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Pharmacological properties

mechanism of action. tiotropium is a specific long-acting anticholinergic agent. tiotropium has a similar affinity for all subtypes of muscarinic receptors (from m1 to m5). in the respiratory tract, inhibition of m3 receptors causes relaxation of smooth muscles. in preclinical studies in vitro and in vivo, the bronchoprotective effect was dose-dependent and lasted more than 24 hours.

The duration of the effect is due to a very slow release from M3receptors; T½ tiotropium is much larger than ipratropium. As N-Quaternary anticholinergic tiotropium is local (broncho) selective for inhalation use, it demonstrates an acceptable therapeutic range for the detection of systemic anticholinergic effects. Dissociation from M2receptors is faster than that of M3 in functional studies in vitro. M3 - a more acceptable (kinetically controlled) selectivity subtype receptor than M2. High activity and slow dissociation from receptors are clinically correlated with significant and prolonged bronchodilation in patients with chronic obstructive pulmonary disease (COPD).

Pharmacodynamic effects. Bronchodilation after inhalation, tiotropium, in the first place, is a local effect on the respiratory tract, and not a systemic one.

When using the drug Spiriva once a day, a significant improvement in lung function was noted (an increase in forced expiratory volume in 1 second (FEV1) and forced vital lung capacity (VC) for 30 minutes after the 1st dose, the effect lasted 24 hours. A pharmacodynamic stable state is achieved within 1 week. In most patients, bronchodilation occurs on the 3rd day.

According to daily measurements, Spiriva significantly improves morning and evening maximum expiratory flow. Improvement in lung function persists without signs of tolerance. Bronchodilation lasts for a 24-hour dosing interval compared to placebo. It was not taken into account; Spiriva was prescribed in the morning or in the evening.

Spiriva significantly reduces shortness of breath; improvement continued throughout the treatment period.

Spiriva significantly reduces the number of exacerbations of COPD and increases the period of time until the onset of the first exacerbation. The use of the drug significantly improves the quality of life; improvement was maintained throughout the treatment period. Spiriva significantly reduces the number of hospitalizations of patients with exacerbations of COPD and delays the time of the first hospitalization.

In two studies, Spiriva significantly improved exercise tolerance, limited by the symptoms of the disease, by 19.7 and 28.3%. In the study, the use of the drug at 18 and 54 μg (3 times 18 μg) for 12 days did not cause an extension of the Q – T interval in terms of ECG.

In a 4-year study involving 5993 patients, Spiriva supported an improvement in FEV1 over the entire period, which, however, did not change the annual rate of decrease in FEV1.

During treatment, the risk of mortality decreased by 16%. The overall mortality rate was 4.79 per 100 patient-years in the placebo group compared with 4.10 per 100 patient-years in the tiotropium group (risk ratio (tiotropium / placebo) 0.84, 95% confidence interval (CI) 0 , 73–0.97). Tiotropium treatment reduced the risk of respiratory failure by 19% (2.09 compared with 1.68 cases per 100 patient-years, relative risk (tiotropium / placebo) 0.81; 95% CI 0.65–1.00).

Pharmacokinetics Tiotropium is a quaternary ammonium compound that is moderately soluble in water. Tiotropium is used in the form of a dry powder for inhalation. As a rule, with the inhalation method of administration, most of the released dose settles in the digestive tract, and a smaller one in the lungs.

Absorption.After inhalation of the dry powder, the absolute bioavailability is 19.5%, which is a sign of the high bioavailability of the fraction reaching the lungs. The absolute bioavailability of r-ra tiotropium for oral administration is 2-3%. Cmax plasma tiotropia is achieved 5-7 minutes after inhalation.

When stable, the maximum level of tiotropium in the blood plasma of patients with COPD is 12.9 pg / ml and rapidly decreases in a multistage manner. The lower level of tiotropium concentration in blood plasma at a stable state reaches 1.71 pg / ml. Systemic exposure after inhalation of tiotropium via HandyHeiler devices was similar to exposure after inhalation of tiotropium through Respimat inhaler.

Distribution. 72% of the drug binds to plasma proteins. The volume of distribution is 32 l / kg. The local concentration in the lungs is unknown, but, based on the method of application, a high concentration in the lungs is assumed. Animal studies have shown that tiotropium does not penetrate the BBB in a significant volume.

Biotransformation. The degree of biotransformation is small, since 74% of the unchanged substance was excreted in the urine after iv administration to healthy volunteers. Tiotropium as an ester decomposes non-enzymatically to N-methylscopicine alcohol and dithienyl glycolic acid, which do not bind to muscarinic receptors.

Further, according to in vitro studies, on the microsomes of the liver and hepatocytes, tiotropium (20% of the dose after iv administration) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to various phase II metabolites. This enzyme chain can be inhibited by CYP 450 2D6 (and 3A4) inhibitors, quinidine, ketoconazole and gestodene. These CYP 450 2D6 and 3A4 are involved in metabolic transformations, which are responsible for the elimination of a smaller part of the dose. Tiotropium even in supra-therapeutic concentrations does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A on liver microsomes.

Elimination. Effective T½ occurs between the 27th and 45th hour in patients with COPD. The total clearance was 880 ml / min after iv administration to young healthy volunteers. After iv administration of tiotropium, it is mainly excreted in the urine unchanged. After inhalation of the dry powder, excretion in urine is 7% (1.3 μg) of unchanged amount for 24 hours, the remainder is not absorbed in the intestine and excreted in the feces. Renal clearance of tiotropium exceeds creatinine clearance, which indicates excretion in the urine. After constant daily inhalation in patients with COPD, a pharmacokinetically stable state is reached after 7 days without subsequent cumulation.

Linearity / nonlinearity. Tiotropium demonstrated linear pharmacokinetic properties in the therapeutic range regardless of the dosage form.

Pharmacokinetics in elderly patients. As with all other drugs, which are mainly excreted in the urine, the use of tiotropium in elderly patients reduces renal clearance (365 ml / min in patients with COPD 65 years old compared with 271 ml / min in patients with COPD ≥65 years old ) This will not result in a corresponding increase in AUC values.0–6,ss or Cmax,ss.

Pharmacokinetics in patients with impaired renal function. After inhalation administration, tiotropium 1 time per day in patients with COPD in equilibrium with mild renal impairment (creatinine clearance 50–80 ml / min) showed a slight increase in AUC values0–6,ss (1.8–30%) and similar indicators Cmax compared with patients with normal renal function (creatinine clearance 80 ml / min).

In patients with COPD with moderate or severe impaired renal function (creatinine clearance of 50 ml / min), iv administration of tiotropium leads to a doubling of the total exposure (AUC0–4 h 82% higher and Cmax 52% higher) compared with patients with normal renal function, as evidenced by data on plasma concentrations after dry powder inhalation.

Pharmacokinetics in patients with impaired liver function. Hepatic insufficiency does not significantly affect the pharmacokinetics of tiotropium. Tiotropium is mainly secreted by renal elimination (up to 74% in healthy young volunteers) and by simple non-enzymatic breakdown of ether to products that do not bind to muscarinic receptors.

COPD patients in the Japanese population. During cross comparison, the average Cmax plasma tiotropia 10 minutes after dosing in equilibrium was 20–70% higher in Japanese patients compared to Europeans after inhalation tiotropium, but no signs of increased mortality or risk of heart complications in Japanese patients compared with Europeans . For other races or ethnic groups, there is insufficient pharmacokinetic data.

The relationship of pharmacokinetics / pharmacodynamics. There is no direct relationship between pharmacokinetics and pharmacodynamics.


Supportive bronchodilator therapy to relieve symptoms in a host.


The drug is intended for inhalation use only.

The recommended dose of Spiriva consists of inhaling the contents of 1 capsule 1 time per day using the HandyHeiler inhalation device. Inhalation should be done at the same time of day.

The recommended dose should not be exceeded. Capsules are not intended for oral use; Spiriv capsules cannot be swallowed.

The drug should be used only with the HandyHeiler inhalation device.

Special groups

Elderly patients should use Spiriva only at the dose recommended by the doctor.

Patients with renal failure should take Spiriva according to the dose recommended by the doctor. Information on the use of the drug in patients with moderate to severe renal failure (creatinine clearance ≤50 ml / min) is given in the SPECIAL INSTRUCTIONS and Pharmacokinetics sections.

Spiriva can be used in patients with hepatic insufficiency according to the dose recommended by the doctor (see Pharmacokinetics).

Instructions for use. To ensure proper use of the drug, it is necessary to inform the patient how to use the inhaler.

When using the drug Spiriva should adhere to the recommendations of the doctor.

HandyHailer inhalation device was developed specifically for Spiriv capsules. It should not be used with other medicines.

Handyheiler can be used for 1 year, using it as intended.

1. To open the dust cap, press the spray button all the way and release.

2. Open the dust cap by lifting it up.

Then open the mouthpiece by lifting it up.

3. Remove the Spiriva capsule from the blister (just before use) and place it on a platform with a central camera. It doesnt matter which side the capsule is placed in.

4. Close the mouthpiece tightly until it clicks, leave the dust cap open.

5. Hold HandyHailer with the mouthpiece up and press the spray button all the way once and release. This makes holes in the capsule shell and allows the medicine to be released by inhalation.

6. Exhale completely.

Important: do not exhale into the mouthpiece in any case.

7. Lift the HandyHeyler device to your mouth and grip the mouthpiece tightly with your lips. Keep your head straight and inhale slowly and deeply, but in such a way as to hear or feel the vibration of the capsule.

Inhale until the lungs are full; then hold your breath for as long as possible and at the same time remove the mouthpiece from your mouth.

Resume breathing.

Repeat steps 6 and 7 to completely empty the capsule.

8. Open the mouthpiece again. Remove used capsule and discard.

Close the mouthpiece and dust cap for storing the HandyHeiler device.

Handy Heiler device cleaning

Handyheiler needs to be cleaned once a month.

Open the dust cap and mouthpiece. Then open the base by raising the spray button. Rinse the entire inhaler with warm water to remove the powder. Thoroughly dry the HandyHeiler device by blotting the remaining water with a paper towel and air drying, leaving the dust cap, mouthpiece and base open. Air drying takes 24 hours, therefore, cleaning should begin immediately after use, so that the device is ready for the next use.

If necessary, the mouthpiece can be cleaned externally with a damp but not wet cloth.

Blister Disclosure

A. Separate the blister strip by tearing along the perforation.

B. Open (just before use) to the words “Stop”. If another capsule was accidentally opened, then it should be discarded.

C. Take out the capsule.

Spiriv capsules contain a small amount of powder, so the capsule is only partially filled.


Spiriva inhalation powder is contraindicated in patients with a known hypersensitivity to tiotropium bromide, atropine or its derivatives (ipratropium or oxytropium) or other components of the drug.

Side effects

Many of these side effects can be attributed to the anticholinergic properties of Spiriva.

Adverse reactions to the drug were determined according to data obtained from clinical studies and from spontaneous reports during the post-registration period. The clinical trial database includes 9647 patients who received tiotropium in 28 placebo-controlled clinical trials with a treatment period of 4 weeks to 4 years.

Incidence of adverse reactions in accordance with the MedDRA Convention: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); single (≥1 / 10,000, 1/1000); very rarely (1/10 000); unknown (impossible to determine from the available data).

From the side of metabolism: unknown - dehydration.

From the side of the central nervous system: infrequently - dizziness, headache, violation of taste sensations; single - insomnia.

From the side of the organ of vision: infrequently - blurred vision; single - glaucoma, increased intraocular pressure.

From the cardiovascular system: infrequently - atrial fibrillation; single - supraventricular tachycardia, tachycardia, palpitations.

From the respiratory system, chest and mediastinal organs: infrequently - cough, dysphonia, pharyngitis; single - bronchospasm, nosebleeds, laryngitis, sinusitis.

From the digestive system: often - dry mouth; infrequently - constipation, gastroesophageal reflux disease, candidiasis of the oral cavity and pharynx; single - bowel obstruction, including paralytic bowel obstruction; dysphagia, gingivitis, glossitis, stomatitis, nausea; unknown - tooth decay.

From the immune system, skin and subcutaneous tissue: infrequently - rash; single - angioedema, hypersensitivity (including immediate allergic reactions), itching, urticaria; unknown - dry skin, skin infections and ulceration, anaphylactic reactions.

From the musculoskeletal system and connective tissue: unknown - swelling of the joints.

From the urinary system: infrequently - urinary retention, dysuria; single - urinary tract infection.

Description of individual adverse reactions. In controlled clinical trials, anticholinergic adverse reactions, such as dry mouth, that occurred in about 4% of patients were usually observed.

In 28 clinical trials, dry mouth led to discontinuation of the drug in 18 (0.2%) of 9647 patients.

Serious side effects include glaucoma, constipation, bowel obstruction, including paralytic bowel obstruction and urinary retention.

Other special populations. The number of anticholinergic effects may increase with age.

special instructions

Spiriva is a bronchodilator, which is prescribed 1 time per day for maintenance therapy, and which is not intended for the initial treatment of acute attacks of bronchospasm.

After using the drug, immediate-type hypersensitivity reactions may occur.

Like other anticholinergics, Spiriv should be used with caution in patients with angle-closure glaucoma, prostatic hyperplasia, or obstruction of the bladder neck (see ADVERSE EFFECTS).

Inhaled drugs can cause inhalation-induced bronchospasm.

The drug should be used with caution in such patients: recent myocardial infarction (6 months); with any unstable or life-threatening arrhythmia or arrhythmia that required intervention or a change in therapy last year; during hospitalization with heart failure (NYHA class III or IV) during the last year. These patients were excluded from clinical trials. Under these conditions, the anticholinergic effect may harm them.

Since plasma concentrations of tiotropium bromide increase in patients with moderate to severe renal insufficiency (creatinine clearance ≤50 ml / min), Spiriva should be used only if the expected benefit outweighs the potential risk. Data on long-term use of the drug in patients with renal failure are absent (see Pharmacokinetics).

Patients should avoid contact with the powder in the eyes. This can lead to worsening of angle-closure glaucoma, pain or discomfort in the eyes, temporary blurred vision, a sensation of the appearance of a halo or colored spots in front of the eyes, combined with redness of the eye in the form of conjunctival or corneal hyperemia.

If these symptoms appear in any combination, you should, without wasting time, seek specialized medical help.

Dry mouth, noted during anticholinergic therapy, may in the future be associated with caries.

Spiriva should not be used more than 1 time per day.

The drug contains 5.5 mg of lactose monohydrate in 1 capsule.

Use during pregnancy and lactation. Pregnancy. Data on the use of tiotropium in pregnant women are very limited. In preclinical studies, no direct or indirect harmful effects were found regarding reproductive toxicity at clinically significant doses. As a precaution, the use of Spiriva should be avoided during pregnancy.

Lactation. It is not known whether tiotropium bromide passes into breast milk. The use of the drug during lactation is not recommended.

Tiotropia bromide is a long-acting compound. The decision to continue / stop breastfeeding or to continue / stop using Spiriva should be made taking into account the assessment of the benefits of breastfeeding for the baby and the benefits of therapy for the mother.

Children. The drug is not intended for use in children.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies of the effect on the ability to drive a car or other mechanisms have not been conducted. Dizziness or blurred vision may affect your ability to drive vehicles or operate mechanical devices.


Despite the fact that formal studies of the interaction with other drugs were not carried out, tiotropium bromide was used simultaneously with other drugs (sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids that are used in the treatment of the host) without clinical evidence of their interaction.

It has not been established that the use of long-acting β-adrenergic receptor agonists or inhaled corticosteroids changes the tiotropium exposure.

However, the use of Spiriva in combination with anticholinergic drugs has not been investigated and, therefore, is not recommended.


High doses of Spiriva may cause anticholinergic symptoms.

However, systemic anticholinergic side effects were absent in healthy volunteers after a single dose up to 340 μg tiotropium bromide.

No serious adverse reactions, other than dry mouth, were observed after 7 days of taking tiotropium bromide up to a dose of 170 mcg in healthy volunteers.

In studies of multiple dosing in patients with COPD, the use of a maximum daily dose of 43 μg tiotropium bromide for 4 weeks did not cause serious adverse reactions.

Acute intoxication with oral administration of capsules, tiotropium is unlikely due to the low oral bioavailability.

Storage conditions

At a temperature not exceeding 25 ° c. Protect from direct sunlight, heat and frost.

Term of use. After the first opening, the blister strip should be used for 9 days.

Tags: Spiriva® [Tiotropia Bromide]