What is the duration of taking Spiriva mk 18. Spiriva: instructions for use. From the respiratory system

Instructions for use

Spiriva instructions for use

Dosage form

Capsules with powder for inhalation, hard gelatin, size No. 3, light greenish-blue, opaque; with company symbol and "TI 01" printed in black ink; the contents of the capsules are white powder.

Compound

Tiotropium 18 mcg

Equal to tiotropium bromide monohydrate (=tiotropium bromide) 22.5 mcg

Excipients: lactose monohydrate, 200 M; lactose monohydrate micronized.

Capsule composition: macrogol 3350 (PEG 3350), indigo carmine (E132), titanium dioxide (E171), yellow iron oxide (E172).

Pharmacodynamics

A bronchodilator - a long-acting m-cholinergic receptor blocker.

It has equal affinity for various subtypes of muscarinic receptors from M1 to M5. As a result of inhibition of M3 receptors in the airways, smooth muscles relax. The bronchodilator effect is dose dependent and lasts for at least 24 hours. The significant duration of action is probably due to a very slow release from M3 receptors compared to ipratropium bromide. When administered by inhalation, tiotropium bromide, as an anticholinergic agent of N-quaternary structure, has a local selective effect, while in therapeutic doses it does not cause systemic anticholinergic side effects. The release of tiotropium bromide from the connection with the M2 receptors occurs faster than from the connection with the M3 receptors. High affinity for receptors and slow release from binding to them determine an intense and long-lasting bronchodilator effect in patients with COPD.

Bronchodilation after inhalation of tiotropium bromide is a consequence of local rather than systemic action.

Clinical studies have shown that 30 minutes after a single dose of Spiriva® for 24 hours significantly improves lung function (increased FEV1 and FVC). Pharmacodynamic equilibrium was achieved within the 1st week, and a pronounced bronchodilator effect was observed on the 3rd day. Spiriva® significantly increases morning and evening peak expiratory flow rates measured by patients. The bronchodilator effect of Spiriva, assessed over a year, did not reveal any manifestations of tolerance.

Spiriva® significantly reduces the incidence of exacerbations of COPD and increases the period until the first exacerbation compared with placebo. Significantly improves the quality of life, which is observed throughout the entire treatment period. Spiriva® significantly reduces the number of hospitalizations associated with exacerbation of COPD and increases the time to first hospitalization.

Pharmacokinetics

Tiotropium bromide is a quaternary ammonium compound, sparingly soluble in water.

Tiotropium bromide has linear pharmacokinetics within therapeutic limits after intravenous administration and dry powder inhalation.

Suction

When administered by inhalation, the absolute bioavailability of tiotropium bromide is 19.5%, which indicates the high bioavailability of the drug fraction reaching the lungs. Cmax in blood plasma is achieved 5 minutes after inhalation. Tiotropium bromide is poorly absorbed from the gastrointestinal tract. For the same reason, food intake does not affect the absorption of tiotropium. When taking tiotropium bromide orally in solution form, the absolute bioavailability was 2-3%.

Distribution

Plasma protein binding - 72%. Vd - 32 l/kg. At steady state, Cmax in blood plasma in patients with COPD is 17-19 pg/ml 5 minutes after inhalation of powder at a dose of 18 mcg and decreases rapidly. Css in blood plasma was 3-4 pg/ml.

Does not penetrate the BBB.

Metabolism

The degree of biotransformation is insignificant. Tiotropium bromide is broken down nonenzymatically to alcohol N-methylscopine and dithienylglycolic acid, which do not bind to muscarinic receptors.

Metabolic disturbances are possible when using inhibitors of CYP2D6 and 3A4 isoenzymes (quinidine, ketoconazole, gestodene). Thus, the isoenzymes CYP2D6 and 3A4 are included in the metabolism of the drug. Tiotropium bromide, even at supratherapeutic concentrations, does not inhibit cytochrome P450 isoenzymes 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 in human liver microsomes.

Removal

After inhalation administration, terminal T1/2 is 5-6 days. The total clearance when administered intravenously to healthy young volunteers is 880 ml/min, with an individual variability of 22%. Tiotropium bromide after intravenous administration is excreted mainly in the urine unchanged - 74%. After inhalation of the powder, renal excretion is 14%, the rest, not absorbed in the intestine, is excreted in the feces. The renal clearance of tiotropium bromide exceeds the CC, indicating tubular secretion of the drug. After long-term administration of the drug once a day in patients with COPD, the equilibrium state of pharmacokinetic parameters is achieved after 2-3 weeks, with no further cumulation observed.

Pharmacokinetics in special clinical situations

In elderly patients, there is a decrease in the renal clearance of tiotropium bromide (326 ml/min in patients with COPD under 58 years of age, up to 163 ml/min in patients with COPD over 70 years of age), which is apparently due to a decrease in renal function with age. After inhalation, urinary excretion of tiotropium bromide is reduced from 14% (young healthy volunteers) to 7% (patients with COPD), but in elderly patients with COPD there was no significant change in plasma concentrations when inter- and intra-individual variability was taken into account (after inhalation of powder increases AUC0-4 by 43%).

Side effects

From the digestive system: slight dry mouth, often disappearing with continued treatment (? 1% and< 10%); кандидоз полости рта (? 0.1% и < 1%); запор, гастроэзофагеальный рефлюкс (? 0.01% и < 1%); в единичных случаях - кишечная непроходимость (включая паралитический илеус), дисфагия.

From the respiratory system: dysphonia, bronchospasm, cough and local irritation of the pharynx (? 0.1% and< 1%); носовое кровотечение (? 0.01% и < 1%).

From the cardiovascular system: tachycardia, palpitations (? 0.01% and< 1%); в единичных случаях - суправентрикулярная тахикардия, мерцательная аритмия.

From the side of the central nervous system: dizziness (? 0.1% and< 1%).

From the urinary system: difficulty urinating and urinary retention in men with predisposing factors, urinary tract infections (? 0.01% and< 1%).

Allergic reactions: rash, urticaria, itching, hypersensitivity reactions, including immediate reactions (? 0.01% and< 1%); в единичных случаях - ангионевротический отек.

Other: in isolated cases - blurred vision, increased intraocular pressure (? 0.01% and< 1%); глаукома.

Most of the above adverse reactions may be associated with the anticholinergic effect of Spiriva.

Selling Features

prescription

Special conditions

The drug Spiriva® is not intended for the relief of acute attacks of bronchospasm.

After inhalation of Spiriva powder, immediate hypersensitivity reactions may develop.

The process of inhalation of Spiriva (as well as other inhaled drugs) can cause bronchospasm.

Patients with renal insufficiency (CrCl 50 ml/min) should be carefully monitored when prescribing Spiriva.

Patients should be familiarized with the rules for using the inhaler. Do not allow the powder to get into your eyes. Eye pain or discomfort, blurred vision, visual halos in combination with eye redness, conjunctival congestion and corneal edema may indicate an acute attack of angle-closure glaucoma. If any combination of these symptoms develops, the patient should consult a doctor immediately. The use of only drugs that cause miosis is not an effective treatment in this case.

One capsule contains 5.5 mg of lactose monohydrate.

Use in pediatrics

The use of the drug in children and adolescents under 18 years of age is contraindicated.

Impact on the ability to drive vehicles and operate machinery

No studies have been conducted to study the effect of the drug on the ability to drive vehicles and operate machinery. Cases of dizziness and blurred vision while using the drug may have a negative impact on the above-mentioned ability.

Indications

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

Contraindications

I trimester of pregnancy;

Children and adolescents up to 18 years of age;

Hypersensitivity to atropine or its derivatives (including ipratropium and oxitropium);

Hypersensitivity to the components of the drug.

The drug should be used with caution in case of angle-closure glaucoma, prostatic hyperplasia, and bladder neck obstruction.

Drug interactions

It is possible to prescribe Spiriva in combination with other drugs commonly used to treat COPD: sympathomimetics, methylxanthine derivatives, oral and inhaled corticosteroids.

Limited information on combined use with anticholinergic drugs was obtained from two clinical studies: a single dose of 1 dose of ipratropium bromide against the background of continuous use of Spiriva in patients with COPD (64 people) and in healthy volunteers (20 people) did not lead to a decrease in adverse reactions or changes in life parameters and ECG. However, chronic concomitant use of anticholinergic drugs and Spiriva has not been studied and is therefore not recommended.

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Mode of application

Dosage

Prescribe 1 capsule/at the same time in the form of inhalations using the HandiHaler inhaler.

The drug should not be swallowed. Spiriva should not be used more than once/Spiriva capsules should only be used with the HandiHaler inhaler.

Elderly patients should take the drug in recommended doses.

If kidney function is impaired, patients can use Spiriva in recommended doses. However, when prescribing Spiriva in combination with other drugs that are excreted primarily by the kidneys, monitoring the patient’s condition is necessary. Patients with moderate or severe renal failure (CR? 50 ml/min) require careful monitoring.

Patients with liver failure can take the drug in recommended doses.

How to use the HandiHaler® inhaler

The HandiHaler inhaler is designed specifically for the use of Spiriva and is not intended for taking other medications.

The inhaler includes: dust cap, mouthpiece, base, piercing button, central chamber.

Using the HandiHaler inhaler:

1. open the dust cap by pressing the piercing button fully and then releasing it;

2. completely open the dust cap by lifting it up; then open the mouthpiece by lifting it up;

3. immediately before use, remove the Spiriva capsule from the blister and place it in the central chamber (it does not matter which side the capsule is placed in the chamber);

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

5. Holding the HandiHaler with the mouthpiece up, press the piercing button fully once and then release; thus, a hole is formed through which the drug is released from the capsule during inhalation;

6. exhale completely; never exhale into the mouthpiece.

