Spiriva capsules with powder for inhalation 18mkg N30 + inhaler
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Active ingredients
Tiotropium Bromide
Release form
Solution
Composition
Tiotropium bromide monohydrate 22.5 mcg, which corresponds to the content of tiotropium 18 mcg; Excipients: lactose monohydrate, 200 M - 5.2025 mg, lactose monohydrate micronized - 0.2750 mg.
Pharmacological effect
Bronchodilator drug - long-acting m-cholinergic receptor blocker .; It has the same affinity for different subtypes of muscarinic receptors from M1 to M5. As a result of inhibition of M3 receptors in the airways, smooth muscle relaxes. The bronchodilatory effect is dose dependent and lasts for at least 24 hours. A significant duration of action is probably associated with a very slow release from the association with M3 receptors, compared with ipratropium bromide. When inhaled, tiotropium bromide, as an anticholinergic agent of N-quaternary structure, has a local selective effect, while in therapeutic doses does not cause systemic anticholinergic side effects. The release of tiotropium bromide from communication with M2 receptors occurs faster than from communication with M3 receptors. High affinity for receptors and slow release from their association with them cause an intense and prolonged bronchodilatory effect in patients with COPD .; Bronchodilation after inhalation of tiotropium bromide is a consequence of local, not systemic effects .; In clinical studies, it was shown that 30 minutes after a single dose of Spiriva; over 24 hours, significantly improves lung function (increased FEV1 and FVC). Pharmacodynamic equilibrium was achieved during the 1st week, and a pronounced bronchodilating effect was observed on the 3rd day. Spiriva; significantly increases morning and evening peak expiratory flow rate measured by patients. The bronchodilator effect of Spiriva, assessed throughout the year, revealed no manifestations of tolerance .; Spiriva; significantly reduces shortness of breath throughout the entire period of treatment. In two randomized, double-blind, placebo-controlled studies, it was proved that Spiriva; significantly improved exercise tolerance compared with placebo .; Significantly improves the quality of life, which is observed during the entire period of treatment.Spiriva; significantly reduces the number of cases of hospitalization associated with exacerbation of COPD, and increases the time until the first hospitalization .; It was also shown that Spiriva; leads to a sustained improvement in FEV1 after application for 4 years without changing the rate of annual decline in FEV1 .; During treatment, there is a decrease in the risk of death by 16% .; Compared with taking salmeterol, the use of the drug Spiriva; increases the time to first exacerbation (187 days versus 145), with a 17% reduction in the risk of exacerbations (risk ratio 0.83; 95% confidence interval [CI], from 0.77 to 0.90; P = 0,011). Also taking the drug Spiriva; increases the time of the onset of the first severe (requiring hospitalization) exacerbation (hazard ratio 0.72; 95% CI from 0.61 to 0.85; Pnise) 0.001) reduces the annual number of moderate or severe (requiring hospitalization) exacerbations (0.64 vs. 0.72; hazard ratio 0.89; 95% CI from 0.83 to 0.96; P = 0.002), reduces the annual number of severe (requiring hospitalization) exacerbations (0.09 versus 0.13; risk ratio 0.73; 95% CI from 0.66 to 0.82; P => 0.001).
Pharmacokinetics
Tiotropium bromide is a quaternary ammonium compound, sparingly soluble in water .; Tiotropium bromide has linear pharmacokinetics within therapeutic limits after i.v. administration and inhalation of dry powder .; Absorption; With inhalation, the absolute bioavailability of tiotropium bromide is 19.5%, which indicates a high bioavailability of the fraction of the drug reaching the lungs. Cmax in plasma is reached 5-7 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. Upon ingestion of tiotropium bromide in the form of a solution, the absolute bioavailability was 2-3%; Distribution; Plasma protein binding - 72%. Vd - 32 l / kg .; In the equilibrium state, Cmax in the blood plasma of patients with COPD is 12.9 pg / ml and decreases rapidly. This indicates a multi-compartment type of drug distribution. In equilibrium, Cmin tiotropium in plasma is 1.71 pg / ml. Does not penetrate the BBB .; Metabolism; The degree of biotransformation is negligible. This is confirmed by the fact that after i / v administration of the drug, young healthy volunteers in the urine detected 74% of the unchanged substance .; Tiotropium bromide is cleaved non-enzymatically to alcohol-N-methylscopin and dithienylglycolic acid, which do not bind to muscarinic receptors .; When research is shownthat the drug (less than 20% of the dose after i / v administration) is metabolized with the participation of cytochrome P450 isoenzymes, by oxidation and subsequent conjugation with glutathione with the formation of various metabolites. Metabolic disorders can occur with the use of inhibitors of CYP2D6 and CYP3A4 (quinidine, ketoconazole and gestodene). Thus, CYP2D6 and CYP3A4 isoenzymes are involved in drug metabolism .; Withdrawal; T1 / 2 tiotropy after inhalation varies from 27 to 45 hours. The total clearance for on / in the introduction of young healthy volunteers is 880 ml / min. Tiotropium after i / v is mainly excreted by the kidneys in unchanged form (74%). After inhalation of a dry powder in an equilibrium state, renal excretion is 7% per day of the dose, the remaining non-absorbed portion is excreted through the intestine. Renal clearance of tiotropium exceeds