Tiotropium-nativ, 18mcg powder inhalation capsules 30pcs

Composition

Composition for 1 capsule:

Active ingredient:

– Tiotropium bromide monohydrate-22.5 mcg

(in terms of tiotropium) – (18 mcg)

– Excipients:

– Sodium benzoate-20 mcg

-Lactose monohydrate-10 mg

-Solid capsules No. 3:

– Hypromellose – 100%

Pharmacological action

Tiotropium-native-m-long-acting holinoblokator. It has the same affinity for different subtypes of muscarinic receptors from M1 to M5. Inhibition of M3 receptors in the respiratory tract results in smooth muscle relaxation. The bronchodilating (bronchodilating) effect persists for at least 24 hours and depends on the dose of tiotropium bromide.

The significant duration of action is probably due to the very slow dissociation of tiotropium bromide from the M3 receptors compared to ipratropium bromide. When administered by inhalation, tiotropium bromide as an N-quaternary anticholinergic agent has a local selective effect, while at therapeutic doses it does not cause systemic m-holin-blocking adverse reactions.

Dissociation of tiotropium bromide from M2 receptors occurs faster than from M3. High affinity for receptors and slow dissociation cause a pronounced and prolonged bronchodilating effect in patients with chronic obstructive pulmonary disease (COPD). Bronchodilation after tiotropium bromide inhalation is due to a local rather than systemic effect.

Tiotropium bromide significantly increases lung function (forced expiratory volume in 1 second – FEV 1, forced vital capacity of the lungs – FVC) 30 minutes after a single dose for 24 hours.

Pharmacodynamic equilibrium is reached during the first week, and a pronounced bronchodilating effect is observed on the third day. Tiotropium bromide significantly increases the morning and evening peak flow rate of exhalation (PSV). The use of tiotropium bromide for a year does not cause a decrease in the effectiveness of bronchodilation.

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

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

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

Pharmacokinetics

Suction

With the inhaled method of use, the absolute bioavailability of tiotropium bromide is about 19%, which indicates a high bioavailability of the Active ingredient fraction reaching the lungs. The maximum concentration of tiotropium bromide in blood plasma (Cmax) after inhalation is reached in 5-7 minutes. Cmax of tiotropium bromide in blood plasma at steady state in patients with COPD is about 12 pg / ml and rapidly decreases, which indicates a multicompartment type of tiotropium bromide distribution. At steady state, the basal concentration of tiotropium bromide in blood plasma is about 1.71 pg / ml.

Distribution

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

Tiotropium bromide does not cross the blood-brain barrier.

Metabolism

The degree of biotransformation is insignificant. Tiotropium bromide undergoes nonenzymatic cleavage by ether bonds to ethanol-N-methylscopine and dithienylglycolic acid, which do not bind to muscarinic receptors. Tiotropium bromide (

Metabolic disorders may occur when using inhibitors of the CYP2D6 and CYP3A4 isoenzymes (quinidine, ketoconazole, and gestodene). Thus, the isoenzymes CYP2D6 and CYP3A4 are involved in the metabolism of tiotropium bromide. Tiotropium bromide, even in supertherapeutic concentrations, does not inhibit the isoenzymes SUR1A1,1A2,2B6,2C9,2C19,2D6,2E1OR 3A in human liver microsomes.

Deduction

The half-life (T 1/2) of tiotropium bromide after inhalation varies from 27 to 45 hours. Total clearance after intravenous use to healthy volunteers is 880 ml/min. Tiotropium bromide after intravenous use is mainly excreted unchanged by the kidneys-74%. After inhalation, renal excretion at steady state is 7% per day of the dose, the remaining unabsorbed part is excreted through the intestine.

Renal clearance of tiotropium bromide exceeds creatinine clearance, which indicates tubular secretion of tiotropium bromide. After long-term use of tiotropium bromide once a day in patients with COPD, pharmacokinetic equilibrium is reached on day 7, while no accumulation is observed.

Tiotropium bromide has linear pharmacokinetics within therapeutic limits.

Pharmacokinetics in selected groups of patients

Elderly and older patients

In elderly and older patients, there is a decrease in the renal clearance of tiotropium bromide (365 ml / min in patients with COPD < 65 years to 271 ml / min in patients with COPD > 65 years). These changes do not lead to a corresponding increase in the area under the concentration-time pharmacokinetic curve (AUC0-6 h) or Cmax.

Patients with impaired renal function

In patients with COPD and mild renal insufficiency (creatinine clearance 50-80 ml/min), inhaled tiotropium bromide once a day at steady state leads to an increase in AUC0-6 hours by 1.8-30%. The Cmax value remains the same as in patients with normal renal function (creatinine clearance > 80 ml/min).

