Tiotropium-native - instructions for use, dose, side effects, contraindications

Active substanceTiotropium bromideTiotropium bromide

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Spiriva®

capsules d / inhal.

Boehringer Ingelheim International GmbH Germany

Spiriva® Respimat®

solution d / inhal.

Boehringer Ingelheim International GmbH Germany

Tiotropium-native

capsules d / inhal.

NATIVA, LLC Russia

Dosage form: & nbspTOapsules with powder for inhalation.

Composition:For 1 capsule:

Active substance:
Tiotropium bromide monohydrate	22.5 μg
(in terms of tiotropium)	(18 μg)
Excipients:
Sodium benzoate	20 mcg
Lactose Monohydrate	10 mg
Capsules, hard №3:
Hypromellose	100%

Description:

Solid capsules №3, transparent, colorless, with a slightly yellowish tinge. The contents of capsules are white or almost white powder.

Pharmacotherapeutic group:m-holinoblokator

ATX: & nbsp

R.03.B.B Holinblockers

R.03.B.B.04 Tiotropium bromide

Pharmacodynamics:

Tiotropium-native - m-holinoblokator long-term action. Has the same affinity for different subtypes of muscarinic receptors from M₁ up to M₅. The result of inhibition of M₃-receptors in the respiratory tract is the relaxation of smooth muscles. The bronchodilator (bronchodilating) effect is maintained for at least 24 hours and depends on the dose of tiotropium bromide. The considerable duration of action is probably connected with the very slow dissociation of tiotropium bromide from M₃receptors compared to ipratropium bromide.With the inhalation route of administration tiotropium bromide as NA quadruple anticholinergic agent has a local selective effect, while at therapeutic doses it does not cause systemic m-cholinoblocking undesirable reactions. Dissociation of tiotropium bromide from M₂-receptors is faster than from M₃. High affinity for receptors and slow dissociation cause a pronounced and prolonged bronchodilator effect in patients with chronic obstructive pulmonary disease (COPD). Bronchodilation after inhalation of tiotropium bromide is a consequence of local, not systemic effect.

Tiotropium bromide significantly increases lung function (volume of forced expiratory in 1 second - FEV₁ forced vital capacity of the lungs - FVC) 30 minutes after a single dose for 24 hours. Pharmacodynamic equilibrium is achieved during the first week, and pronounced bronchodilator effect is observed on the third day.

Tiotropium bromide significantly increases the morning and evening peak flow rate of expiration (PSV). The use of tiotropium bromide during the year does not cause a decrease in effectiveness with regard to bronchodilation.

Tiotropium bromide significantly reduces shortness of breath throughout the treatment period, significantly improves exercise tolerance, significantly reduces the number of exacerbations of COPD and prolongs the period before the first exacerbation, and significantly reduces the number of hospitalizations associated with exacerbation of COPD, and increases the time until the first hospitalization . Tiotropium bromide leads to a sustained improvement of FEV₁ after applying for four years without changing the rate of annual decline in FEV_1.

There are data on reducing the risk of death at 16% during treatment with tiotropium bromide, as well as data on the increase in time to the first exacerbation with a decrease in the risk of exacerbations by 17% with tiotropium bromide compared with salmeterol.

Also, taking tiotropium bromide increases the time until the onset of the first severe (requiring hospitalization) exacerbation, reduces the annual number of medium or severe (requiring hospitalization) exacerbations.

Pharmacokinetics:

Suction

In the inhalation mode of administration, the absolute bioavailability of tiotropium bromide is about 19%,which indicates a high bioavailability of the fraction of the active substance reaching the lungs. The maximum concentration of tiotropium bromide in blood plasma (C_mOh) after inhalation is achieved in 5-7 minutes. FROM_mOhtiotropium bromide in blood plasma in an equilibrium state in patients with COPD is about 12 pg / ml and rapidly decreases, indicating a multi-compartmental distribution type of tiotropium bromide. In the equilibrium state, the basal concentration of tiotropium bromide in the blood plasma is about 1.71 pg / ml.

Distribution

The binding of tiotropium bromide to plasma proteins is 72% of the dose taken, the volume of distribution is 32 l / kg.