7. take HandiHaler into your mouth and press your lips tightly around the mouthpiece; keeping your head straight, you should inhale slowly and deeply, but at the same time with enough force to hear the vibration of the capsule; inhale until your lungs are completely filled; then hold your breath as long as possible and remove the HandiHaler from your mouth; continue to breathe calmly; repeat procedures 6 and 7 to completely empty the capsule.

Cleaning the HandiHaler® inhaler

HandiHaler should be cleaned once a month. To do this, open the mouthpiece and dust cap, then open the base of the device by lifting the piercing button. Rinse the inhaler thoroughly in warm water until the powder is completely removed. HandiHaler should be wiped with a paper towel and with the mouthpiece, base and dust cap open, left to air dry for 24 hours. Once cleaned in this manner, the device is ready for subsequent use. If necessary, the outer surface of the mouthpiece can be cleaned using a damp, but not wet, cloth.

Overdose

When using high doses, manifestations of anticholinergic effects are possible - dry mouth, accommodation disturbances, increased heart rate.

In this article you can read the instructions for use of the drug Spiriva. Reviews of site visitors - consumers of this medicine, as well as the opinions of specialist doctors on the use of Spiriva in their practice are presented. We kindly ask you to actively add your reviews about the drug: whether the medicine helped or did not help get rid of the disease, what complications and side effects were observed, perhaps not stated by the manufacturer in the annotation. Analogues of Spiriva in the presence of existing structural analogues. Use for the treatment of bronchial asthma, obstructive bronchitis in adults, children, as well as during pregnancy and lactation.

Spiriva- bronchodilator.

Tiotropium bromide (the active ingredient of the drug Spiriva) is a long-acting m-anticholinergic blocker. The drug has the same affinity for the M1-M5 subtypes of muscarinic receptors. The result of inhibition of M3 receptors in the airways is smooth muscle relaxation. The bronchodilator effect depends on the dose and lasts for at least 24 hours. The significant duration of action is probably due to the very slow dissociation of the drug from 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-anticholinergic side effects. Dissociation from M2 receptors occurs faster than from M3 receptors, which indicates the predominance of selectivity for the M3 receptor subtype over M2 receptors. High affinity for receptors and slow dissociation of the drug from connection with receptors determine a pronounced and long-lasting bronchodilator effect in patients with chronic obstructive pulmonary disease (COPD).

Bronchodilation after inhalation of tiotropium bromide is a consequence of local rather than systemic action.

In clinical studies, 30 minutes after a single dose of Spiriva for 24 hours it was shown to significantly improve lung function (increase in FEV1 and FVC). Pharmacodynamic equilibrium was achieved within the 1st week, and a pronounced bronchodilator effect was observed on the 3rd day. Spiriva significantly increases morning and evening peak expiratory flow rates measured by patients. The bronchodilator effect of Spiriva, assessed over a year, did not reveal any manifestations of tolerance.

Spiriva significantly reduces the incidence of COPD exacerbations and increases the time to first exacerbation compared to placebo. Significantly improves the quality of life, which is observed throughout the entire treatment period. Spiriva significantly reduces the number of hospitalizations associated with exacerbation of COPD and increases the time to first hospitalization.

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

In clinical studies in patients suffering from bronchial asthma and continuing to experience symptoms of the disease despite maintenance therapy with inhaled glucocorticosteroids (GCS), incl. in combination with a long-acting beta2-adrenergic receptor agonist, it was found that the addition of Spiriva Respimat to maintenance therapy led to a significant improvement in lung function compared with placebo, significantly reduced the number of serious exacerbations and periods of worsening of symptoms of bronchial asthma, and increased the period until their first onset , led to a significant improvement in quality of life and an increase in the number of patients with a positive response to maintenance therapy.

The bronchodilating effect of the drug persisted throughout 1 year of use, and no signs of addiction were observed.

Compound

Tiotropium bromide monohydrate + excipients.

Pharmacokinetics

When administered by inhalation, the absolute bioavailability of tiotropium bromide is 19.5%, which indicates the high bioavailability of the drug fraction reaching the lungs. Tiotropium bromide is poorly absorbed from the gastrointestinal tract. For the same reason, food intake does not affect the absorption of tiotropium. When taking tiotropium bromide orally in solution form, the absolute bioavailability was 2-3%. Does not penetrate the blood-brain barrier (BBB). The degree of biotransformation is insignificant. Tiotropium bromide is broken down nonenzymatically to alcohol N-methylscopine and dithienylglycolic acid, which do not bind to muscarinic receptors. Metabolic disturbances are possible when using inhibitors of CYP2D6 and 3A4 isoenzymes (quinidine, ketoconazole, gestodene). Thus, the isoenzymes CYP2D6 and 3A4 are included in the metabolism of the drug. Tiotropium bromide, even at supratherapeutic concentrations, does not inhibit cytochrome P450 isoenzymes 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 in human liver microsomes. Tiotropium bromide after intravenous administration is excreted mainly in the urine unchanged - 74%. After inhalation of the powder, renal excretion is 14%, the rest, not absorbed in the intestine, is excreted in the feces. After long-term administration of the drug once a day in patients with COPD, the equilibrium state of pharmacokinetic parameters is achieved after 2-3 weeks, with no further cumulation observed.

Indications

for maintenance treatment of patients with COPD, chronic bronchitis, emphysema, for maintenance therapy with persistent shortness of breath, to improve the quality of life impaired due to COPD, to reduce the frequency of exacerbations;
for additional maintenance therapy in patients with bronchial asthma with persistent symptoms of the disease while taking inhaled corticosteroids, to reduce symptoms of bronchial asthma, improve quality of life and reduce the frequency of exacerbations.

Release forms

Capsules with powder for inhalation 18 mcg.

Solution for inhalation with Spiriva Respimat inhaler.

Instructions for use and method of use

Powder capsules

Prescribe 1 capsule per day at the same time in the form of inhalations using the HandiHaler inhaler.

The drug should not be swallowed. Spiriva should not be used more than once a day. Spiriva capsules should only be used with the HandiHaler inhaler.

Patients with liver failure can take the drug in recommended doses.

How to use the HandiHaler inhaler

The HandiHaler inhaler is designed specifically for the use of Spiriva and is not intended for taking other medications.

The inhaler includes: dust cap, mouthpiece, base, piercing button, central chamber.

Using the HandiHaler inhaler

Open the dust cap by pressing the piercing button fully and then releasing.
Open the dust cap completely by lifting it up; then open the mouthpiece by lifting it up.
Immediately before use, remove the Spiriva capsule from the blister and place it in the central chamber (it does not matter which side the capsule is placed in the chamber).
Close the mouthpiece tightly until it clicks, leaving the dust cap open.
Holding the HandiHaler with the mouthpiece facing up, press the piercing button all the way once and then release; This creates an opening through which the drug is released from the capsule during inhalation.
Exhale completely; never exhale into the mouthpiece.
Place the HandiHaler in your mouth and press your lips tightly around the mouthpiece; keeping your head straight, you should inhale slowly and deeply, but at the same time with enough force to hear the vibration of the capsule; inhale until your lungs are completely filled; then hold your breath as long as possible and remove the HandiHaler from your mouth; continue to breathe calmly; repeat procedures 6 and 7 to completely empty the capsule.
Next, you should open the mouthpiece again, remove and discard the used capsule. Close the mouthpiece and dust cap.

Cleaning the HandiHaler inhaler

Opening the blister

Separate the blister strip along the perforated line. Open the blister strip immediately before use so that one capsule is completely visible. The capsule contains a small amount of powder, so it is not completely filled.

If the capsule is accidentally opened and exposed to air, it should not be used. Neither in the device nor in the blister, capsules should be exposed to high temperatures or exposure to sunlight.

When treating bronchial asthma, the full therapeutic effect occurs within a few days.

In elderly patients, patients with impaired liver function and patients with minor impaired renal function (creatinine clearance 50-80 ml/min), Spiriva Respimat can be used at the recommended dose.

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

COPD does not usually occur in children. The safety and effectiveness of Spiriva Respimat in children have not been studied.

Rules for using the Spiriva Respimat inhaler

Inserting the cartridge and preparing for use

Before using the inhaler for the first time, you must complete the steps below:

With the green cap closed, press the lock button and at the same time remove the transparent sleeve by pulling it down.
Remove the cartridge from the packaging. Insert the narrow end into the inhaler until it locks into place. To ensure that the cartridge is fully inserted, press the cartridge firmly onto a hard surface. In this case, the bottom of the cartridge should not be flush with the bottom edge of the inhaler; the bottom part of the silver cartridge should be visible. Once the cartridge is inserted into the inhaler, it should not be removed.
Put the transparent sleeve back on. After this, the sleeve should no longer be removed.

Preparing to use the Spiriva Respimat inhaler for the first time

The Spiriva Respimat inhaler should be held vertically with the green cap on. You need to turn the transparent sleeve in the direction of the red arrows indicated on the label until it clicks (half a turn).
Remove the green cap.
Point the Spiriva Respimat inhaler downwards. Press the dose button. Close the green cap.

Repeat steps a, b and c until an aerosol cloud appears.

Then repeat steps a, b and c 3 more times to ensure the inhaler is ready for use.

The Spiriva Respimat inhaler is now ready for use.

The implementation of these steps does not reduce the number of doses of the drug. Once prepared, the Spiriva Respimat inhaler delivers 30 doses (60 inhalations).