In patients with COPD and moderate or severe renal insufficiency (CC A similar increase in the concentration of tiotropium bromide in the blood plasma is also noted after inhalation.

Patients with impaired liver function

It is assumed that hepatic insufficiency does not significantly affect the pharmacokinetics of tiotropium bromide, since it is mainly excreted by the kidneys and by non-enzymatic cleavage of ether bonds with the formation of metabolites that do not bind to muscarinic receptors.

Indications

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

Use during pregnancy and lactation

Data on the use of tiotropium bromide in human pregnancy are limited. No direct or indirect adverse effects on pregnancy, embryo/fetal development, the delivery process, or postnatal development have been reported in animal studies.

As a precautionary measure, 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. Preclinical studies have shown that small amounts of tiotropium bromide are excreted in breast milk.

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

Recommendations for use

Tiotropium-native is prescribed in the form of inhalations of one capsule per day at the same time using the inhaler ” Inhaler CDM®”.

The drug should not be swallowed.

Tiotropium-native should be used no more than once a day.

Elderly and older patients and patients with impaired renal or hepatic function can take Tiotropium-native in the recommended doses. However, patients with moderate or severe renal insufficiency receiving Tiotropium native in combination with other drugs that are mainly excreted by the kidneys should be carefully monitored.

Instructions for use of the inhaler ” Inhaler CDM®”.

Inhaler CDM® inhaler is a plastic device with a movable upper part and a retractable capsule compartment, about 6 cm high. Inhaler CDM® is a single-dose inhaler that allows you to dose and inhale the drug in very small doses.Tiotropium native enters the patient’s respiratory tract along with air flows when performing active inhalation through the mouthpiece. Tiotropium-native capsules should only be used with the inhaler ” Inhaler CDM®”, in order to ensure the correct dosage of the drug.

The Inhaler CDM® inhaler is very easy to use. When using

it, follow the step-by-step instructions below:

Remove the transparent cap from the Inhaler CDM® device as shown in Figure 1.

Hold the device firmly in one hand, and use your index finger and thumb to open the capsule compartment, as shown in Fig. 2. To do this, use your index finger to press “PUSH” on the Inhaler CDM ® moving part, sliding the compartment in the opposite direction.

While holding the device with one hand, insert the capsule with the drug into the slot of the compartment (Fig. 3).

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

While holding the Inhaler CDM® in an upright position, close the compartment by pressing the thumb backwards until it stops, until a click is heard (Fig. 5).

Keep the Inhaler CDM® device strictly upright (Fig. 6).

Bring it to working condition as shown in Fig. 7. To do this, press the mouthpiece with force so that the arrow marked on the case disappears beyond the borders of the lower part of the device to the upper line. Then release the mouthpiece to return it to its original position. By doing so, you will pierce the capsule, opening access to the drug in the lumen of the mouthpiece.

Warning: due to the destruction of the gelatin capsule, small pieces of gelatin may enter the mouth or throat as a result of inhalation. In order to minimize this phenomenon, do not pierce the capsule more than 1 time.

Caution: Exhale before inhalation (fig.

8). Do not exhale through the mouthpiece! 

Carefully squeeze the Inhaler CDM® mouthpiece between your teeth, wrap your lips tightly around it, and take a deep and strong breath through your mouth (Fig. You will hear a vibrating sound inside the capsule compartment, produced by the capsule as it rotates and disperses the drug. Caution: the mouthpiece must not be chewed or clenched with your teeth! Do not press the mouthpiece when inhaling. This may block the movement of the capsule. Hold your breath for about 10 seconds or as long as possible.

Remove the inhaler from your mouth. Exhale slowly. Then breathe normally.

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

After inhalation, open the capsule compartment (Step 2), remove the empty capsule

, and then close it as shown in Figure 5.

Attention:

When performing inhalation, try not to cover the holes located on the sides of the mouthpiece. This may interfere with the free movement of air inside the inhaler, thereby reducing the dispersion of the capsule contents.

Always cover the Inhaler CDM® tightly with the cap after use to

keep the mouthpiece clean.

Clean the outside of the mouthpiece regularly (once a week) with a dry cloth.

There are isolated reports of patients accidentally swallowing whole capsules of the drug, without using an inhalation device. Most of these cases are not associated with the development of adverse events. The health professional should explain to the patient how to use the drug correctly, especially if the patient’s breathing does not improve after inhalation.

Contraindications

•  Hypersensitivity to atropine or its derivatives (including ipratropy and oxytropy) 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).

* The first trimester of pregnancy.

•  Under 18 years of age.

