Spiriva, 2.5 mcg/dose 4 ml (60 doses) cartridges complete with inhaler

Tiotropium bromide is a long-acting m-cholinoblocker. The drug has equal affinity for M ₁ -M ₅ muscarinic receptor subtypes. The result of inhibition of M ₃ -receptors in the airways is relaxation of the smooth muscles. The bronchodilator effect is dose-dependent and lasts for at least 24 hours. The considerable duration of action is probably due to very slow dissociation of the drug from M ₃ -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 at therapeutic doses does not cause systemic m-cholinoblocking side effects. Dissociation from M ₂ -receptors is faster than from M ₃ -receptors, indicating a predominance of selectivity for M ₃ receptor subtype over M ₂ -receptors. High affinity to the receptors and slow dissociation of the drug from binding to the receptors are responsible for the pronounced and prolonged bronchodilator effect in patients with chronic obstructive pulmonary disease (COPD).

The bronchodilation that develops after inhalation of tiotropium bromide is due primarily to local (airway) rather than systemic action.

In clinical studies, Spiriva Respimat once daily has been shown to significantly improve (compared to placebo) lung function (1-second forced expiratory volume SPE1 and forced vital capacity FEL) within 30 minutes of the first dose. The improvement in lung function persists for 24 h at equilibrium concentration.

Pharmacodynamic equilibrium was achieved within one week. Spiriva Respimat significantly improved morning and evening peak expiratory volume velocity (PEFV) measured by patients. Use of Spiriva Respimat led to a decrease (compared with placebo) in the use of a bronchodilator as an emergency aid. The bronchodilator effect of the drug persisted for 48 weeks of use of the drug; no signs of habituation were noted.

A combined data analysis of two randomized, placebo-controlled, crossover clinical trials showed that the bronchodilator effect of Spiriva Respimat (5 mcg) after a 4-week treatment period was quantitatively greater 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 two 12-month studies, and this difference was maintained throughout the treatment period; Spiriva Respimat significantly reduced the number of COPD exacerbations, and increased the time to first exacerbation compared to placebo.

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

In a retrospective analysis of selected clinical trials, a statistically non-significant increase, compared to placebo, in the number of deaths in patients with cardiac rhythm disturbances was observed. However, these findings are not statistically confirmed and may be related to heart disease.

Pharmacokinetics

Tiotropium bromide is a quaternary ammonium derivative that is moderately water soluble. Tiotropium bromide is available as an inhalation solution, which is used with the Respimat inhaler. Approximately 40% of the inhaled dose is deposited in the lungs and the remainder enters the gastrointestinal tract. Some of the pharmacokinetic data described below have been obtained using doses in excess of those recommended for treatment.

Absorption

After inhalation of the solution in young healthy volunteers, approximately 33% of the inhaled dose was found to enter the systemic circulation. Food intake does not affect absorption of tiotropium bromide, due to the fact that it is poorly absorbed from the gastrointestinal tract. Absolute bioavailability when oral administration is 2-3%. C _max in plasma is observed 5 min after inhalation.

Distribution

The drug’s binding to plasma proteins is 72%; V _d is 32 l/kg. At the stage of dynamic equilibrium the peak plasma concentration of tiotropium bromide in patients with COPD is 10.5-11.7 pg/ml in 10 min after the use of the drug in a dose of 5 mcg using 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 through the HEB.

Metabolism

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

In in vitro studies it has been shown that some portion of the drug (< 20% of the dose after IV administration) is metabolized by cytochrome P450 oxidation followed by conjugation with glutathione to form various metabolites. This mechanism can be inhibited by inhibitors of CYP 2D6 and 3A4 isoenzymes (quinidine, ketoconazole and gestoden). Thus, CYP2D6 and 3A4 are involved in the metabolism of the drug. Tiotropium bromide does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes even in supertherapeutic concentrations.

Elimination

The terminal T _1/2 of tiotropium bromide after inhalation is 5-6 days. Total clearance after IV administration to young healthy volunteers was 880 mL/min, with an individual variability of 22%. Tiotropium bromide after IV administration 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. Renal clearance of tiotropium bromide exceeds creatinine clearance, indicating its tubular secretion. After long-term inhaled administration of the drug once daily in patients with COPD, pharmacokinetic equilibrium is reached on day 7; no further cumulation is observed.

