,01%), including individual messages.

From the metabolic and nutrition: isolated cases — dehydration*.

From the nervous system: rare — dizziness isolated cases — insomnia*.

From the body of the vision: rarely — increased intraocular pressure, glaucoma, blurry vision.

From the CCC: often — atrial fibrillation, tachycardia, including supraventricular, palpitations.

Side respiratory, thoracic and mediastinal: infrequent cough, epistaxis, pharyngitis, dysphonia rarely — paradoxical bronchospasm, laryngitis isolated cases — sinus*.

By the blood: often — transient slight dryness of the mucous membrane of the pharynx rarely, constipation, oral candidiasis, dysphagia rarely gastroesophageal reflux, gingivitis, glossitis, stomatitis, isolated cases of intestinal obstruction, including paralytic ileus*.

From the skin: rarely — skin infections and skin ulcers, dry skin.

Allergic reactions: infrequently — rash, itching, rarely — angioedema, urticaria isolated cases — hypersensitivity reactions including immediate type*.

From the musculoskeletal system and related connective tissue: isolated cases — swelling of the joints*.

The kidneys and urinary system: rarely — dysuria, urinary retention (usually in men with the presence of predisposing factors) rarely — urinary tract infection.

*in a unified database of clinical trials, these adverse reactions were not detected was observed only few reports on adverse reactions data with the broad use of the drug, however, the relationship with m-holinoblokirutm effect of the drug has not been proven the frequency of these rare events is difficult to assess.

Drug interactions:

Although there were no specific drug interactions studies have not been conducted, tiotropiya bromide was used in conjunction with other drugs used for the treatment of COPD, including sympathomimetic bronchodilator, methylxanthines, steroids for oral and inhalation use and the clinical signs of drug interactions were noted.

Long joint tiotropiya bromide use with other m-holinoblokirutuyu drugs have not been studied. Therefore, long-term use of the drug Spiriva, Respimat with other m-holinoblokirutmi drugs is not recommended.

Method of application and dose:

Recommended therapeutic dose of two inhaled doses of spray from the inhaler, Respimat (5 µg/dose) 1 time a day, at the same time of the day.

Older patients/patients with impaired liver function and with minor violations kidney function (Cl creatinine 50-80 ml/min) the drug can be used, Respimat Spiriva at the recommended dose.

However, the use of the drug in patients with moderate or significant renal impairment (creatinine Cl <50 ml/min) should be carefully monitoriruemye.

COPD is not usually found in children. The safety and efficacy of Spiriva, Respimat in children have not been studied.

Overdose:

With the use of high doses of the drug possible manifestations of m-holinoblokirutego action.

After a 14-day inhalation use tiotropiya bromide in doses, reaching 40 µg, in healthy individuals was not observed significant adverse events in addition to feelings of dryness of the mucous membranes of the nose and oropharynx, the frequency of which depended on the dose (10-40 mg per day). The exception was a significant decrease in salivation, starting with the 7 day treatment. 6 long-term studies in patients with COPD inhalation use solution tiotropiya bromide in a daily dose of 10 mcg for 4-48 weeks showed significant adverse events.

Due to the low oral bioavailability of the occurrence of acute poisoning in case of accidental swallowing of the solution tiotropiya bromide for inhalation from the cartridge unlikely.

Precautions:

Drug Spiriva, Respimat as a bronchodilator, used 1 time per day for maintenance treatment should not be used as initial therapy for acute attacks of bronchospasm, i.e. in urgent cases.

After applying the drug may develop immediate hypersensitivity reactions.

Spiriva, Respimat, like other m-holinoblokirutuyu funds, should be used with caution in patients with angle-closure glaucoma, prostatic hyperplasia or bladder neck obstruction.

Inhalation of the drug can cause bronchospasm.

In moderate or severe renal insufficiency (Cl creatinine <50 ml/min) the drug should be closely monitored, as the acceptance of drugs excreted primarily by the kidneys.

Patients should be familiar with the instructions for use. Do not allow liquids or aerosol into the eye. Pain or discomfort in the eyes, blurred vision, visual halos, combined with the redness of the eyes, swelling of the conjunctiva and cornea may be symptoms of acute angle-closure glaucoma. With the development of any combination of these symptoms should immediately consult a specialist. Eye drops, have miotic action are not considered effective treatment.

Spiriva, Respimat should not be used more than 1 time a day.

Cartridges Spiriva should be used only with the inhaler, Respimat.

Effects on ability to drive or to perform work requiring high speed physical and mental reactions. Studies on the effects on ability to drive vehicles and mechanisms was conducted. Care should be taken when performing these types of activities, because the development of dizziness or blurred vision.

Storage conditions:

Use within 3 months after the first inhalation.