Using the Spiriva Respimat inhaler

This inhaler should only be used once a day. Each time you need to do 2 inhalations.

1. Hold the Spiriva Respimat inhaler upright with the green cap on to prevent accidental release of the medication. Turn the transparent sleeve in the direction of the red arrows indicated on the label until it clicks (half a turn).

2. Remove the green cap. Exhale slowly and deeply. Cover the end of the mouthpiece tightly with your lips. The air hole of the inhaler must be free. Point the inhaler towards the back of the throat.

While inhaling slowly and deeply through your mouth, press the dose button and continue inhaling as long as possible. Hold your breath for 10 seconds or as long as comfortable.

3. Repeat steps 1-2 to get the full dose. This inhaler should only be used once a day. Each time you need to do 2 inhalations.

Close the green cap of the inhaler until you use it again.

If the Spiriva Respimat inhaler has not been used for more than 7 days, you should point it down before use and press the dose button once. If the inhaler has not been used for more than 21 days, repeat steps 4-6 until an aerosol cloud is obtained. Then repeat steps 4-6 three more times.

Determining when to start using a new inhaler

The Spiriva Respimat inhaler contains 30 doses (60 inhalations). The dose indicator shows approximately how much of the drug is left. When the inhaler pointer points to the red area of the scale, this means there is approximately 7 days of medication left (14 inhalations). During this period, you must obtain a prescription for a new inhaler Spiriva Respimat.

When the inhaler pointer reaches the end of the red area of the scale (i.e. when 30 doses have been used), this means that the Spiriva Respimat inhaler is empty. The inhaler will be automatically blocked. From this point on, turning the transparent sleeve will not be possible.

After the first use, the Spiriva Respimat inhaler should be discarded no later than after 3 months, even if not the entire amount of the medicine has been used.

Caring for your inhaler

The mouthpiece and metal part of the atomizer must be cleaned with a damp, soft cloth at least once a week.

Slight discoloration of the mouthpiece does not affect the functioning of the inhaler. If necessary, wipe the outside of the inhaler with a damp cloth.

Side effect

dehydration;
dizziness;
insomnia;
increased intraocular pressure, glaucoma;
blurred vision;
atrial fibrillation;
tachycardia (including supraventricular tachycardia);
feeling of heartbeat;
cough;
nose bleed;
pharyngitis;
dysphonia;
paradoxical bronchospasm;
laryngitis;
sinusitis;
slight transient dryness of the pharyngeal mucosa;
constipation;
oral candidiasis;
dysphagia;
gastroesophageal reflux;
gingivitis;
glossitis;
stomatitis;
intestinal obstruction, including paralytic ileus;
skin infections and skin ulcers;
dry skin;
rash;
angioedema;
hives;
hypersensitivity, including immediate reactions;
swelling of the joints;
dysuria;
urinary retention (more often in men with predisposing factors);
urinary tract infection.

Contraindications

1st trimester of pregnancy;
children and adolescents under 18 years of age (due to the lack of data on effectiveness and safety);
hypersensitivity to atropine or its derivatives, for example, ipratropium bromide, oxitropium bromide or to any component of the drug.

The drug should be used with caution in cases of angle-closure glaucoma, prostatic hyperplasia, and bladder neck obstruction.

Use during pregnancy and breastfeeding

The drug is contraindicated for use in the 1st trimester of pregnancy.

In the 2nd and 3rd trimesters of pregnancy and lactation, the drug should be prescribed only in cases where the expected benefit of therapy for the mother outweighs the potential risk for the fetus or infant.

Data on the effect of Spiriva on pregnancy are limited. When studying reproductive toxicity in animals, there was no indication of direct or indirect adverse effects of the drug. As a precaution, it is preferable to avoid using Spiriva during pregnancy.

There are no clinical data on the effects of tiotropium bromide during breastfeeding.

Use in children

Contraindicated for use in children and adolescents under 18 years of age.

Use in elderly patients

Elderly patients should take the drug in recommended doses.

special instructions

Spiriva is not intended for the relief of acute bronchospasm attacks.

After inhalation of Spiriva powder, immediate hypersensitivity reactions may develop.

The process of inhalation of Spiriva (as well as other inhaled drugs) can cause bronchospasm.

Patients with renal failure (creatinine clearance less than 50 ml/min) should be carefully monitored when prescribing Spiriva.

One capsule contains 5.5 mg of lactose monohydrate.

The drug Spiriva Respimat, as a bronchodilator used once a day for maintenance treatment, should not be used as initial therapy for acute attacks of bronchospasm or to eliminate acute symptoms. In case of an acute attack, fast-acting beta2-agonists are used.

Spiriva Respimat should not be used for the treatment of bronchial asthma as first-line therapy. Patients should be advised to continue anti-inflammatory therapy (for example, inhaled corticosteroids) while taking Spiriva Respimat, even if symptoms improve.

Immediate hypersensitivity reactions may occur after using the drug.

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

Spiriva cartridges should only be used with the Respimat inhaler.

Impact on the ability to drive vehicles and operate machinery

Drug interactions

Although specific drug interaction studies have not been conducted, tiotropium bromide has been used in conjunction with other drugs used to treat COPD, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled corticosteroids, antihistamines, mucolytics, leukotriene modifiers, cromones, anti-IgE drugs; however, there were no clinical signs of drug interaction.

Long-term combined use of tiotropium bromide with other m-anticholinergic drugs has not been studied. Therefore, long-term combined use of Spiriva Respimat with other m-anticholinergic drugs is not recommended.

Analogues of the drug Spiriva

Structural analogues of the active substance:

Spiriva Respimat;
Tiotropium bromide monohydrate.

Analogs for therapeutic effect (drugs for the treatment of chronic obstructive pulmonary disease):

Ambroxol;
Amoxiclav;
Amoxicillin;
Astmopent;
ACC Long;
Beclomethasone;
Benacort;
Brillid;
Budesonide;
Vicef;
Daxas;
Doxycycline;
Imunofan;
Ipramol;
Ipratropium;
Clenbuterol;
Codelac Broncho;
Lendatsin;
Lycopid;
Natsef;
Oriprim;
Perti;
Pefloxacin;
Picillin;
Pulmicort Turbuhaler;
Pulmozyme;
Salamol Eco Easy Breathing;
Salbutamol;
Symbicort Turbuhaler;
Spiriva Respimat;
Super;
Tazocin;
Tarcefandol;
Tarcefoxime;
Tevacombe;
Theophylline;
Terzef;
Flavamed;
Flucloxacillin;
Fromilid uno;
Halixol;
Cephabol;
Ceftriabole;
Cibutol Cyclocaps;
Ciprofloxacin;
Erdomed.

If there are no analogues of the drug for the active substance, you can follow the links below to the diseases for which the corresponding drug helps, and look at the available analogues for the therapeutic effect.

Description of the dosage form

Hard gelatin capsules, size 3, light greenish-blue, opaque, imprinted with the company symbol and TI 01 in black ink.

The contents of the capsules are white powder.

pharmachologic effect

pharmachologic effect- bronchodilator, anticholinergic, m-cholinolytic.

Pharmacodynamics

Tiotropium bromide is a long-acting antimuscarinic anticholinergic drug, often called an anticholinergic in clinical practice. It has the same affinity for various subtypes of muscarinic receptors - from M 1 to M 5. The result of inhibition of M 3 receptors in the respiratory tract is relaxation of smooth muscles. The bronchodilator effect is dose dependent and lasts for at least 24 hours. The significant duration of action is probably due to the very slow dissociation from M3 receptors compared to ipratropium bromide. When administered by inhalation, tiotropium bromide as an N-quaternary anticholinergic agent has a local selective effect, while in therapeutic doses it does not cause systemic m-anticholinergic side effects. Dissociation from M2 receptors occurs faster than from M3. High affinity for receptors and slow dissociation determine a pronounced and long-lasting bronchodilator effect in patients with COPD.

Bronchodilation after inhalation of tiotropium bromide is a consequence of a local rather than a systemic effect.

Spiriva ® has been shown to significantly increase pulmonary function (FEV1, forced vital capacity - FVC) 30 minutes after a single dose over 24 hours. Pharmacodynamic equilibrium was achieved within the first week, and a pronounced bronchodilator effect was observed on the 3rd day. Spiriva ® significantly increases morning and evening peak expiratory flow rates measured by patients. The bronchodilator effect of the drug Spiriva ® , assessed over a year, did not reveal any manifestations of tolerance.

Spiriva ® significantly reduces shortness of breath throughout the treatment period.

In two randomized, double-blind, placebo-controlled studies, Spiriva ® was shown to significantly improve exercise capacity compared with placebo.

Spiriva ® significantly reduces the number of exacerbations of COPD and increases the period until the first exacerbation compared to placebo.

Spiriva ® significantly improves quality of life. This improvement is observed throughout the entire treatment period.

Spiriva ® has been shown to significantly reduce the number of hospitalizations associated with exacerbation of COPD and increase the time to first hospitalization.

Spiriva ® has also been shown to result in sustained improvements in FEV1 after 4 years of use, with no change in the rate of annual decline in FEV1.

During treatment, there was a 16% reduction in the risk of death.

