Spiriva, cartridge 2.5 µg/dose, respimat

Composition

In 1 dose of the solution for inhalation contains:

Active ingredient:

tiotropium bromide monohydrate – 3.1235 mcg, which corresponds to the content of tiotropium-2.5 mcg.

Auxiliary substances:

benzalkonium chloride – 1.105 mcg,

disodium edetate-1.105 mcg,

hydrochloric acid 1 M-up to pH 2.8-3.0,

water – up to 11.05 mg

Pharmacological action

Tiotropium bromide-m is a long-acting holinoblokator. The drug has the same affinity for _{M1M5 subtypes of} muscarinic receptors. Inhibition _{of M3} receptors in the airways results in smooth muscle relaxation. The bronchodilating effect depends on the dose and persists for at least 24 hours. A significant duration of action is probably associated with a very slow dissociation of the drug from _{the M3} receptors; the half-dissociation period is significantly longer than that of ipratropium bromide.

When administered by inhalation, 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-holinoblocking side effects. Dissociation from _M2 receptors occurs faster than from _M3 receptors, which indicates a predominance of selectivity for _{the M3} subtype of receptors over _m2 receptors. High affinity for receptors and slow dissociation of the drug from its binding to receptors cause a pronounced and prolonged bronchodilating effect in patients with chronic obstructive pulmonary disease (COPD).

Bronchodilation that develops after tiotropium bromide inhalation is primarily caused by local (on the respiratory tract), and not by systemic action.

In clinical studies, it was shown that the use of Spiriva Respimat 1 time/day leads to a significant improvement (compared to placebo)in lung function (forced expiratory volume in 1 second FEV 1 and forced vital capacity FVC) within 30 minutes after the first dose. Improvement in lung function persists for 24 hours at steady-state concentrations.

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

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

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

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

Spiriva Respimat has been shown to reduce the risk of COPD exacerbation and significantly reduce the number of hospitalizations.

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

Pharmacokinetics

Tiotropium bromide is a quaternary ammonium derivative that is moderately soluble in water. Tiotropium bromide is available as a solution for inhalation, which is used with the Respimat inhaler. Approximately 40% of the inhaled dose is deposited in the lungs, the remaining amount enters the gastrointestinal tract. Some of the pharmacokinetic data described below were obtained when using doses higher than recommended for treatment.

Suction

After inhalation of the solution by young healthy volunteers, it was found that about 33% of the inhaled 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%. _Cmax in plasma is observed 5 minutes after inhalation.

Distribution

Binding of the drug to plasma proteins is 72%; vd-32 l / kg. At the dynamic equilibrium stage, the peak plasma concentration of tiotropium bromide in patients with COPD is 10.5-11.7 pg / ml 10 minutes after use of the drug at a dose of 5 mcg using the Respimat inhaler. At the dynamic equilibrium stage, the lowest plasma concentration was 1.49-1.68 pg / ml. Studies have shown that tiotropium bromide does not penetrate the BBB.

Metabolism

The degree of biotransformation is insignificant. This is confirmed by the fact that after intravenous use of the drug to young healthy volunteers,74% of the substance tiotropium bromide is detected in the urine in unchanged form. Tiotropium bromide is an ester that is broken down into ethanol-N-methylscopine, and dithienylglycolic acid; these compounds do not bind to muscarinic receptors.

In vitro studies have shown that some of the drug ( This mechanism can be inhibited by inhibitors of the CYP 2D6 and 3A4 isoenzymes (quinidine, ketoconazole, and gestodene). Thus, CYP2D6 and 3A4 are involved in drug metabolism. Tiotropium bromide, even in supertherapeutic concentrations, does not inhibit cytochrome P 4501A1,1A2,2B6,2C9,2C19,2D6,2E1OR 3A in human liver microsomes.

Deduction

The terminal T _1/2 of tiotropium bromide after inhalation is 5-6 days. The total clearance after intravenous use of the drug to young healthy volunteers was 880 ml / min, with an individual variability of 22%. Tiotropium bromide after intravenous use is mainly excreted unchanged by the kidneys (74%). After inhalation of the solution, renal excretion is 20.1-29.4%, the remaining unabsorbed part is excreted through the intestine. The renal clearance of tiotropium bromide exceeds that of creatinine, which indicates its tubular secretion. After prolonged inhalation of the drug 1 time/day in patients with COPD, pharmacokinetic equilibrium is reached on day 7; however, no further accumulation is observed.

