Spiriva Respimat solution for inhalation 2.5 mcg dose cartridge complete with inhaler 60 doses
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Active ingredients
Tiotropium Bromide
Release form
Solution
Composition
Tiotropium bromide monohydrate is 3.1235 mcg, which corresponds to a tiotropium content of 2.5 mcg. Adjuvants: benzalkonium chloride - 1.105 mcg, disodium edetate - 1.105 mcg, hydrochloric acid 1M - to pH 2.8-3.0, water - up to 11.05 mg.
Pharmacological effect
Bronchodilator drug. Thiotropy bromide - long-acting m-cholinoblocker. The drug has the same affinity for the M1-M5 subtypes of muscarinic receptors. The result of inhibition of M3-cholinergic receptors in the respiratory tract is the relaxation of smooth muscles. The bronchodilating effect is dose dependent and lasts for at least 24 hours. A significant duration of action is probably associated with a very slow dissociation of the drug from M3-cholinergic receptors; The half-dissociation period is significantly longer than that of ipratropium bromide. In the case of inhalation of administration of tiotropium, bromide, as an N-quaternary ammonium derivative, has a local selective effect (on the bronchi), while at therapeutic doses it does not cause systemic m-cholinoblocking side effects. Dissociation from M2-cholinergic receptors occurs faster than from M3-cholinergic receptors, which indicates the predominance of selectivity for the M3 receptor subtype over M2-cholinergic receptors. The high affinity for receptors and the slow dissociation of the drug from its association with receptors cause a pronounced and prolonged bronchodilating effect in patients with COPD. Bronchodilation, which develops after inhalation of tiotropium bromide, is due primarily to local (in the respiratory tract), and not systemic effects. clinical studies have shown that the use of the drug Spiriva; Respimat; 1 time / day leads to a significant improvement (compared with placebo) lung function (FEV1 and FVC) within 30 minutes after using the first dose. Improvement of lung function is maintained for 24 hours at equilibrium concentration. The pharmacodynamic equilibrium is achieved within one week. Spiriva; Respimat; significantly improved morning and evening peak expiratory flow rate (ESP) measured by patients. Use of the drug Spiriva; Respimat; led to a decrease (compared with placebo) use of bronchodilator as a means of emergency.Bronchodilating effect of the drug is maintained for 48 weeks of use of the drug; no signs of habituation are noted. An analysis of the combined data of two randomized, placebo-controlled, cross-sectional clinical studies showed that the bronchodilating effect of the drug Spiriva; Respimat; (5 mcg) after a 4-week treatment period was quantitatively higher than the effect of the drug Spiriva; (18 mcg). In long-term (12-month) studies, it was found that Spiriva; Respimat; significantly reduces shortness of breath; improves the quality of life; reduces the psychosocial impact of COPD and increases the activity. The drug Spiriva; Respimat; significantly improved overall health (overall score) compared with placebo at the end of two 12-month studies, this difference persisted throughout the entire treatment period; drug Spiriva; Respimat; significantly reduced the number of exacerbations of COPD, and increased the period until the first exacerbation compared with placebo. It is proved that Spiriva; Respimat; reduces the risk of COPD exacerbation and significantly reduces the number of hospitalizations. In a retrospective analysis of individual clinical studies, a statistically insignificant increase in the number of deaths in patients with heart rhythm disturbances was observed in comparison with placebo. However, these data are not statistically confirmed and may be associated with heart disease. In clinical studies in patients with asthma and continuing to experience symptoms of the disease, despite supportive therapy with inhaled corticosteroids, including in combination with a long-acting beta2-adrenoreceptor agonist, it was found that the addition of the drug 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 symptoms of bronchial asthma, increased the period before their first occurrence, led to a significant improvement in the quality of life and an increase in the number of patients with a positive response to maintenance therapy. Bronchodilating effect of the drug was maintained for 1 year of use, no signs of addiction were noted.