Compared with salmeterol, Spiriva increased the time to first exacerbation (187 days versus 145), with a 17% reduction in the risk of exacerbations (hazard ratio (RR) 0.83; 95% CI: 0.77-0. 90;p<0,001). Также прием препарата Спирива ® увеличивает время наступления первого тяжелого (требующего госпитализации) обострения (ОР 0,72; 95% ДИ: 0,61-0,85; p<0,001) снижает ежегодное число средних или тяжелых (требующих госпитализации) обострений (0,64 против 0,72; ОР 0,89; 95% ДИ: 0,83-0,96; p=0,002), снижает ежегодное число тяжелых (требующих госпитализации) обострений (0,09 против 0,13; ОР 0,73; 95% ДИ: 0,66-0,82; p<0,001).

Pharmacokinetics

Tiotropium is a quaternary ammonium compound, sparingly soluble in water.

Suction. When administered by inhalation, the absolute bioavailability of tiotropium is 19.5%, indicating that the fraction of the drug that reaches the lungs is highly bioavailable. Tiotropium in solution when taken orally has an absolute bioavailability of 2-3%. Eating does not affect the absorption of tiotropium. Cmax after inhalation is reached within 5-7 minutes. At the dynamic equilibrium stage, the peak plasma concentration of tiotropium in patients with COPD is 12.9 pg/ml and decreases rapidly. This indicates a multicompartmental type of drug distribution. At the stage of dynamic equilibrium, the basal concentration of tiotropium in the blood plasma is 1.71 pg/ml.

Distribution. 72% of the dose taken is bound to plasma proteins, and Vd is 32 l/kg.

Studies have shown that tiotropium does not cross the BBB.

Biotransformation. The degree of biotransformation is insignificant. This is confirmed by the fact that after intravenous administration of the drug to healthy young volunteers, 74% of unchanged substance is found in the urine. Tiotropium is broken down nonenzymatically to alcohol-N-methylscopine and dithienylglycolic acid, which do not bind to muscarinic receptors.

Studies have shown that the drug (<20% от дозы после в/в применения) метаболизируется цитохромом P450, этот процесс зависит от оксидации и последующей коньюгации с глютатионом с образованием различных метаболитов. Нарушение метаболизма может иметь место при использовании ингибиторов CYP 450 2D6 и 3А4 (хинидина, кетоконазола и гестодена). Таким образом, CYP 450 2D6 и 3А4 включаются в метаболизм препарата. Тиотропий даже в сверхтерапевтических концентрациях не ингибирует цитохром P450, 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, или 3А в микросомах печени человека.

Excretion. T1/2 tiotropium after inhalation varies from 27 to 45 hours. The total clearance when administered intravenously to healthy young volunteers is 880 ml/min. Tiotropium after intravenous administration is mainly excreted unchanged by the kidneys (74%). After inhalation of the dry powder at the stage of dynamic equilibrium, renal excretion is 7% per day of the dose, the remaining unabsorbed portion is excreted through the intestines. The renal clearance of tiotropium exceeds the clearance of creatinine, indicating tubular secretion of the drug. After long-term administration of the drug once a day by patients with COPD, pharmacokinetic equilibrium is achieved on the 7th day, with no further accumulation observed.

Tiotropium has linear pharmacokinetics within therapeutic limits regardless of the dosage form of the drug.

Elderly patients. In elderly patients, a decrease in the renal clearance of tiotropium is observed (365 ml/min in patients with COPD under 65 years of age, to 271 ml/min in patients with COPD over 65 years of age). These changes did not result in a corresponding increase in AUC 0-6 or C max values.

Patients with impaired renal function. In patients with COPD and mild renal impairment (Cl creatinine 50-80 ml/min), inhaled tiotropium once daily during the dynamic equilibrium stage resulted in an increase in AUC 0-6 by 1.8-30%. The Cmax value remained the same as in patients with normal renal function (Cl creatinine >80 ml/min). In patients with COPD and moderate or severe renal impairment (Cl creatinine<50 мл/мин) в/в введение тиотропия приводило к двукратному увеличению концентрации препарата в плазме (значение AUC 0-4 увеличивалось на 82% а значение C max увеличивалось на 52%) по сравнению с пациентами с ХОБЛ и нормальной функцией почек. Аналогичное повышение концентрации тиотропия в плазме отмечалось и после ингаляции сухого порошка.

Patients with impaired liver function. It is expected that hepatic impairment will not have a significant effect on the pharmacokinetics of tiotropium because Tiotropium is primarily excreted by the kidneys and via non-enzymatic cleavage of ester bonds, producing metabolites that do not bind to muscarinic receptors.

Indications for Spiriva ®

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

Contraindications

hypersensitivity to atropine or its derivatives (for example, ipratropium or oxitropium) or components of this drug (in particular, lactose monohydrate, which contains milk protein, due to lactase deficiency, lactose intolerance, glucose-galactose malabsorption);

pregnancy (first trimester);

children under 18 years of age.

Carefully: angle-closure glaucoma, prostatic hyperplasia, bladder neck obstruction.

Use during pregnancy and breastfeeding

Data on the use of tiotropium in human pregnancy are limited. Animal studies provide no indication of direct or indirect adverse effects on pregnancy, embryo/fetal development, childbirth or postnatal development.

As a precaution, it is preferable to avoid using Spiriva ® during pregnancy.

There are no clinical data on the use of tiotropium in breastfeeding women. Preclinical studies have shown that small amounts of tiotropium are excreted into breast milk.

Spiriva ® should not be used in pregnant or breastfeeding women unless the expected benefit outweighs the possible risk to the fetus or child.

Side effects

Adverse drug reactions were identified based on data obtained during clinical trials and individual reports during post-registration use of the drug.

The frequency of adverse reactions that may occur during therapy is given in the following gradation: often (≥1 and<10%); нечасто (≥0,1 и <1%); редко (≥0,01% и <0,1%).

Metabolism and nutrition: dehydration*.

From the gastrointestinal tract: often - dry mouth, usually mild; infrequently - stomatitis; constipation, GERD; rarely - oropharyngeal candidiasis, gingivitis, glossitis; intestinal obstruction, including paralytic ileus, dysphagia.

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

From the SSS side: uncommon - atrial fibrillation; rarely - tachycardia (including supraventricular tachycardia), palpitations.

From the kidneys and urinary tract: uncommon - difficulty urinating and urinary retention (in men with predisposing factors), dysuria; rarely - urinary tract infections.

Allergic reactions: uncommon - rash; rarely - urticaria, itching, hypersensitivity reactions, including immediate reactions, angioedema*.

From the skin: skin infections and skin ulcers, dry skin*.

Musculoskeletal system and related connective tissue diseases: swelling of the joints*.

From the nervous system: infrequently - dizziness; rarely - insomnia.

From the side of the organ of vision: infrequently - blurred vision; rarely - increased IOP, glaucoma.

*These adverse reactions were not identified in the combined database of clinical studies; There have been only isolated reports of these adverse reactions with widespread use of the drug, but the connection with the m-anticholinergic effect of the drug Spiriva ® has not been proven; the frequency of these rare events is difficult to estimate.

Interaction

It is possible to use tiotropium in combination with other drugs commonly used to treat COPD: sympathomimetics, methylxanthines, oral and inhaled corticosteroids. Combined use with long-acting beta 2 agonists, inhaled corticosteroids and their combinations does not affect the effect of tiotropium.

Limited information on combined use with anticholinergic drugs was obtained from 2 clinical studies: a single dose of 1 dose of ipratropium bromide against the background of continuous use of the drug Spiriva ® in patients with COPD (64 patients) and healthy volunteers (20 people) did not lead to a decrease in adverse reactions, changes in vital parameters and ECG. However, chronic concomitant use of anticholinergic drugs and Spiriva ® has not been studied and is therefore not recommended.

Directions for use and doses

Inhalation.

When using the drug Spiriva ® in the form of inhalations using the HandiHaler ® device, it is recommended to use 1 capsule/day, at the same time. The drug does not need to be swallowed.

Elderly patients should take Spiriva ® in recommended doses.

Patients with impaired renal function can use Spiriva ® in recommended doses.

However, careful monitoring is required in patients with moderate or severe renal impairment receiving Spiriva ® (as is the case with other drugs excreted primarily by the kidneys).

Patients with liver failure can take Spiriva ® at recommended doses.

Instructions for use of the HandiHaler ® device

The HandiHaler ® device was specially designed for the drug Spiriva ® . It should not be used to take other medications. The patient can use his HandiHaler ® for one year.

The HandiHaler ® device includes:

1) dust cap;

2) mouthpiece;

3) base;

4) piercing button;

5) central chamber.

Using the HandiHaler ® device

1. Open the dust cap by pressing the piercing button fully and then releasing it.

2. Open the dust cap completely by lifting it up. Then open the mouthpiece by lifting it up.

3. Remove the Spiriva ® capsule from the blister (immediately before use) and place it in the central chamber, as shown in the figure. It does not matter which side the capsule is placed in the chamber.

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

5. Holding the HandiHaler ® with the mouthpiece up, press the piercing button only once fully and then release. This creates an opening through which the drug is released from the capsule during inhalation.

6. Exhale completely. Attention: never exhale into the mouthpiece.

7. Take HandiHaler ® into your mouth and press your lips tightly around the mouthpiece. Keeping your head straight, inhale slowly and deeply, but at the same time with enough force to hear or feel the vibration of the capsule. Inhale until your lungs are completely filled; then hold your breath until you feel discomfort, while simultaneously removing HandiHaler ® from your mouth. Continue to breathe calmly. Repeat procedures 6 and 7 to completely empty the capsule.

8. Open the mouthpiece again. Remove and discard the used capsule. Close the mouthpiece and dust cap to store the HandiHaler ® device.

Clean HandiHaler ® once a month.