creatinine clearance, which indicates the tubular secretion of the drug. After long-term use of the drug once a day by patients with COPD, pharmacokinetic equilibrium is reached on day 7, with no further cumulation observed .; Pharmacokinetics in special groups of patients; In elderly patients, there is a decrease in renal clearance of tiotropium (365 ml / min in patients with COPD younger than 65 years, to 271 ml / min in patients with COPD older than 65 years). These changes did not lead to a corresponding increase in AUC0-6 or Cmax .; In patients with COPD and mildly impaired renal function (CC 50–80 ml / min), inhalation of tiotropium 1 time / day in an equilibrium state led to an increase in AUC0–6 value of 1.8–30%. The Cmax value was kept the same as in patients with normal renal function (CC more than 80 ml / min). In patients with COPD and moderate or severe impaired renal function (CC less than 50 ml / min), iv administration of tiotropium resulted in a twofold increase in plasma concentration (AUC0–4 h increased by 82% and Cmax increased by 52%) compared with patients with COPD and normal renal function. A similar increase in plasma concentration of tiotropium was also observed after inhalation of a dry powder .; It is assumed that liver failure will not have a significant effect on the pharmacokinetics of tiotropium bromide, since the drug is mainly excreted in the urine and the formation of pharmacologically active metabolites is not associated with the participation of enzymes.
Indications
- as maintenance therapy in patients with COPD, including chronic bronchitis and emphysema (maintenance therapy with persistent dyspnea and to prevent exacerbations).
Contraindications
- I trimester of pregnancy; - children's and teenage age up to 18 years; - hypersensitivity to atropine or its derivatives (including to ipratropium and oxitropium); - hypersensitivity to the components of the drug .; With caution should use the drug in angle-closure glaucoma, prostatic hyperplasia, obstruction of the bladder neck.
Use during pregnancy and lactation
Data on the use of tiotropium in pregnancy in humans is limited. In animal studies, no indications of direct or indirect adverse effects on pregnancy, embryo / fetus development, childbirth or postnatal development have been obtained .; As a precautionary measure, it is preferable to refrain from using the drug Spiriva; during pregnancy .; Clinical data on the use of tiotropium in women who are breastfeeding is not available. In preclinical studies, data were obtained that a small amount of tiotropium is excreted into breast milk .; Spiriva; should not be used in pregnant or lactating women, unless the expected benefit exceeds the possible risk to the fetus or child.
Dosage and administration
Assign 1 capsule / day at the same time in the form of inhalation using the inhaler HandiHaler; The drug should not be swallowed. Spirivu should not be used more than 1 time per day. Spiriva capsules should only be used with a HandiHaler inhaler; Elderly patients should take the drug in recommended doses .; For impaired renal function, patients can use the drug Spiriva; in recommended doses. However, careful monitoring of patients with moderate or severe renal insufficiency receiving the drug Spiriva is necessary; (as is the case with other drugs, excreted mainly by the kidneys) .; Patients with hepatic insufficiency may take the drug in recommended doses .; Method of use of the inhaler HandiHaler; Inhaler HandiHaler; designed specifically for use Spiriva and is not intended to receive other drugs. A patient can use their HandiHaler; for one year .; The inhaler includes: a dust cap, a mouthpiece, a base, a piercing button, a central chamber .; Use of the inhaler HandiHaler;:; 1.Open the dust cap by pressing the piercing button completely and then releasing.; 2. Fully open the dust cap by lifting it up; then open the mouthpiece by lifting it up .; 3. Immediately before use, take the Spiriva capsule out of 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, leave the dust cap open .; 5. Holding a HandiHaler; mouthpiece up, press the piercing button once to the end 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; in the mouth and tightly squeeze the lips around the mouthpiece; keeping your head straight, you should inhale slowly and deeply, but at the same time with sufficient force to hear or feel the vibration of the capsule; inhale until the lungs are completely filled; then hold your breath for as long as possible and take out the HandiHaler; from mouth; keep breathing calmly; repeat procedures 6 and 7 to empty the capsule completely .; 8. Next, re-open the mouthpiece, remove and discard the used capsule. Close the mouthpiece and dust cap .; Cleaning the inhaler HandiHaler; HandiHaler cleaning; should be carried out 1 time per month. To do this, you need to 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; wipe with a paper towel and leave the mouthpiece open, the base and dust cap leave to air dry for 24 hours. After cleaning in this way, the device is ready for subsequent use. If necessary, the outer surface of the mouthpiece can be cleaned with a damp but not wet tissue .; Opening the blister; Separate the strip of blister along the perforated line. Open the blister strip immediately before use so that one capsule is fully visible. The capsule contains a small amount of powder, so it is not completely filled .; If the capsule was accidentally opened and exposed to air, it should not be used.Neither the device nor the blister capsules should not be exposed to high temperatures, exposure to sunlight.