Tiotropium bromide has linear pharmacokinetics within therapeutic limits after IV administration, inhalation of dry powder and inhalation of solution.

Pharmacokinetics in special clinical cases

In elderly patients

In the elderly, there is decreased renal clearance of tiotropium bromide (326 mL/min in patients with COPD under 58 years of age and 163 mL/min in patients with COPD over 70 years), which may be due to decreased renal function. Urinary excretion of tiotropium bromide after inhaled administration decreased from 14% in young healthy volunteers to approximately 7% in COPD patients, but plasma concentrations in elderly COPD patients were not significantly altered when inter- and intraindividual variability were considered (AUC increased by 43% after inhalation of dry powder).

In patients with impaired renal function

Small renal dysfunction (CK 50-80 ml/min), which may be seen in elderly patients, is accompanied by a slight increase in plasma concentration of tiotropium bromide (AUC increased by 39% after intravenous infusion). In patients with COPD and moderate or significant renal impairment (CK < 50 ml/min), intravenous administration of tiotropium bromide resulted in a twofold increase in plasma concentration (AUC increased by 82%); a similar increase in plasma concentration was observed after inhalation of dry powder.

In patients with impaired hepatic function

Hepatic impairment is not thought to have a significant effect on the pharmacokinetics of tiotropium bromide since tiotropium bromide is primarily excreted by the kidneys.

Indications

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

Active ingredient

Composition

In 1 dose of inhalation solution contains:

Active ingredient:

Tiotropium bromide monohydrate is 3.1235 µg, which corresponds to a tiotropium content of 2.5 µg.

Auxiliary substances:

benzalkonium chloride – 1.105 µg,

dinatrium edetate – 1.105 µg,

Hydrochloric acid 1M – up to pH 2.8 – 3.0,

water – up to 11.05 mg.

How to take, the dosage

The recommended therapeutic dose is 2 inhalation doses of Respimat Inhaler Spray (5 mcg/dose) once daily, at the same time of day.

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

Spiriva Respimat can be used in the recommended dose.

However, use of the drug in patients with moderate to significant impaired renal function (CKI less than 50 mL/min) should be monitored closely.

Interaction

The simultaneous use with other anticholinergic agents is not recommended.

Tiotropium bromide may be used in combination with other drugs commonly used to treat COPD – sympathomimetics, methylxanthines, oral and inhaled steroids.

Special Instructions

Spiriva Respimat, as a once-daily bronchodilator for maintenance treatment, should not be used as initial therapy for acute attacks of bronchospasm, i.e. in emergency cases.

After using the drug, immediate hypersensitivity reactions may develop.

Spiriva Respimat, like other m-cholinoblocking agents, should be used with caution in patients with closed-angle glaucoma, prostatic hyperplasia or bladder cervical obstruction.

Inhalation of the drug may cause bronchospasm.

In moderate to severe renal insufficiency (CK < 50 ml/min), administration of the drug should be closely monitored, as with all drugs that are excreted primarily by the kidneys.

Patients should read the instructions for use before initiating use.

The solution or aerosol should not be allowed to come into contact with the eyes. Pain or discomfort in the eyes, blurred vision, visual halos combined with red eyes, and conjunctival and corneal edema may be symptoms of acute closed angle glaucoma. If any combination of these symptoms develops, see a specialist immediately. Myotic eye drops are not considered an effective treatment.

Spiriva Respimat should not be used more frequently than once daily.

The Spiriva Respimat cartridges must only be used with the Respimat inhaler.

Impact on driving and operating machinery

There have been no studies to study the effect on driving and operating machinery. Caution should be exercised when performing these activities as dizziness or blurred vision may occur.

Contraindications

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

Side effects

Gastrointestinal system: dry mouth (usually mild, often disappears with continued treatment), constipation.

Respiratory system: cough, local irritation, bronchospasm may develop, as with other inhalants.

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

Overdose

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

Treatment: symptomatic therapy.

Pregnancy use

Pregnancy

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

There have been no indications of direct or indirect adverse effects on pregnancy, embryo/fetal development, the birth process, or postnatal development in preclinical studies.

Lactation

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

The drug should not be used in pregnant or lactating women unless the potential benefit to the mother exceeds the potential risk to the fetus and child. Breastfeeding of the child should be stopped during the period of use of the drug.

Similarities