Open the mouthpiece and dust cap. Then open the base of the device by lifting the piercing button. Rinse the inhaler thoroughly in warm water until the powder is completely removed. Wipe HandiHaler ® with a paper towel and leave the mouthpiece, base and dust cap open to air dry for 24 hours. After cleaning the device according to the instructions, it will be ready for the next use. If necessary, the outer surface of the mouthpiece can be cleaned using a damp, but not wet, cloth.

Opening the blister

Peel off the blister strip along the perforated line (A).

Open the blister strip immediately before use so that 1 cap. was completely visible. If the capsule is accidentally opened (exposed to air), it should not be used (B).

Take the capsule (C).

Neither in the device nor in the blister, capsules should be exposed to high temperatures, i.e. exposure to sunlight.

The capsule contains a small amount of powder, so the capsule is not completely filled.

Overdose

When using high doses, manifestations of anticholinergic effects are possible. However, systemic anticholinergic side effects were not observed after a single inhalation dose of up to 282 mcg of tiotropium when administered to healthy volunteers.

Bilateral conjunctivitis in combination with dry mouth was observed in healthy volunteers after repeated administration of a single daily dose of 141 mcg, which disappeared with continued treatment. In a study that examined the effect of multiple doses of tiotropium in patients with COPD receiving a maximum of 36 mcg of the drug for more than 4 weeks, dry mouth was the only side effect. Acute intoxication associated with accidental ingestion of capsules is unlikely due to the low bioavailability of the drug.

special instructions

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

After inhalation of Spiriva ® powder, immediate hypersensitivity reactions may occur.

Inhalation of the drug may lead to bronchospasm.

Patients with moderate or severe renal impairment (Cl creatinine ≤50 ml/min) should be carefully monitored when taking Spiriva, as is necessary in other cases of prescribing drugs excreted primarily by the kidneys.

Patients should be familiar with the rules for using Spiriva ® capsules. Do not allow the powder to get into your eyes. Eye pain or discomfort, blurred vision, visual halos, combined with eye redness, 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 specialist. The use of drugs that cause miosis is not an effective treatment in this case.

The drug should not be used more than once a day. Spiriva ® capsules should only be used with the HandiHaler ® device.

Name: SPIRIVA®, Boehringer Ingelheim

pharmacodynamics. Tiotropium is considered a specific long-acting anticholinergic agent. Tiotropium has similar affinity for all muscarinic receptor subtypes (M1 to M5). In the airways, inhibition of M3 receptors causes smooth muscle relaxation. In preclinical studies in vitro And in vivo the bronchoprotective result was dose-dependent and lasted more than 24 hours.
The duration of the effect is due to the very slow release from M3 receptors; The half-life of tiotropium is significantly longer than that of ipratropium. As an N-quaternary anticholinergic, tiotropium is considered to be locally (broncho-)selective when used by inhalation and exhibits an acceptable therapeutic range for systemic anticholinergic effects. Dissociation with M2 receptors is considered faster than with M3 in functional studies in vitro. M3 is a more acceptable (kinetically controlled) receptor subtype selectivity than M2. High activity and slow dissociation from the receptors have been clinically correlated with significant and prolonged bronchodilation in patients with COPD. Bronchodilation following inhaled tiotropium is primarily thought to be a local effect in the airways rather than a systemic effect.
When using Spiriva once a day, there was a significant improvement in lung function (increase in forced expiratory volume in 1 second (FEV1) and forced vital capacity) within 30 minutes after the 1st dosage, the result lasted 24 hours. Pharmacodynamic steady state was 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 over the 24-hour dosing interval compared to placebo. It did not take into account whether Spiriva was prescribed in the morning or in the evening.
Spiriva significantly reduces shortness of breath; the improvement was maintained throughout the entire treatment period.
Spiriva significantly reduces the number of exacerbations of COPD and stops the occurrence of the first exacerbation. The use of Spiriva significantly improves the quality of life; the improvement was maintained throughout the entire treatment period. Spiriva significantly reduces the number of hospitalized patients with exacerbations of COPD and delays the time of first hospitalization.
In two studies, Spiriva significantly improved symptom-limited exercise capacity by 19.7% and 28.3%. In a study, the use of Spiriva 18 and 54 mcg (3 times 18 mcg) for 12 days did not prolong the interval Q-T according to ECG indicators.
In a 4-year study of 5,993 patients, Spiriva maintained improvement in FEV1 over the entire period, but did not change the overall annual decline in FEV1.
During treatment, the risk of mortality decreased by 16%. The overall incidence of death was 4.79 per 100 patient-years in the placebo group compared with 4.10 per 100 patient-years in the tiotropium group (hazard ratio (tiotropium/placebo) 0.84; 95% CI 0.73; 0 ,97). Treatment with tiotropium reduced the risk of respiratory failure by 19% (2.09 versus 1.68 cases per 100 patient-years, relative risk (tiotropium/placebo) 0.81; 95% CI 0.65, 1.00).
Pharmacokinetics. Tiotropium is considered a quaternary ammonium compound that is moderately soluble in water. Tiotropium is used in the form of a dry powder for inhalation. Mainly, with the inhalation method of administration, most of the released dosage is deposited in the gastrointestinal tract, and a smaller part in the lungs.
Absorption. After inhalation of the dry powder, the absolute bioavailability is 19.5%, which is considered a sign of high bioavailability of the fraction reaching the lungs. Based on the chemical structure of the compound (quaternary ammonium compound), it is assumed that tiotropium is poorly absorbed from the gastrointestinal tract. For the same reason, simultaneous consumption of food does not affect the absorption of tiotropium. The absolute bioavailability of tiotropium solution for oral administration is 2-3%. Cmax of tiotropium in blood plasma is achieved 5 minutes after inhalation.
Distribution. 72% of the drug binds to plasma proteins. The volume of distribution is 32 l/kg. At steady state, the maximum level of tiotropium in the blood plasma of patients with COPD was 17-19 pg/ml when determined 5 minutes after inhalation of a dosage of 18 mcg and decreased rapidly in a multistage manner. The lower level of tiotropium concentration in blood plasma at steady state is 3-4 pg/ml. Local concentration in the lungs is unknown, but based on the route of administration, high concentrations in the lungs are expected. Animal studies have shown that tiotropium does not penetrate the BBB to a significant extent.
Biotransformation. The degree of biotransformation is low, since 74% of the unchanged substance was excreted in the urine after intravenous administration to healthy volunteers. Tiotropium ester breaks down non-enzymatically to the alcohol M-methylscopine and dithienylglycolic acid, which do not bind to muscarinic receptors.
Further on research in vitro on liver microsomes and hepatocytes tiotropium (<20% дозировки после в/в введения) метаболизируется путем зависимого от цитохрома P450 окисления и последующей глутатионовой конъюгации до различных метаболитов фазы II. Эта ферментная цепь может угнетаться ингибиторами CYP450 2D6 (и 3A4), хинидином, кетоконазолом и гестоденом. Указанные CYP450 2D6 и 3A4 участвуют в метаболических превращениях, которые отвечают за выведение меньшей части дозировки. Тиотропий даже в супратерапевтических концентрациях не ингибирует цитохром P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 и 3A на микросомах печени.
Elimination. The final elimination half-life occurs on the 5-6th day after inhalation. The total clearance was 880 ml/min after IV administration in young healthy volunteers with an interindividual variability of 22%. After intravenous administration, tiotropium is mainly excreted unchanged in the urine. After inhalation of the dry powder, urinary excretion is 14% of the dosage, the remainder is not absorbed by the intestines and is excreted in the feces. The renal clearance of tiotropium exceeds the clearance of creatinine, which indicates excretion in the urine. After continuous daily inhalation in patients with COPD, a pharmacokinetically stable state was achieved within 2-3 weeks without subsequent accumulation.
Linearity/nonlinearity. Tiotropium demonstrated linear pharmacokinetic properties in the therapeutic range after dry powder inhalation.
Pharmacokinetics in elderly patients. As with all drugs that are predominantly excreted in the urine, when tiotropium is used in elderly patients, renal clearance is reduced as a consequence of decreased renal function (326 ml/min in patients with COPD<58 лет по сравнению с 163 мл/мин у пациентов с ХОБЛ >70 years). Urinary excretion of tiotropium after inhalation decreases from 14% (in young healthy volunteers) to 7% (in patients with COPD), but the plasma concentration does not change significantly in elderly patients with COPD compared with inter- and intra-individual variability (43% increase in AUC after inhalation of dry powder).
Pharmacokinetics in patients with impaired renal function. As with all drugs that are primarily excreted in the urine, renal failure is associated with increased plasma drug concentrations and decreased clearance following IV infusion and dry powder inhalation. With minor renal impairment (creatinine clearance 50-80 ml/min), which is often observed in elderly patients, the concentration of tiotropium in the blood plasma slightly increases (39% increase in AUC0-4 hours after IV infusion). In COPD patients with moderate or severe renal impairment (creatinine clearance<50 мл/мин) в/в введение тиотропия приводит к повышению вдвое концентрации в плазме крови (82% повышение AUC0-4 ч), что подтверждается данными о концентрации в плазме крови после ингаляции сухого порошка.
Pharmacokinetics in patients with impaired liver function. Hepatic impairment does not have a significant effect on the pharmacokinetics of tiotropium. Tiotropium is predominantly eliminated by renal elimination (up to 74% in young healthy volunteers) and by simple non-enzymatic ester degradation to products that do not bind to muscarinic receptors.

Composition and release form

por. d/ing., caps. hard 18 mcg blister, No. 30

por. d/ing., caps. hard 18 mcg blister, with HandiHeiler® device, No. 30

Other ingredients: micronized lactose monohydrate, lactose monohydrate 200 M.