Pharmacokinetics
Tiotropium bromide is a quaternary ammonium derivative, moderately soluble in water.Tiotropium bromide is produced as an inhalation solution, which is used with the Respimat inhaler ;. Approximately 40% of the inhalation dose is deposited in the lungs, the rest goes to the gastrointestinal tract. Some pharmacokinetic data, described below, were obtained using doses higher than recommended for treatment. Absorption After inhalation of the solution by young healthy volunteers, it was found that about 33% of the inhalation dose is delivered to the systemic circulation. Meal does not affect the absorption of tiotropium bromide, due to the fact that it is poorly absorbed from the gastrointestinal tract. Absolute bioavailability when administered is 2-3%. Cmax in plasma is observed 5-7 minutes after inhalation. The distribution of the drug binding to plasma proteins is 72%; Vd - 32 l / kg. In the equilibrium state, C max plasma tiotropy in patients with COPD is 10.5 pg / ml and decreases rapidly. This indicates a multi-compartment type of drug distribution. In equilibrium, the basal concentration of tiotropium in plasma is 1.6 pg / ml. In equilibrium, Cmax of tiotropium in the blood plasma of patients with asthma was 5.15 pg / ml and was reached after 5 minutes. Studies have shown that tiotropium bromide does not penetrate the BBB. Metabolism The biotransformation degree is insignificant. This is confirmed by the fact that after iv administration of the drug, young healthy volunteers in the urine detect 74% of the substance of tiotropium bromide in unchanged form. Tiotropium bromide is an ether that is cleaved into ethanol-N-methylscopin and dithienyl glycolic acid; these compounds do not bind to muscarinic receptors. In vitro studies have shown that some of the drug (less than 20% of the dose after iv administration) is metabolized by oxidation with cytochrome P450 followed by conjugation with glutathione and the formation of various metabolites. This mechanism can be inhibited by inhibitors of CYP2D6 and 3A4 isoenzymes (quinidine, ketoconazole, and gestodene). Thus, CYP2D6 and 3A4 are involved in the drug metabolism. Tiotropium bromide, even at supertherapeutic concentrations, does not inhibit cytochrome P450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A in human liver microsomes. In patients with bronchial asthma, the effective T1 / 2 after inhalation is 34 hours. The total clearance after iv administration of the drug to young healthy volunteers was 880 ml / min.Tiotropium bromide after IV injection is mainly excreted by the kidneys in unchanged form (74%). After inhalation of the solution in patients with COPD, renal excretion is 18.6% (0.93 μg), the remaining unabsorbed part is excreted through the intestine. In an equilibrium state in patients with bronchial asthma, 11.9% (0.595 μg) of the dose is excreted unchanged in the urine 24 hours after taking the drug. Renal clearance of tiotropium bromide exceeds KK, which indicates its tubular secretion. After a long inhalation dose of the drug 1 time / day in patients with COPD, an equilibrium state is reached on day 7; however, no further cumulation is observed. Tiotropia bromide has linear pharmacokinetics within therapeutic limits after IV application, inhalation of dry powder and solution inhalation. Pharmacokinetics in special clinical cases In elderly patients, there is a decrease in renal clearance of tiotropium bromide (347 ml / min in patients with COPD before the age of 65 and 275 ml / min in patients with COPD and asthma over 65). It was established that in patients with bronchial asthma, the effect of tiotropium bromide does not depend on the age of patients. After inhalation use of tiotropium 1 time / day in an equilibrium state in patients with COPD and mild renal impairment (CK 50-80 ml / min), a slight increase in AUC0 –6, ss by 1.8–30% and Cmax, ss compared with patients with normal renal function (CK more than 80 ml / min). In patients with COPD and moderate or significant renal impairment (less than 50 ml / min), tiotropium bromide was used to double the overall exposure (AUC0–4 h increased by 82%, and Cmax increased by 52%) compared to in patients with COPD and normal renal function. A similar increase in plasma concentration was also observed after inhalation of dry powder. In patients with bronchial asthma and minor impairment of renal function (CK 50-80 ml / min), inhalation use of tiotropium bromide did not lead to a significant increase in exposure compared with patients with normal renal function. It is assumed that hepatic impairment does not have a significant effect on the pharmacokinetics of tiotropium bromide, since Thiotropium bromide is mainly excreted by the kidneys and by non-enzymatic cleavage of the ester bond with the formation of derivatives that do not possess pharmacological activity.
Indications
- for maintenance treatment of patients with COPD, chronic bronchitis, pulmonary emphysema, for maintenance therapy with persistent dyspnea, to improve the quality of life impaired due to COPD, to reduce the frequency of exacerbations - as an additional maintenance therapy in patients with bronchial asthma with continuing symptoms of the disease while receiving, at least, inhaled GCS, to reduce the symptoms of bronchial asthma, improve the quality of life and reduce the frequency of exacerbations. With caution: closed Glaucoma, prostatic hyperplasia, bladder neck obstruction.
Contraindications
- hypersensitivity to the components of the drug, to atropine or its derivatives: ipratropium bromide, oxitropium bromide; - children and adolescents under 18 years of age (due to the lack of data on efficacy and safety). bladder neck obstruction.