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

Pharmacokinetics in special clinical cases

In elderly patients

In the elderly, there is a decrease in the renal clearance of tiotropium bromide (326 ml / min in patients with COPD under the age of 58 years and 163 ml / min in patients with COPD over 70 years), which may be due to a decrease in renal function. Urinary excretion of tiotropium bromide after inhalation decreases from 14% in young healthy volunteers to approximately 7% in patients with COPD, but plasma concentrations in elderly patients with COPD did not change significantly, taking into account inter – and intra-individual variability (after inhalation of dry powder, AUC increased by 43%).

In patients with impaired renal function

Mild renal impairment (creatinine clearance 50-80 ml / min), which can be observed in elderly patients, is accompanied by a slight increase in the concentration of tiotropium bromide in plasma (after intravenous infusion, AUC increased by 39%). In patients with COPD and moderate to significant renal impairment (CC

In patients with impaired liver function

It is assumed that hepatic insufficiency does not significantly affect the pharmacokinetics of tiotropium bromide, since tiotropium bromide is mainly excreted by the kidneys.

Indications

As maintenance therapy in patients with COPD, including chronic bronchitis and emphysema (with persistent shortness of breath and to prevent exacerbations).

Use during pregnancy and lactation

Pregnancy

There are no clinical data on the safety and efficacy of Spiriva Respimat during pregnancy.

Preclinical studies have not indicated direct or indirect adverse effects on pregnancy, embryo/fetus development, the delivery process, or postnatal development.

Lactation

There are no clinical data on the safety and efficacy of tiotropium bromide during breastfeeding.

The drug should not be used in pregnant or breast-feeding women, unless the potential benefit to the mother outweighs the potential risk to the fetus and child. During the period of use of the drug, it is necessary to stop breastfeeding the child.

Contraindications

Age up to 18 years, hypersensitivity to the components of the drug Spiriva.

Side effects

From the digestive tract: dry mouth (usually mild, often disappears with continued treatment), constipation.

From the respiratory system: cough, local irritation, possible development of bronchospasm, as well as when taking other inhaled drugs.

Others: tachycardia, difficulty or delayed urination (in men with predisposing factors), angioedema, blurred vision, acute glaucoma (associated with anticholinergic effects).

Interaction

Concomitant use with other anticholinergic agents is not recommended.

It is possible to use tiotropium bromide in combination with other drugs commonly used for the treatment of COPD, such as sympathomimetics, methylxanthines, oral and inhaled steroids.

How to take, course of use and dosage

The recommended therapeutic dose is 2 inhaled doses of Respimat inhaler spray (5 mcg/dose) 1 time / day, at the same time of day.

In elderly patients, patients with impaired liver function and patients with minor renal impairment (creatinine clearance 50-80 ml / min).

You can use the drug Spiriva Respimat in the recommended dose.

However, the use of the drug in patients with moderate or significant renal impairment (creatinine clearance less than 50 ml/min) should be carefully monitored.

Overdose

Symptoms: possible dry mouth, poor accommodation, increased heart rate.

Treatment: symptomatic therapy.

Special instructions

The drug Spiriva Respimat, as a bronchodilator used 1 time/day for maintenance treatment, should not be used as an initial therapy for acute attacks of bronchospasm, that is, in urgent cases.

Immediate hypersensitivity reactions may occur after use of the drug.

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

Inhalation of the drug may cause bronchospasm.

With moderate or severe renal insufficiency (CC

Before starting use, patients should be familiar with the instructions for use.

Do not allow the solution or aerosol to get into the eyes. Pain or discomfort in the eyes, blurred vision, visual halos in combination with redness of the eyes, swelling of the conjunctiva and cornea can be symptoms of acute angle-closure glaucoma. If any combination of these symptoms develops, you should immediately consult a specialist. Eye drops that have a myotic effect are not considered an effective treatment.

Spiriva Respimat should not be used more than once a day.

Spiriva cartridges should only be used with the Respimat inhaler.

Influence on the ability to drive motor vehicles and manage mechanisms

Studies on the effect on the ability to drive vehicles and mechanisms have not been conducted. Caution should be exercised when performing these activities, as dizziness or blurred vision may develop.

Form of production

Spiriva solution for inhalation.

Storage conditions

At a temperature not exceeding 25 °C (do not freeze). Do not freeze.

Active ingredient

Tiotropium bromide

Conditions of release from pharmacies

By prescription

Dosage form

solution for inhalation

Purpose

Adults as prescribed by a doctor

Indications

Bronchial Asthma, Bronchitis, Low learning rate