1 capsule contains tiotropium bromide monohydrate 22.5 mcg, which corresponds to tiotropium 18 mcg.

No. UA/6495/01/01 from 02/23/2012 to 02/23/2017

Indications

maintenance therapy for COPD, including chronic bronchitis and emphysema; maintenance treatment of shortness of breath due to COPD and prevention of exacerbation of the disease.

Application

The recommended dosage of Spiriva consists of inhaling the contents of 1 capsule once a day using the HandyHaler inhalation device.
Inhalation should be done at the same time of day.
Spiriva capsules should not be swallowed.
Elderly patients can use Spiriva at the dose recommended by the doctor.
Patients with kidney failure can use Spiriva at the dose recommended by the doctor. As with other drugs that are typically excreted by the kidneys, the use of Spiriva should be under medical supervision in patients with moderate to severe renal impairment.
Patients with liver failure can use Spiriva in the dose recommended by the doctor.
Based on the fact that there is no experience with the use of Spiriva for the treatment of children, the drug is proposed for use only in adults.
Instructions for use. When using the medicine Spiriva, you should follow your doctor's recommendations.
The HandiHaler inhalation device was developed specifically for Spiriva capsules. It should not be used with other medications.
It is possible to use HandiHaler for 1 year, using it as directed.
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 (immediately before use) and place it in the center of the membrane. It does not matter which side the capsule is placed in the chamber.
4. Close the mouthpiece tightly until it clicks, leaving the dust cap open.
5. Holding the HandyHeiler with the mouthpiece up, press the spray button all the way 1 time and release.
This makes holes in the capsule shell and allows the medicine to be released when inhaled.
6. Exhale completely.
Important: do not exhale into the mouthpiece under any circumstances.
7. Raise the HandyHaler device to your mouth and wrap your lips tightly around the mouthpiece. Keeping your head straight, inhale slowly and deeply, but in such a way that you hear or feel the vibration of the capsule.
Inhale until your lungs are full, then hold your breath as long as possible and at the same time remove the mouthpiece from your mouth.
Resume breathing.
Repeat the steps indicated in steps 6 and 7 once - this will completely empty the capsule.
8. Open the mouthpiece again. Remove the used capsule and discard.
Close the mouthpiece and dust cap to store the HandyHaler.
Cleaning the HandyHaler. The HandiHaler device should be cleaned once a month.
Open the dust cap and mouthpiece. Then open the base by lifting the spray button. Rinse the entire inhaler with warm water to remove the powder. Dry the HandyHaler thoroughly by blotting off any remaining water with a paper towel and air drying, leaving the dust cap, mouthpiece and base open. Air drying takes 24 hours, so cleaning should begin immediately after use to ensure the device is ready for the next use.
If necessary, the outside of the mouthpiece can be cleaned using a damp, but not wet, cloth.
Blister opening
A. Separate the blister strips by tearing along the perforations.
B. Open (immediately before use) until the inscription “STOP”.
If another capsule is accidentally opened, it should be thrown away.
C. Remove the capsule.
Capsules should not be exposed to extreme temperatures.
Spiriva capsules contain only a small amount of powder, so the capsule is only partially filled.

Contraindications

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

Side effects

many of the listed side effects can be attributed to the anticholinergic properties of Spiriva.
Adverse reactions to the drug were determined from data obtained from clinical trials and spontaneous reports during the post-marketing period. The clinical trials database included 9647 patients treated with tiotropium in 28 placebo-controlled clinical trials with treatment periods ranging from 4 weeks to 4 years, corresponding to 12,469 patient-years of tiotropium use.
From the side of metabolism: dehydration.
From the side of the central nervous system: dizziness, insomnia, headache, disturbance of taste.
From the side of the organ of vision: blurred vision, glaucoma, increased intraocular pressure.
Cardiovascular disorders: atrial fibrillation, supraventricular tachycardia, tachycardia, palpitations.
From the respiratory system, chest and mediastinal organs: cough, dysphonia, pharyngitis, bronchospasm, nosebleeds, laryngitis, sinusitis.
From the digestive system: dry mouth, often mild, constipation, gastroesophageal reflux disease, candidiasis of the oral cavity and pharynx, intestinal obstruction, including paralytic ileus, dysphagia, gingivitis, glossitis, stomatitis, nausea, dental caries.
From the immune system, skin and subcutaneous tissue: rash, angioedema, hypersensitivity (including immediate allergic reactions), itching, urticaria, dry skin, skin infections and ulceration.
From the musculoskeletal system and connective tissue: swelling of the joints.
From the urinary system: urinary retention (often in predisposed men), dysuria, urinary tract infection.

special instructions

Spiriva is considered a bronchodilator that is prescribed once daily for maintenance therapy and is not intended for the initial treatment of acute bronchospasm.
Immediate hypersensitivity reactions may occur after using the medicine.
As with other anticholinergic drugs, Spiriva should be used with caution in patients with angle-closure glaucoma, prostatic hyperplasia, or bladder neck obstruction.
Inhaled drugs may cause inhalation-induced bronchospasm. As with other drugs that are typically excreted by the kidneys, the use of Spiriva should be monitored in patients with moderate to severe renal impairment (creatinine clearance<50 мл/мин).
Patients should be instructed regarding the correct use of the medication. Do not get the powder into your eyes! Signs of angle-closure glaucoma may include pain or discomfort in the eyes, blurred vision, the sensation of a halo or colored spots in front of the eyes, combined with redness of the eye in the form of hyperemia of the conjunctiva or cornea. If these symptoms appear in any combination, you should immediately seek specialized medical help. Treatment with eye drops that cause pupil constriction is not considered effective.
Spiriva should not be used more than once a day.
Spiriva capsules should only be used with the HandiHaler device.
The drug contains 5.5 mg of lactose monohydrate per capsule.
Use during pregnancy and lactation. There are no clinical data regarding the use of Spiriva during pregnancy. Preclinical studies have not revealed direct or indirect effects on the course of pregnancy, embryo/fetal development, childbirth and postnatal development.
Thus, the drug should not be used during pregnancy without assessing the balance between the expected benefit and the possible risk to the fetus or child.
The use of the medicine during breastfeeding is not recommended. If its use is necessary, breastfeeding should be stopped.
Children. Based on the fact that there is no experience with the use of Spiriva in children, the drug is proposed for use only in adults.
The ability to influence the reaction speed when driving vehicles or working with other mechanisms. Studies of the effect on the ability to drive a car or use other machinery have not been conducted. Dizziness or blurred vision may affect your ability to drive or operate potentially hazardous machinery.

Interactions

However, although no formal drug interaction studies have been conducted, tiotropium bromide has been used concomitantly with other drugs (sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids used in the treatment of COPD) without clinical evidence of interaction with other drugs.
Limited information on the concomitant use of other anticholinergic drugs with Spiriva comes from two clinical studies: a single dose of ipratropium bromide during long-term use of Spiriva in patients with COPD and healthy volunteers was not associated with an increase in adverse reactions, changes in vital signs or electrocardiographic parameters. results.
But Spiriva has not been studied in combination with anticholinergic drugs and is therefore not recommended for use.

Overdose

High dosages of Spiriva may cause anticholinergic symptoms.
But systemic anticholinergic side effects were absent in healthy volunteers after single doses of up to 282 mcg of tiotropium.
Bilateral conjunctivitis in addition to dry mouth has been observed in healthy volunteers following repeated inhalation of 141 mcg of tiotropium per day, but these effects resolve with the recommended dosage of the drug.
In multiple-dose studies in patients with COPD, use of a maximum daily dose of 36 mcg tiotropium for 4 weeks resulted only in dry mouth.
Acute intoxication from oral use of tiotropium capsules is unlikely due to low oral bioavailability.

Storage conditions

at a temperature not exceeding 25 °C. Protect from direct sunlight, heat and frost. Keep out of the reach of children.
Term of use. After the first opening, the blister strips must be used within 9 days.

Compound

1 capsule contains:

Active Ingredient: 22.5 mcg tiotropium bromide monohydrate, equivalent to 18 mcg tiotropium.

Excipients: lactose monohydrate 200 M; lactose monohydrate micronized.

Capsule composition: gelatin, polyethylene glycol, indigo carmine (E 132), titanium dioxide (E 171), yellow iron oxide (E 172).

Description

Hard gelatin capsules, size 3, light greenish-blue, opaque, imprinted with the company symbol and TI 01 in black ink. The contents of the capsules are white powder.

Pharmacotherapeutic group

Other inhalation agents for the treatment of obstructive airway diseases. Anticholinergics. ATX code: R03BB04.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Tiotropium bromide is a specific long-acting muscarinic receptor antagonist. By binding to muscarinic receptors in bronchial smooth muscle, tiotropium bromide blocks the cholinergic (bronchoconstrictor) effects of acetylcholine released from parasympathetic nerve endings. It has similar affinity for the M1-M5 muscarinic receptor subtypes. In the respiratory tract, tiotropium bromide competitively and reversibly binds to M3 receptors of bronchial smooth muscle, which leads to a decrease in smooth muscle tone and bronchodilation. The effect is dose-dependent and lasts for more than 24 hours. The duration of action is likely due to the very slow dissociation of the binding to the M3 receptor, which is reflected in a significantly longer half-life than ipratropium. Being an N-quaternary anticholinergic blocker, tiotropium bromide, when administered by inhalation, has a local selective effect on the bronchi, demonstrating an acceptable therapeutic dose range without the occurrence of systemic anticholinergic effects.