With caution

Tiotropium-native should be used with caution in patients with diseases such as angle-closure glaucoma, bladder neck obstruction, and prostatic hyperplasia. Patients with moderate to severe renal insufficiency (creatinine clearance < 50 ml/min) should be carefully monitored when using Tiotropium-native.

Side effects

The adverse reactions listed below are listed according to the lesion of organs and organ systems and frequency of occurrence. The frequency of adverse reactions is estimated as follows: occurring “very often” – > 10%; “often” – > > 1% and >>< 10%, “infrequently” – > 0.1% and < 10%, “infrequently” – > < 1%, “rarely” – > 0.01% and < 1%, “rarely” – > < 0.1%, “very rarely” –

Immune system disorders: rarely-urticaria, hypersensitivity reactions, including immediate reactions, angioedema (angioedema); frequency unknown – anaphylactic reactions.

Metabolic and nutritional disorders: frequency unknown-dehydration. Nervous system disorders: infrequently – dizziness, headache, taste disorder; rarely-insomnia.

Visual disturbances: infrequently – blurred vision; rarely-increased intraocular pressure, glaucoma.

Cardiac disorders: infrequently-atrial fibrillation; rarely-tachycardia (including supraventricular tachycardia), palpitation sensation.

Respiratory, thoracic and mediastinal disorders: infrequently-dysphonia, cough, pharyngitis; rarely-paradoxical bronchospasm, laryngitis, sinusitis, nosebleeds.

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

Skin and subcutaneous tissue disorders: infrequently-rash; rarely-pruritus; frequency unknown-infectious skin diseases, skin ulcers, dry skin.

Musculoskeletal and connective tissue disorders: frequency unknown-joint swelling.

Kidney and urinary tract disorders: infrequently-difficulty urinating and urinary retention (in men with predisposing factors), dysuria; rarely – urinary tract infection.

If any of the adverse reactions listed in the instructions get worse, or you notice any other adverse reactions not listed in the instructions, tell your doctor.

Interaction

Tiotropium-native may be used in combination with other medications commonly used to treat COPD: sympathomimetics, methylxanthines, oral and inhaled glucocorticosteroids.

Combined use with long-acting beta-2-adrenomimetics, inhaled glucocorticosteroids and their combinations does not affect the effect of tiotropium bromide.

Continuous co-use of other anticholinergic drugs and Tiotropium-native has not been studied and, therefore, is not recommended.

How to take, course of use and dosage

Tiotropium-native is prescribed in the form of inhalations of one capsule per day at the same time using the inhaler ” Inhaler CDM®”.

The drug should not be swallowed.

Tiotropium-native should be used no more than once a day.

Elderly and older patients and patients with impaired renal or hepatic function can take the drug Tiotropium-native in recommended doses.

However, patients with moderate or severe renal insufficiency who are receiving the following medications should be carefully monitored. Tiotropium-native in combination with other drugs secreted mainly by the kidneys.

Overdose

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

However, systemic anticholinergic adverse reactions were not detected after a single inhalation of tiotropium bromide at a dose of up to 340 mcg in healthy volunteers.

When using tiotropium bromide at a dose of up to 170 mcg in healthy volunteers for 7 days, no corresponding adverse reactions were observed, with the exception of dry mouth

There is evidence that no significant adverse reactions were observed when tiotropium bromide was administered to patients with COPD at a maximum daily dose of 43 mcg for more than 4 weeks.

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

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.

Immediate hypersensitivity reactions may occur after inhalation of Tiotropium-native. Like other inhaled medications, Tiotropium native can cause paradoxical bronchospasm.

Patients should be familiar with the rules for using Tiotropium-native capsules using an inhaler. Do not allow the powder to get into your eyes.Eye pain or discomfort, blurred vision, or visual halos combined with redness of the eyes, conjunctival congestion, and corneal edema may indicate an acute attack of angle-closure glaucoma.

If any combination of these symptoms develops, 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 should not be used more than once a day.

Tiotropium-native capsules should only be used with the Inhaler

CDM ® inhaler.

The use of Tiotropium-native does not affect the results of doping tests in athletes.

Influence on the ability to drive a car and other vehicles, to work with moving mechanisms

Studies on the effect of Tiotropium – native on the ability to drive vehicles and manage mechanisms have not been conducted. In case of development of such undesirable reactions as dizziness, headache and blurred vision, it is necessary to refrain from driving vehicles and operating mechanisms, as well as from engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

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

Storage conditions

Keep out of the reach of children in a dark place, at a temperature not exceeding 25°C.

Shelf life

2 years

Active ingredient

Tiotropium bromide

Conditions of release from pharmacies

By prescription

Dosage form

Capsules

Purpose

For adults as directed by your doctor

Indications

Chronic obstructive pulmonary disease, Bronchitis, Bronchial asthma