Tiotropium bromide does not penetrate the blood-brain barrier.

Metabolism

The degree of biotransformation is insignificant. Tiotropium bromide is subjected to non-enzymatic cleavage by ether bonds to ethanol-N-methylskopine and dithienylglycolic acid, which do not bind to muscarinic receptors. Tiotropium bromide (<20% of the dose after intravenous administration) is metabolized by cytochrome P₄₅₀, this process depends on oxidation and subsequent conjugation with glutathione with formation ofvarious metabolites. Metabolic disorders can occur with the use of inhibitors of isoenzymes CYP2D6 and CYP3A4 (quinidine, ketoconazole and gestodene). Thus, isoenzymes CYP2D6 and CYP3A4 are included in the metabolism of tiotropium bromide. Tiotropium bromide even in super therapeutic concentrations does not inhibit isoenzymes CYP1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes.

Excretion

The half-life (T₁_/₂) tiotropium bromide after inhalation varies from 27 to 45 hours. The total clearance for intravenous administration of healthy volunteers is 880 ml / min. Tiotropium bromide after intravenous administration, is basically excreted by the kidneys in unchanged form - 74%. After inhalation, renal excretion in the equilibrium state is 7% per day from the dose, the remaining non-sucked part is excreted through the intestine. The renal clearance of tiotropium bromide exceeds the creatinine clearance that; indicates the tubular secretion of tiotropium bromide. After long-term administration of tiotropium bromide, once a day in patients with COPD, pharmacokinetic equilibrium is reached on day 7, with no cumulation observed.

Tiotropium bromide has a linear pharmacokinetics within therapeutic limits.

Pharmacokinetics the separate patient groups

Older and older patients

Older and older patients experience a decrease in renal clearance of tiotropium bromide (365 ml / min in patients with COPD <65 years to 271 ml / min in patients with COPD ≥ 65 years of age). These changes do not lead to a corresponding increase in the area under the pharmacokinetic curve "concentration-time" (AUC_0-6_h) or FROM_m_Oh.

Patients with impaired renal function

In patients with COPD and mild renal insufficiency (creatinine clearance (CK) of 50-80 ml / min), the inhalational application of tiotropium bromide once a day in an equilibrium state leads to an increase in the value AUC_0-6_h on 1,8-30%. The value of C_mOh remains the same as in patients with normal renal function (CC> 80 ml / min). In patients with COPD and moderate or severe renal failure (CK <50 mL / min), intravenous tiotropium bromide leads to a twofold increase in plasma concentration (AUC_0-4hincreases by 82%, and the value FROM_m_Oh - by 52%) compared with patients with COPD and normal renal function.A similar increase in the concentration of tiotropium bromide in the blood plasma is observed after inhalation.

Patients with hepatic impairment

It is suggested that liver failure does not have a significant effect on the pharmacokinetics of tiotropium bromide, since it is mainly excreted by the kidneys and by the non-enzymatic cleavage of the ester bonds to the formation of metabolites that do not bind to muscarinic receptors.

Indications:

Supportive therapy in patients with COPD, including chronic bronchitis and pulmonary emphysema (maintenance therapy with persistent dyspnea and to prevent exacerbations).

Contraindications:

- Hypersensitivity to atropine or its derivatives (including ipratropium and oxytropium) and / or to other components of the drug (in particular, to lactose monohydrate, which contains milk protein, with lactase deficiency, lactose intolerance, glucose-galactose malabsorption).

- I trimester of pregnancy.

- atozrast to 18 years.

Carefully:

It should be used with caution Tiotropium-native patients with diseases such as angle-closure glaucoma, obstruction of the neck of the bladder, prostatic hyperplasia.

When using the drug Tiotropium-native patients with moderate to severe renal insufficiency (CC <50 mL / min) should be closely monitored.

Pregnancy and lactation:

Data on the use of tiotropium bromide in pregnancy in humans are limited. In animal studies, no indication of direct or indirect adverse effects on pregnancy, embryo / fetal development, delivery process or postnatal development has been obtained.

As a precaution, it is preferable to refrain from using tiotropium bromide during pregnancy.