Pharmacodynamic effects

The bronchodilator effect is predominantly local without systemic action. An in vitro study established a more rapid release of tiotropium from the connection with M2 receptors than from connection with the M3 receptors, which leads to a pharmacokinetically determined selective effect of the drug in relation to the M3 receptor subtype compared to the Mg subtype. High activity, very slow release from the receptor and local selective action when administered by inhalation leads to a clinically significant long-term bronchodilator effect of tiotropium in patients with COPD.

Electrophysiology of the heart

In specifically conducted studies of the drug's effect on the QT interval involving 53 healthy volunteers, SPIRIVA, taken in doses of 18 mcg and 54 mcg (i.e., three times the therapeutic dose) for 12 days, did not cause a significant prolongation of the QT interval on the ECG.

Clinical efficacy and safety

The clinical research program included four one-year, two 6-month, randomized, double-blind studies involving 2663 patients (of which 1308 patients received tiotropium). The 1-year program consisted of two placebo-controlled studies and two active-controlled studies (ipratropium). Both six-month studies were controlled with salmeterol and placebo. All studies included studies of the drug's effect on lung function and the outcomes of dyspnea, exacerbations and health-related quality of life.

Lung function

Once-daily tiotropium bromide provided significant improvements in lung function (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)) within 30 minutes of the first dose, with effects lasting for 24 hours . Pharmacodynamic equilibrium was achieved within one week with maximum bronchodilation from the third day of administration. Tiotropium bromide significantly increased peak expiratory flow (PEF) measured daily in the morning and evening and recorded by the patient. The bronchodilator effect of tiotropium bromide persisted throughout the study period (1 year) without signs of tolerance. A randomized placebo-controlled clinical trial in 105 patients with COPD showed that bronchodilation was maintained over a 24-hour dosing interval compared with placebo, regardless of whether the drug was administered in the morning or evening.

Clinical studies (lasting up to 12 months)

Shortness of breath, exercise intolerance

Tiotropium bromide significantly reduced dyspnea (as assessed using the transient dyspnea index). The improvement was maintained throughout the entire treatment period.

The effect of the drug on the severity of dyspnea during exercise was investigated in two randomized, double-blind, placebo-controlled studies involving 433 patients with moderate to severe COPD. These studies demonstrated a significant increase in symptom-limited endurance training time on bicycle ergometry performed at 75% of maximum work capacity by 19.7% (Study A) and 28.3% (Study B) during six weeks of treatment with SPIRIVA. ) compared to placebo.

Health-related quality of life

In a randomized, double-blind, placebo-controlled, 9-month clinical trial of 492 patients, SPIRIVA improved global health-related quality of life as assessed by the St. George's Respiratory Questionnaire (SGRQ). The number of patients taking SPIRIVA who achieved a significant improvement in total SGRQ score (i.e. > 4 units) was 10.9% higher than in the placebo group (59.1% in the SPIRIVA group vs. 48.2% in the placebo group). placebo group (p=0.029)). The mean difference between groups was 4.19 units (p=0.001; confidence interval: 1.69-6.68). Improvements in the SGRQ domains were 8.19 units for the symptom domain, 3.91 units for the activity domain, and 3.61 units for the influence on daily activities domain. Improvements in all of these areas were statistically significant.

Exacerbation of COPD

In a randomized, double-blind, placebo-controlled study of 1829 patients with moderate to very severe COPD, tiotropium bromide statistically significantly reduced the number of patients with exacerbations of COPD (from 32.2% to 27.8%) and resulted in a statistically significant reduction in the number of exacerbations by 19% (1.05 to 0.85 cases/patient/year of exposure). Hospitalization due to exacerbation of COPD was 7.0% of patients in the tiotropium bromide group and 9.5% of patients in the placebo group (p = 0.056). The number of patients hospitalized for COPD was 30% lower (0.25 to 0.18 cases/patient/year of exposure).

A randomized, double-blind, double-dummy, parallel-group study of 1 year assessed the effect of treatment with SPIRIVA 18 mcg once daily and salmeterol metered-dose aerosol 50 mcg twice daily on the incidence of moderate to severe exacerbations in 7376 patients with COPD and the presence of an exacerbation during the previous year.

Compared with salmeterol, SPIRIVA increased the time to first exacerbation (187 days compared with 145 days) with a 17% reduction in the risk of developing an exacerbation (hazard ratio 0.83; 95% confidence interval (CI) 0.77-0.90, p Long-term clinical studies (more than 1 year, up to 4 years)

A 4-year, randomized, double-blind, placebo-controlled clinical trial involving 5993 randomized patients (3006 placebo patients and 2987 SPIRIVA patients) demonstrated an improvement in FEV1 with SPIRIVA compared with placebo that was maintained over 4 years. The number of patients completing treatment after ≥ 45 months was higher in the SPIRIVA group compared with the placebo group (63.8% versus 55.4%, p

Active-controlled tiotropium studies

A long-term, large-scale, randomized, double-blind, active-controlled study with a follow-up of up to 3 years was conducted to compare the efficacy and safety of SPIRIVA with the HandiHaler inhaler and SPIRIVA with the RESPIMAT inhaler (5694 patients treated with SPIRIVA HandiHaler; 5711 patients treated with SPIRIVA RESPIMAT). Primary endpoints were time to first exacerbation of COPD, time to all-cause mortality and, in a substudy (906 patients), trough FEV1 (pre-dose).

Time to first COPD exacerbation during the study was numerically comparable between the SPIRIVA HandiHaler and SPIRIVA RESPIMAT groups (hazard ratio (SPIRIVA HandiHaler/SPIRIVA RESPIMAT) 1.02; 95% CI 0.97-1.08). The median number of days to first exacerbation of COPD was 719 days for SPIRIVA HandiHaler and 756 days for SPIRIVA RESPIMAT.

The bronchodilator effect of SPIRIVA HandiHaler lasted more than 120 weeks and was similar to that of SPIRIVA RESPIMAT. Average difference in minimum FEV! for SPIRIVA, HandiHaler compared with SPIRIVA was 0.010 L (95% CI -0.018-0.038 L).

The TIOSPIR post-marketing comparative study between SPIRIVA RESPIMAT and SPIRIVA HandiHaler demonstrated similar rates of all-cause mortality, including vital signs monitored, between study groups (hazard ratio (SPIRIVA HandiHaler/SPIRIVA RESPIMAT) 1.04 with 95% CI 0.91-1 ,19).

Pharmacokinetics

Tiotropium bromide is a non-chiral quaternary ammonium compound, poorly soluble in water. Tiotropium bromide is used in the form of a dry powder for inhalation. Typically, with the inhalation route of administration, most of the administered dose is deposited in the gastrointestinal tract and, to a lesser extent, reaches the lungs. Many of the pharmacokinetic data described below were obtained using doses higher than those recommended for treatment.

Absorption

After inhalation of the powder in young healthy volunteers, the absolute bioavailability of 19.5% indicates a high bioavailability of the proportion of the drug reaching the lungs. Tiotropium bromide solutions for oral administration have an absolute bioavailability of 2-3%.

Maximum concentrations of tiotropium in blood plasma are observed 5-7 minutes after inhalation. At steady state, peak plasma levels of tiotropium in patients with COPD were 12.9 pg/mL, with a rapid decline consistent with the multicompartment model. The steady-state residual plasma concentration was 1.71 pg/ml.

Systemic exposure following inhalation of tiotropium via the HandiHaler inhaler was similar to exposure following inhalation via the RESPIMAT inhaler.

Distribution

Tiotropium binds to plasma proteins by 72%, the volume of distribution is 32 l/kg. Local concentrations in the lungs are unknown, but the route of administration suggests significantly higher concentrations of the drug in the lungs. Studies in rats have shown that tiotropium bromide does not cross the blood-brain barrier even in minimal quantities.

Biotransformation

The degree of biotransformation is insignificant. This is confirmed by the fact that after intravenous administration of the drug to young healthy volunteers, 74% unchanged tiotropium bromide is found in the urine. Tiotropium bromide is an ester that degrades non-enzymatically to alcohol (N-methylscopine) and dithienylglycolic acid, which do not bind to muscarinic receptors. In vitro studies of human liver microsomes and human hepatocyte cell cultures have shown that some part of the drug (

Removal

The effective half-life of tiotropium is 27-45 hours in patients with COPD. The total clearance after intravenous administration of the drug to young healthy volunteers was 880 ml/min. Intravenously administered tiotropium bromide is excreted mainly by the kidneys unchanged (74%). After inhalation of the dry powder in patients with COPD, the steady-state renal excretion is 7% (1.3 mcg) unchanged over 24 hours, the remaining unabsorbed portion is excreted through the intestine. The renal clearance of tiotropium bromide exceeds the clearance of creatinine, which confirms the excretion of the drug in the urine. With regular once-daily inhaled tiotropium use in patients with COPD, the pharmacokinetic steady state was achieved on day 7, with no evidence of accumulation thereafter.

Linearity/nonlinearity of pharmacokinetics

Tiotropium exhibits linear pharmacokinetics at therapeutic doses regardless of dosage form.

Special patient groups

Elderly patients

As with all drugs with predominantly renal excretion, increasing patient age was associated with decreased renal clearance of tiotropium (from 365 ml/min in older COPD patients

Renal dysfunction

When steady state was achieved with inhaled tiotropium administered once daily in patients with COPD and mild renal failure (creatinine clearance 50-80 ml/min.), a slight increase in AUC0-6.ss (1.8-30% higher) was observed and similar values of Cmax,ss compared to patients with normal renal function (creatinine clearance > 80 ml/min.).

In patients with COPD and moderate or severe renal impairment

Liver dysfunction

Hepatic impairment is not expected to significantly affect the pharmacokinetics of tiotropium. Tiotropium is excreted primarily by the kidneys (74% in healthy young volunteers) and is metabolized by simple non-enzymatic ester cleavage to pharmacologically inactive metabolites.

Pharmacokinetic/pharmacodynamic relationships

There is no direct relationship between pharmacokinetics and pharmacodynamics.

Indications for use

SPIRIVA is indicated as maintenance bronchodilator therapy to relieve symptoms in patients with chronic obstructive pulmonary disease (COPD).

Directions for use and doses

The medicinal product is intended for inhalation use only.

SPIRIVA capsules are for inhalation only and not for oral administration.

SPIRIVA capsules should not be swallowed.

SPIRIVA capsules should only be used with the HandiHaler inhaler.

Special patient groups

Elderly patients can take tiotropium bromide at the recommended dose.

Patients with impaired renal function can use tiotropium bromide at the recommended dose. For information on the use of the drug in patients with moderate or severe renal impairment (creatinine clearance ≤ 50 ml/min.), see sections “Pharmacokinetics” and “Precautions”.

Patients with impaired liver function can take tiotropium bromide at recommended doses (see section "Pharmacokinetics").

Children

COPD

There is no experience with the use of SPIRIVA in children and adolescents under the age of 18 years for the indications listed in the “Indications for Use” section.

Cystic fibrosis

The safety and effectiveness of SPIRIVA 18 mcg in children and adolescents have not been established. No data available.

Instructions for use of the HandiHaler inhaler

In order to use the medicine correctly, the healthcare professional must show the patient how to use the inhaler.

Remember that when using SPIRIVA, you must carefully follow all your doctor's instructions.

The HandiHaler inhaler is specially designed for SPIRIVA. It should not be used for other medicines. You can use your HandiHaler for one year.

HandiHaler inhaler includes:

Dust cap; Mouthpiece; Base; Piercing button; Central chamber. Open the dust cap by pressing the piercing button all the way, then release it. Open the dust cap completely by folding it up. Then open the mouthpiece by lifting it up. Remove the SPIRIVA capsule from the blister (immediately before use) and place it in the central chamber (5) as shown in the illustration. It does not matter which side the capsule is placed in the chamber. Close the mouthpiece tightly until you hear a click. Leave the dust cap open. Holding the HandiHaler with the mouthpiece up, press the piercing button once until it stops, and then release. This creates an opening through which the drug is released from the capsule during inhalation. Exhale completely.

Caution: Never exhale into the mouthpiece.

Place the HandiHaler in your mouth and press your lips tightly around the mouthpiece. Keeping your head straight, inhale slowly and deeply, but at the same time with enough force to hear or feel the vibration of the capsule. Inhale until your lungs are completely filled; then hold your breath until you feel discomfort, while simultaneously removing the HandiHaler from your mouth. Continue to breathe calmly. Repeat procedures 6 and 7 until the capsule is completely empty. Open the mouthpiece again. Throw away the used capsule. Close the mouthpiece and dust cap.

CleaningHandiHalera

Clean your HandiHaler once a month. Open the mouthpiece and dust cap. Then lift up the lancing button to open the base of the inhaler. Rinse the inhaler thoroughly with warm water until the powder is completely removed. Wipe HandiHaler with a paper towel and with mouthpiece, base and dust cap open, air dry for 24 hours. After cleaning the device according to the instructions, it will be ready for next use. If necessary, wipe the outer surface of the mouthpiece with a damp, but not wet, cloth.

Opening the blister

Separate the blister strip along the perforated line.

B. Immediately before use, open the blister strip so that one capsule is completely visible.

If the capsule is opened accidentally and exposed to air, it should be discarded.

Remove the capsule.

SPIRIVA capsules contain a small amount of powder, so the capsule is not completely filled.

Side effect

Many of the following side effects can be attributed to the anticholinergic properties of SPIRIVA.

The frequencies reported for the following adverse effects are based on the overall incidence of adverse effects (i.e., tiotropium-related events) observed in the tiotropium group (9647 patients) in 28 pooled placebo-controlled clinical trials with a treatment duration of four weeks or more up to four years.

Frequency is defined as follows: very often (≥ 1/10), often (≥ 1/100 to

From the side of metabolism: unknown - dehydration.

From the nervous system: uncommon - dizziness, headache, taste disturbances; rarely - insomnia.

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

From the heart: infrequently - atrial fibrillation; rarely - supraventricular tachycardia, tachycardia, palpitations.

From the respiratory system: infrequently - pharyngitis, dysphonia, cough; rarely - bronchospasm, nosebleeds, laryngitis, sinusitis.

Co sides of the gastrointestinal tract: often - dry mouth; uncommon - gastroesophageal reflux, constipation, oral candidiasis; rarely - intestinal obstruction, including paralytic ileus, gingivitis, glossitis, difficulty swallowing, stomatitis, nausea; unknown - caries.

For the skin and subcutaneous tissues: uncommon - rash; rarely - urticaria, itching, hypersensitivity, including immediate reactions, angioedema; unknown - anaphylactic reaction, skin infections and ulcers, dry skin.

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

From the kidneys and urinary tract: uncommon - dysuria, urinary retention; rarely - urinary tract infection.

In controlled clinical trials, the most common adverse effects were related to the anticholinergic properties of the drug and were dry mouth in approximately 4% of patients. In 28 clinical studies, dry mouth led to treatment discontinuation in 18 of 9647 patients receiving tiotropium (0.2%).

Serious adverse effects associated with the anticholinergic properties of the drug include: glaucoma, constipation, intestinal obstruction including paralytic ileus, and urinary retention.

The incidence of anticholinergic effects may increase with increasing age.

Inhaled drugs may cause bronchospasm.

Tiotropium should be used with caution in patients with recent myocardial infarction (

Due to the increase in plasma concentrations of the drug in patients with moderate or severe renal impairment (creatinine clearance ≤ 50 ml/min), tiotropium bromide can be used in this group of patients only in cases where the expected benefit outweighs the possible risk. There are no data on long-term use of the drug in patients with severe renal failure.

Patients should be warned not to allow the powder to come into contact with the eyes. Patients should be advised that this may result in precipitation or worsening of angle-closure glaucoma, ocular pain or discomfort, temporary blurred vision, visual halos or colored images combined with eye redness resulting from conjunctival hyperemia and corneal edema. If any of the above symptoms occur, the patient should stop taking tiotropium bromide and consult a doctor immediately.

Dry mouth, observed with the use of anticholinergic drugs, can lead to dental caries if present for a long time.

SPIRIVA capsules should not be used more than once daily.

SPIRIVA capsules contain 5.5 mg of lactose monohydrate. This amount usually does not cause problems in patients with lactose intolerance. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome are not recommended to take this medicine. The excipient lactose monohydrate may contain small amounts of milk proteins, which may cause allergic reactions.

Pregnancy and lactation

Pregnancy

Data on the use of tiotropium in pregnancy are very limited. Animal studies have not revealed direct or indirect adverse effects on the reproductive system when using therapeutic doses. As a precaution, it is preferable to avoid the use of SPIRIVA during pregnancy.

Breastfeeding period

It is not known whether tiotropium bromide passes into breast milk in women. Although studies in rodents have demonstrated that only small amounts of tiotropium bromide are excreted in breast milk, the use of SPIRIVA during breastfeeding is not recommended. Tiotropium bromide is a long-acting agent. The decision to continue/discontinue breastfeeding or continue/discontinue therapy with SPIRIVA should be made after assessing the benefits of breastfeeding for the child and the benefits of SPIRIVA therapy for the woman.

Fertility

There are no clinical data on the effect of tiotropium on fertility. Preclinical studies have not demonstrated a negative effect of the drug on fertility.

Impact on the ability to drive a car and operate machinery

Studies on the effect of tiotropium on the ability to drive vehicles and operate machinery have not been conducted. However, dizziness, blurred vision, or headaches while taking the drug may affect your ability to drive and operate machines.

Overdose

When tiotropium bromide is used in high doses, manifestations of anticholinergic effects are possible.

However, systemic anticholinergic side effects were not reported when a single dose of up to 340 mcg of tiotropium bromide was administered to healthy volunteers by inhalation. Additionally, after 7 days of dosing up to 170 mcg of tiotropium bromide in healthy volunteers, no side effects other than dry mouth were observed. In a multiple-dose study in patients with COPD using a maximum daily dose of 43 mcg tiotropium bromide for four weeks, no significant adverse effects were observed.

The development of acute intoxication due to accidental ingestion of tiotropium bromide capsules is unlikely due to low bioavailability when administered orally.

Interaction with other drugs

Although specific drug interaction studies have not been conducted, tiotropium bromide powder for inhalation has been used in combination with other drugs without clinical evidence of drug interaction. These drugs included bronchodilators (sympathomimetics), methylxanthines, and oral and inhaled steroids, which are widely used in the treatment of COPD.

There was no effect of long-acting beta-adrenergic agonists or inhaled corticosteroids on tiotropium exposure.

Do not use after the expiration date stated on the package. Once opened, use the blister within 9 days.

Conditions for dispensing from pharmacies

By doctor's prescription.

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.

Agency in Belarus

Minsk, st. V. Khoruzhey, 22-1402.

Tel.: (+375 17) 283 16 33, fax: (+375 17) 283 16 40.