Precautionary measures
During treatment, psoriasis may worsen. During pheochromocytoma, propranolol can only be used after taking an alpha blocker. After a long course of treatment, propranolol should be discontinued gradually, under the supervision of a physician. during anesthesia, you must stop taking propranolol or find a remedy for anesthesia with minimal negative inotropic effects. The impact on the ability to drive vehicles and control mechanisms of patients whose activities require increased attention, the question of the use of propranolol on an outpatient basis should be addressed only after evaluating the individual response of the patient.
Use during pregnancy and lactation
Data on the effect of the drug Spiriva; Respimat; for pregnancy are limited. In the study of reproductive toxicity in animals, no indications of direct or indirect adverse effects of the drug were obtained. As a precautionary measure, it is preferable to refrain from using the drug Spiriva; Respimat; during pregnancy. There are no clinical data on the effect of tiotropium bromide during breastfeeding. The drug should not be used in pregnant or lactatingbreastfeeding women, if only the expected benefit to the mother outweighs the potential risk to the fetus and baby. For the period of use of the drug should stop breastfeeding.
Dosage and administration
The recommended therapeutic dose is 2 inhalation doses of spray from Respimat inhaler; (5 mcg / dose) 1 time / day, at the same time of the day. When treating bronchial asthma, the full therapeutic effect occurs in a few days. In elderly patients, patients with impaired liver function and patients with minor impaired renal function (CC 50-80 ml / min) the drug Spiriva can be used; Respimat; at the recommended dose. However, the use of the drug in patients with moderate or significant renal impairment (CC less than 50 ml / min) should be carried out under close supervision. COPD is usually not found in children. Safety and efficacy of the drug Spiriva; Respimat; have not been studied in children. The rules for using the Spiriva inhaler; Before starting to use the drug, you should learn the rules for using the Spiriva inhaler; Respimat;. Inhalyator designed to use 1 time / day. Each time you use it, you should do 2 inhalations. Caring for the Spiriv inhaler; The mouthpiece and the metal part of the mouthpiece must be cleaned with a damp cloth or cloth at least once a week. Any slight change in the color of the mouthpiece does not affect the operation of the inhaler. The Inhibitor Spiriva; Respimat; contains 60 inhalation doses (ie, 30 therapeutic doses), provided that they are used in accordance with the dosing regimen (2 inhalation doses 1 time / day). The dose indicator shows how many doses are approximately left. When the indicator shows on the red area of the scale, it means that the medication is left for about 7 days (14 inhalation doses). When the dose indicator of the inhaler reaches the end of the red area of the scale, it means that the inhaler is Dirive; Respimat; is empty. The inhaler will be automatically blocked. From this point on, it will not be possible to rotate the transparent sleeve. 3 months after the first use, the Spiriva inhaler; Respimat; should be thrown away even if it is not fully used. Preparation for first use: 1.Remove the transparent sleeve-Keep the cap closed. -Press the locking button and pull the transparent sleeve tightly with the other hand. Insert the cartridge — Insert the narrow end of the cartridge into the inhaler. - Place the inhaler with the bottom of the cartridge on a hard surface and press it firmly until the cartridge snaps into place with a click. Install the transparent sleeve in place — Place the transparent sleeve in place until it clicks.4. Turn sleeve - Keep the cap closed. - Turn the transparent sleeve in the direction indicated by the arrows on the label until it clicks (half a turn) 5. Open the cap.-Open the cap until it stops.6. Press the button-Direct the inhaler down. -Press the dose button. -Close the cap.-Repeat steps 4-6 until the aerosol cloud appears. -Then repeat steps 4-6 3 more times. Daily applicationTo rotate-Keep the cap closed.-Rotate transparent the sleeve in the direction indicated by the arrows on the label until it clicks (half a turn). Open the cap-Open the cap until it stops. Press the button Make a slow full exhalation. Grab the mouthpiece with your lips without blocking the air inlets. Taking a slow, deep breath through your mouth, press the button filing up Threat and continue to inhale. Hold your breath for about 10 seconds. To receive the second inhalation dose, repeat the operation: Rotate, Open, Press.
Side effects
Many of the adverse reactions listed below may be due to the m-anticholinergic properties of the drug. Side reactions were identified based on data obtained during clinical studies and individual reports during post-registration use of the drug. On the metabolic side: dehydration *. On the nervous system: infrequently (≥0.1% and less than 1%) - dizziness; insomnia *. From the side of the organ of vision: rarely (≥0.01% and less than 0.1%) - increased intraocular pressure, glaucoma, blurred vision. From the side of the cardiovascular system: infrequently (more than 0.1% and less than 1%) - atrial fibrillation, tachycardia (including supraventricular tachycardia), palpitations. On the respiratory system: infrequently (≥0.1% and less than 1%) - cough, nosebleeds, pharyngitis, dysphonia; rarely (≥0.01% and less than 0.1%) - paradoxical bronchospasm,laryngitis; sinusitis. From the digestive system: often (≥1% and less than 10%) - slight transient dryness of the pharyngeal mucosa; infrequently (more than 0.1% and less than 1%) - constipation, oral candidiasis, dysphagia; rarely (≥0.01% and less than 0.1%) - gastroesophageal reflux, gingivitis, glossitis, stomatitis; intestinal obstruction, including paralytic intestinal obstruction *. On the skin: rarely (≥0.01% and less than 0.1%) - skin infections and ulcers on the skin, dry skin. Allergic reactions: infrequently (more than 0.1% and less than 1%) - rash, itching; rarely (≥0.01% and less than 0.1%) - angioedema, urticaria; hypersensitivity, including immediate-type reactions *. For the musculoskeletal system: swelling of the joints *. For the urinary system: infrequently (more than 0.1% and less than 1%) - dysuria, urinary retention (more often in men with predisposing factors); rarely (≥0.01% and less than 0.1%) - urinary tract infection. * In the joint database of clinical studies, these adverse reactions were not identified; only isolated reports of these adverse reactions were noted with widespread use of the drug, but the relationship with the m-holinoblokiruyuschim action of the drug has not been proven the frequency of these rare events is difficult to estimate.
Overdose
When using the drug in high doses, manifestations of m-anticholinergic blocking action are possible. After a 14-day inhalation use of tiotropium bromide in doses up to 40 μg, no significant adverse events were observed in healthy individuals, except for a feeling of dryness of the mucous membranes of the nose and oropharynx, the frequency of which depended on the dose (10-40 μg / day). The exception was a clear decrease in salivation, starting from day 7 of the drug. In six long-term studies in patients with COPD with inhalation use of a solution of tiotropium bromide at a daily dose of 10 mcg for 4-48 weeks, no significant adverse events were observed. Due to the low oral bioavailability, the occurrence of acute intoxication in the case of unintentionally swallowing a solution of tiotropium bromide for inhalation from the cartridge of inhaled bromide for inhalation from the cartridge to inhale from the cartridge .
Interaction with other drugs
Although there have been no specific studies of drug interactions, tiotropium bromide has been used in conjunction with other drugs,used for the treatment of COPD, including sympathomimetic bronchodilators, methylxanthines, oral and inhalation GCS, antihistamines, mucolytics, leukotriene modifiers, cromones, anti-IgE drugs; no clinical signs of drug interaction were noted. Long-term combined use of tiotropium bromide with other m-holinoblocking drugs has not been studied. Therefore, long-term joint use of the drug Spiriva; Respimat; with other m-holinoblokiruyuschimi drugs is not recommended.
special instructions
The drug Spiriva; Respimat ;, as a bronchodilator, used 1 time / day for maintenance treatment, should not be used as initial therapy for acute attacks of bronchospasm or for the elimination of acute symptoms. In the case of an acute attack, fast-acting beta2-agonists are used. Spiriva; Respimat; should not be used for the treatment of bronchial asthma as a first-line therapy. Patients should be recommended while taking the drug Spiriva; Respimat; continue anti-inflammatory therapy (for example, inhaled GCS), even if the symptoms diminish. Immediate hypersensitivity reactions may develop after the drug has been used. The drug inhalation can cause bronchospasm. careful observation, as well as when taking all medications excreted mainly by the kidneys. Before starting use, patients should be familiar with the instructions for use Do not let the solution or aerosol in the eye. Pain or discomfort in the eyes, blurred vision, visual halos combined with red eyes, swelling of the conjunctiva and cornea can be symptoms of acute angle-closure glaucoma. With the development of any combination of these symptoms should immediately consult a specialist. Eye drops with a miotic effect are not considered an effective treatment. Spiriva; Respimat; do not use more than 1 time / day. Cartriji Spiriva; should be used only with Respimat inhaler;. Impact on the ability to drive vehicles and control mechanisms Studies have not been conducted to study the effect on the ability to drive vehicles and mechanisms. Care should be taken when performing these activities, becausemay develop dizziness or blurred vision.