Side effects
Metabolism: dehydration * .; On the part of the digestive system: often (≥1% and less than 10%) - dry mouth is usually mild; infrequently (≥0.1% and less than 1%) - stomatitis, constipation, gastroesophageal reflux; rarely (≥0.01% and less than 0.1%) - oropharyngeal candidiasis, gingivitis, glossitis; intestinal obstruction, including paralytic ileus, dysphagia .; On the part of the respiratory system: infrequently (≥0.1% and less than 1%) - dysphonia, cough, pharyngitis; rarely (≥0.01% and less than 0.1%) - paradoxical bronchospasm, laryngitis, sinusitis, nosebleeds .; Since the cardiovascular system: infrequently (≥0.1% and less than 1%) - atrial fibrillation; rarely (≥0.01% and less than 0.1%) - tachycardia (including supraventricular tachycardia), palpitations .; From the urinary system: infrequently (≥0.1% and less than 1%) - difficulty urinating and urinary retention (in men with predisposing factors), dysuria; rarely (≥0.01% and less than 0.1%) - urinary tract infections .; Allergic reactions: infrequently (≥0.1% and less than 1%) - rash; rarely (≥0.01% and less than 0.1%) - urticaria, pruritus, hypersensitivity reactions, including immediate type reactions, angioedema * .; On the part of the skin: skin infections and skin ulcers, dry skin * .; On the part of the musculoskeletal system: swelling of the joints * .; On the part of the nervous system: infrequently (≥0.1% and less than 1%) - dizziness; rarely - (≥0.01% and less than 0.1%) - insomnia .; On the part of the organ of vision: infrequently (≥0.1% and less than 1%) - blurry vision; rarely - (≥0.01% and less than 0.1%) - increase in intraocular pressure, glaucoma .; * in the joint database of clinical studies, these adverse reactions were not identified; only isolated reports of these adverse reactions with widespread use of the drug were noted, however, the relationship with the m-anticholinergic action of the drug Spiriva; not proven; the frequency of these rare events is difficult to estimate.
Overdose
Symptoms: when using high doses, manifestations of anticholinergic action are possible - dry mouth, accommodation disturbances, increase in heart rate .; After inhalation of a single dose of up to 282 mcg in healthy volunteers, no systemic anticholinergic effects were detected.After repeated administration of a single daily dose of 141 mcg in healthy volunteers, bilateral conjunctivitis was observed in combination with dry mouth, which disappeared with continued treatment. In a study that examined the effects of tiotropium with repeated use in patients with COPD who received a maximum of 36 μg 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.
Interaction with other drugs
Perhaps the appointment of the drug Spiriva; in combination with other drugs commonly used for the treatment of COPD: sympathomimetics, methylxanthine derivatives, oral and inhaled GCS. Combined use with long-acting beta2-agonists, inhaled GCS and their combinations does not affect the action of tiotropium .; Limited information on co-administration with anticholinergics was obtained from two clinical studies: a single dose of 1 dose of ipratropium bromide while taking the drug Spiriva; in patients with COPD (64 people) and in healthy volunteers (20 people) did not lead to a decrease in adverse reactions, changes in vital parameters and an ECG. However, the constant combined use of anticholinergic drugs and the drug Spiriva; not studied and therefore not recommended.
special instructions
The drug Spiriva; not intended for the relief of acute attacks of bronchospasm .; Immediate hypersensitivity reactions may develop after inhalation of Spiriva powder. The process of inhalation of Spiriva (as well as other inhaled drugs) can cause bronchospasm .; Patients with renal insufficiency (CC ≤ 50 ml / min) should be carefully monitored when administering Spiriva .; Patients should be familiarized with the use of the inhaler. Do not allow the powder to get into the eyes. Eye pain or discomfort, blurred vision, visual halos in combination with red eyes, conjunctival stagnation and corneal edema may indicate an acute attack of angle-closure glaucoma. With the development of any combination of these symptoms, the patient should immediately consult a doctor.Using only drugs that cause miosis is not an effective treatment in this case .; One capsule contains 5.5 mg of lactose monohydrate .; Impact on the ability to drive vehicles and control mechanisms; Studies on the effect of the drug on the ability to drive vehicles and control mechanisms have not been conducted. Cases of dizziness and blurred vision when using the drug can have a negative impact on the aforementioned ability.