There are no clinical data on the use of tiotropium bromide in breast-feeding women. Pre-clinical studies have shown that a small amount of tiotropium bromide is excreted into breast milk.

Tiotropium-native should not be used in pregnant or lactating^: breast of women, unless the expected benefit does not exceed the possible risk to the fetus or child.

Dosing and Administration:

Tiotropium-native prescribe in the form of inhalations one capsule per day at the same time with the aid of an inhaler "Inhaler CDM®".

The drug should not be swallowed.

Tiotropium-native should not be used more than once a day.

Older and older patients and patients with impaired renal or hepatic function may take the drug Tiotropium-native in recommended doses. However, careful monitoring of patients with moderate or severe renal failure receiving Tiotropium-native in combination with other drugs that are mainly excreted by the kidneys.

Instructions for use of the inhaler Inhaler CDM®"

Inhaler "Inhaler CDM®" - a plastic device with a movable top and with a retractable compartment for the capsule, a height of about 6 see "Inhaler CDM "is a single-dose inhaler that allows you to dose and inhale the drug in very small doses. Tiotropium-native falls into the patient's airway along with the air streams when performing an active breath through the mouthpiece. Capsules of the preparation Tiotropium-native It is necessary to use only with the inhaler "Inhaler CDM® ", in order to ensure the correct dosage of the drug.

Inhaler "Inhaler CDM®" very easy to use. When using it, follow the step-by-step instructions below:

Step 1.

Remove the transparent cap from the device "Inhaler CDM "(Fig. 1).

Step 2.

Hold the device firmly with one hand, with the index finger and the thumb of the other hand, open the capsule compartment (Figure 2). To do this, press the index finger on "PUSH" in the moving part of the device "Inhaler CDM ", moving the compartment in the opposite direction.

Step 3.

Hold the device with one hand, insert the capsule with the drug into the compartment of the compartment (Figure 3).

Step 4.

Make sure that the capsule is correctly inserted into the socket (Figure 4).

Step 5.

Holding the device "Inhaler CDM " in the vertical position, close the compartment by pressing the thumb in the opposite direction until it stops, until a click is heard (Fig. 5).

Step 6.

Hold the device "Inhaler CDM® "is strictly vertical (Fig. 6).

Step 7.

Bring the device "Inhaler CDM® "to the working state (Figure 7) by pressing firmly on the mouthpiece so that the arrow on the body disappears from the bottom of the device to the top line, then release the mouthpiece to return it to its original position. puncture capsule, opening access to the drug in the lumen of the mouthpiece.

Step 8.

Exhale before inhalation (Fig. 8). Do not exhale through the mouthpiece!

Step 9.

Gently squeeze the mouthpiece device "Inhaler CDM® "with your teeth, tightly grasp it with your lips and take a deep and strong breath through your mouth (Figure 9), you will hear a vibrating sound inside the capsule compartment, emitted by the capsule while rotating and dispersing the drug. Hold your breath for about 10 seconds or longer, Remove the device from the mouth, Slowly exhale, then breathe normally.

The mouthpiece should not be chewed and clenched with teeth!

Repeat steps 8-9 again to ensure that the dose of the drug is inhaled.

Step 10.

After the inhalation, open the capsule compartment (Figure 2), remove the empty capsule, and then close it (Figure 5).

Attention:

When carrying out inhalation try not to cover the holes, located on the sides of the mouthpiece. This can interfere with the free movement of air within the inhaler, thereby reducing the dispersion of the contents of the capsule.

Do not press on the mouthpiece when inhaled. This can block the movement of the capsule.

Always close the container after use "Inhaler CDM® "cap, this will allow keep the mouthpiece clean. Regularly (once a week), you should clean the mouthpiece from the outside with a dry cloth.

Side effects:

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. The frequency of occurrence of undesirable reactions is estimated as follows: "very often" -> 10%; "often" -> 1% and < 10%, "infrequently" -> 0,1% and < 1%, "rarely" -> 0,01% and < 0,1%, "very rarely" - < 0,01%, including individual messages, and "frequency unknown."

Immune system disorders: rarely - urticaria, reactions hypersensitivity, including immediate-type reactions, angioedema (Quincke's edema); frequency unknown - anaphylactic reactions.

Disorders from the metabolism and nutrition: frequency unknown - dehydration. Disorders from the nervous system: infrequently - dizziness, headache, a taste disorder; rarely - insomnia.

Disturbances on the part of the organ of sight: infrequently - blurred vision; rarely - increased intraocular pressure, glaucoma.

Heart Disease: infrequently atrial fibrillation; rarely - tachycardia (including supraventricular tachycardia), palpitations.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - dysphonia, cough, pharyngitis; rarely - paradoxical bronchospasm, laryngitis, sinusitis, nosebleeds.

Disorders from the gastrointestinal tract: often - dry mouth, usually mild; infrequently - constipation, gastroesophageal reflux, oropharyngeal candidiasis; rarely - nausea, stomatitis, gingwit, glossitis, intestinal obstruction, including paralytic ileus, dysphagia; frequency unknown - caries.

Disturbances from the skin and subcutaneous tissues: infrequently - rash; rarely - itching; frequency unknown - infectious skin diseases, skin ulcers, dry skin.

Disturbances from musculoskeletal and connective tissue: frequency unknown swelling of the joints.

Disorders from the kidneys and urinary tract: infrequently - difficulty urinating and delayed urination (in men with predisposing factors), dysuria; rarely - Urinary tract infection.

If any of the unwanted reactions listed in the manual is aggravated, or if you notice any other undesirable reactions not listed in the instructions, inform the doctor about it.

Overdose:

When high doses of tiotropium bromide are used, minor manifestations of systemic anticholinergic action are possible.

However, systemic anticholinergic adverse reactions were not detected after a single inhalation application of tiotropium bromide in a dose of up to 340 μg by healthy volunteers. When tiotropium bromide was used in a dose up to 170 μg in healthy volunteers, no corresponding adverse reactions were observed for 7 days, except for dry mouth.

There are data that when tiotropium bromide was used in patients with COPD at a maximum daily dose of 43 μg for more than 4 weeks, no significant adverse reactions were observed.

Acute intoxication associated with accidental ingestion of capsules is unlikely in view of the low bioavailability of tiotropium bromide.

Interaction:

Possible use of the drug Tiotropium-native in combination with other drugs commonly used to treat COPD: sympathomimetics, methylxanthines, oral and inhaled glucocorticosteroids.

Joint application with long-acting β₂-adrenomimetics, inhaled glucocorticosteroids and their combinations does not affect the effect of tiotropium bromide.

Permanent joint use of other anticholinergic drugs and drug Tiotropium-native was not studied and, therefore, not recommended.

Special instructions:

Tiotropium-native as a bronchodilator, used once a day for maintenance treatment, is not intended for initial therapy in acute attacks of bronchospasm, i.e. in urgent cases.

After inhalation of the drug Tiotropium-native immediate hypersensitivity reactions may develop. Like other inhaled drugs, Tiotropium-native can cause a paradoxical bronchospasm.

Patients should be familiar with the use of the capsules of the drug Tiotropium-native with the aid of an inhaler.

Do not let the powder get into the eyes. Pain in the eye or discomfort, blurred vision, visual aureoles in combination with red eyes, conjunctival stasis and corneal edema may indicate an acute attack of angle-closure glaucoma. When developing any combination of these symptoms, you should immediately consult a doctor. The use of drugs that cause miosis, is not an effective method of treatment in this case.

Tiotropium-native Do not use more than once a day.

Capsules of the preparation Tiotropium-native should be used only with inhaler "Inhaler CDM®".

Application of the drug Tiotropium-native Do not affect the results of doping tests in athletes.

Effect on the ability to drive transp. cf. and fur:

Studies on the effect of the drug Tiotropium - native the ability to drive vehicles and manage mechanisms was not carried out. In case of development of such undesirable reactions as dizziness, headache and blurry vision, it is necessary to refrain from driving vehicles and controlling mechanisms, as well as from engaging in other potentially dangerous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Capsules with powder for inhalation, 18 mcg.

Packaging:

10 capsules in a contour mesh package made of combined and aluminum foil.

By 1, 3 or 6 contour cell packs together with the device for inhalation or without it, the instruction for use is placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 of the year.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription