Спирива®

General characteristics. Structure:

Active ingredient: 18 mkg tiotropiya, equal 22.5 mkg monohydrate bromide tiotropiya (= tiotropiya bromide).

Excipients: monohydrate of lactose.

Pharmacological properties:

Pharmacodynamics. Tiotropy - the antimuskarinovy drug of long action which in clinical practice is often called by an anticholinergic. It has identical affinity to various subtypes of muskarinovy receptors from M1 to M5. In respiratory tracts relaxation of smooth muscles is result of M3 receptors inhibition. The Bronkhodilyatiruyushchy effect depends on a dose and not less than 24 hours remain. The considerable duration of action is connected probably with very slow dissociation from M3 receptors, in comparison with ipratropiumy. At an inhalation way of introduction of tiotropiya as the N-quarternary anticholinergic, renders local selective effect, at the same time in therapeutic doses does not cause system anticholinergic side effects. Dissociation from Sq.m - receptors comes quicker, than from M3. High affinity to receptors and slow dissociation cause the expressed and long bronkhodilyatiruyushchy effect at patients with a chronic obstructive pulmonary disease.

Bronchodilatation after inhalation a tiotropiya is a consequence of local, but not system effect.

It was shown that Spiriva considerably increases function of lungs (the volume of the forced exhalation in 1 second of OFV1, the vital capacity of easy ZhEL) 30 minutes later after a single dose for 24 hours. Pharmakodinamichesky balance was reached within the first week, and the expressed bronkhodilyatiruyushchy effect was observed for the 3rd day. Spiriva considerably increases the morning and evening peak stream expiratory rate measured by patients. The Bronkhodilyatiruyushchy effect of Spiriva estimated for a year did not reveal tolerance manifestations.

Spiriva considerably reduces number of aggravations of HOBL, and increases the period until the first aggravation in comparison with placebo.

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

It was shown that Spiriva considerably reduces quantity of cases of the hospitalization connected with an aggravation of HOBL and increases time until the first hospitalization.

Pharmacokinetics. Tiotropy - quarternary ammonium connection, moderately soluble in water. Absorption. At an inhalation way of introduction absolute bioavailability the tiotropiya makes 19.5%, demonstrating that the fraction of drug reaching lungs, highly a biodostupn. Proceeding from chemical structure of connection (quarternary ammonivy connection) of tiotropiya it is badly soaked up from digestive tract. For the same reason meal does not influence absorption a tiotropiya. Reception of solutions the tiotropiya inside has absolute bioavailability of equal 2-3%. The maximum concentration a tiotropiya in a blood plasma after inhalation is reached in 5 minutes. Distribution. 72% of the accepted dose of drug contact proteins of plasma and the volume of distribution is equal to 32 L/kg. At a stage of a dynamic equilibrium peak concentration the tiotropiya in a blood plasma at patients with HOBL makes 17-19 pg/ml in 5 minutes after inhalation of powder in a dose of 18 mkg and quickly decreases. At a stage of balance of concentration in a blood plasma made 3-4 pg/ml. Researches showed that tiotropiya do not get through a blood-brain barrier.

Biotransformation. Degree of biotransformation is insignificant. It is confirmed by the fact that after intravenous administration of drug to healthy young volunteers, in urine 74% of not changed substance are found. Tiotropy is split in the nefermentkny way to N-metilskopina alcohol and ditiyenilglikolivy acid which do not contact muskarinovy receptors.

At researches it is shown that drug (<20% of a dose after intravenous use) is metabolized by P450 cytochrome, this process depends on an oksidation and the subsequent conjugation with glutathione with formation of various metabolites. Disturbance of metabolism can take place when using CYP 450 2D6 and 3A4 inhibitors (quinidine, a ketokonazol and a gestoden). Thus, CYP450 2D6 and 3A4 join in drug metabolism. Tiotropy even in supertherapeutic concentration does not inhibit P450, 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A cytochrome in microsomes of a liver of the person.

Removal. A terminal elimination half-life the tiotropiya after inhalation makes 5-6 days. The general clearance at intravenous administration to healthy young volunteers makes 880ml/mines, at individual variability of 22%. Tiotropy after intravenous administration is generally brought by kidneys in not changed look (74%). After inhalation of dry powder renal excretion makes 14% of a dose, the remained not absorbed part, is removed through intestines. Renal clearance the tiotropiya exceeds clearance of creatinine that demonstrates canalicular secretion of drug. After long administration of drug once in days by patients with HOBL, pharmacokinetic balance is reached 2-3 weeks later, at the same time accumulation is not observed further.

Tiotropy has linear pharmacokinetics in therapeutic limits after intravenous administration and inhalation of dry powder.

Elderly patients. At elderly patients decrease in renal clearance a tiotropiya (patients have 326 ml/min. with HOBL to 58 years, to 163 ml/min. at patients with HOBL 70 years are more senior) is observed that can be explained with depression of function of kidneys. After inhalation excretion the tiotropiya with urine decreases from 14% (healthy young volunteers) to 7% (patients with HOBL), however plasma concentration considerably did not change at elderly patients with HOBL if to consider boundaries - and intra individual variability (43% increase in AUC0-4 after inhalation of dry powder.

Patients with an impaired renal function: As well as in case of other means excreted generally by kidneys, depression of function of kidneys led to increase in concentration of medicine in a blood plasma and to decrease in renal clearance after intravenous administration and inhalation reception. At easy extent of decrease in renal function (clearance of creatinine of 50-80 ml/min.), often observable at elderly patients, increase in concentration a tiotropiya in a blood plasma is insignificant (39% increase in AUC0-4 after intravenous administration). At patients with HOBL with the average or expressed extent of decrease in renal function (clearance of creatinine <50ml/mines) after intravenous administration a tiotropiya double increase in its concentration in a blood plasma (82% increase in AUC0-4), in comparison with the concentration in a blood plasma defined after inhalation administration of dry powder was observed.

Patients with the broken function of a liver: It is supposed that the liver failure will not exert considerable impact on pharmacokinetics a tiotropiya as tiotropiya it is generally removed by kidneys and education pharmacological inactive metabolites it is not connected with enzymatic process.

Indications to use:

Spiriva is shown as a maintenance therapy at patients with HOBL, including chronic bronchitis and emphysema (a maintenance therapy at the remaining asthma and for the prevention of aggravations).

Route of administration and doses:

It is inhalation. When using Spiriva's in the form of inhalations by means of the Handikhaler® device it is recommended to use one capsule a day in one and too time.

It is not necessary to swallow of drug.

Elderly patients have to accept Spiriva in the recommended doses. Patients with an impaired renal function can use Spiriva in the recommended doses. However careful observation of patients with a moderate or heavy renal failure getting Spiriva is necessary (as well as in a case with other drugs, эскретирующимися generally kidneys). Patients with a liver failure can accept Spiriva in the recommended doses.

Application instruction of the Handikhaler® device. The Handikhaler® device was specially developed for Spiriva. It should not be used for reception of other medicines. You can use your Handikhaler® within one year.

The Handikhaler® device includes:

1.pylezashchitny cap;
2.mundshtuk;
3.osnovaniye;
4.prokalyvayushchuyu button;
5.tsentralnuyu camera. 

 

Use of the device Handikhaler:

1. To open a dust-protection cap, having lifted it up. Then to open a mouthpiece. 

 
2. To get Spiriva's capsule from the blister (just before use) and to put it in the central camera, as shown in the drawing. Does not matter by what party the capsule is placed in the cell.

 

3. To densely close a mouthpiece until click, to leave a dust-protection cap open.

 

4. Holding Handikhaler® a mouthpiece up, to press the puncturing button once up to the end and then to release. Thus, the opening through which drug is released from the capsule during a breath is formed.

 

5. Completely exhale. Attention: never exhale in a mouthpiece.

 

6. Take Handikhaler® in a mouth and densely squeeze lips around a mouthpiece. Holding the head directly, inhale slowly and deeply, but in too time with a sufficient force to hear vibration of the capsule. Take a breath before full filling of lungs; then hold the breath to a sensation of discomfort, at the same time taking out Handikhaler® from a mouth. Again continue to breathe quietly. Repeat the procedure that will lead to full emptying of the capsule.

  

7. Again open a mouthpiece. Get and will throw out the used capsule. Close a mouthpiece and a dust-protection cap.

 

ХандиХалера® you purge once a month.

1. Open a mouthpiece and a dust-protection cap. Then open the device basis, having lifted the puncturing button. Carefully wash out an inhaler in warm water before full removal of powder. ХандиХалер® rub off a paper towel and with an open mouthpiece, the basis and a dust-protection cap leave to dry on air within 24 hours. After cleaning of the device according to the instruction, it will be ready to the following use. In case of need the outside surface of a mouthpiece can be cleared by means of wet, but not wet fabric.

 
2. Opening of the blister. Separate a blister strip along the perforated line.

 
3. Open a blister strip just before use so that one capsule was completely visible. If the second capsule was accidentally opened (was affected by air) it is not necessary to use it.

 
4. Get the capsule.

 
5. Neither in the device, nor in the blister of the capsule should not be affected by high temperatures, i.e. to action of sunshine, etc. The capsule contains a small amount of powder - therefore the capsule is filled not completely.

Features of use:

Spiriva - as the bronkhodilyatator applied once a day to the supporting treatment should not be used as initial therapy at bad attacks of a bronchospasm, i.e. in urgent cases.

After inhalation of powder of Spiriva immediate hypersensitivity reactions can develop.
Inhalation of drug can lead to a bronchospasm.

Patients with the moderated or expressed renal failure (clearance of creatinine <50ml/mines) at Spiriva's reception should be observed carefully how it is necessary also in other cases of prescription of medicines which are excreted preferential kidneys.

Patients have to be informed of rules of use of capsules of Spiriva. It is not necessary to allow hits of powder in eyes. Eye pain or discomfort, indistinct sight, visual auras in combination with reddening of eyes, conjunctival stagnation and hypostasis of a cornea can testify to a bad attack of closed-angle glaucoma. At development of any combination of these symptoms it is necessary to address the specialist immediately. Use of the drugs causing a miosis is not efficiently treatments in this case.

Spiriva should not be applied more often than once a day. Spiriva's capsules have to be used only with the Handikhaler® device. One dose / capsule contains 5,5 mg of lactose of monohydrate.

Influence on ability to drive the car or to work with mechanisms. Researches on studying of such influence were not conducted. Cases of dizziness and an illegibility of sight at administration of drug can exert such impact.

Pregnancy and lactation. Spiriva should be applied to pregnant women and the feeding women only if the expected advantage exceeds any possible risk for a fruit or the newborn.

Side effects:

Digestive tract: 1%i <10%-Dryness in a mouth, usually easy degree of manifestation which often disappears at treatment continuation. ≥0.1% and <1% - oral cavity Candidiasis. ≥0.01% and <1% - the Lock, a gastroezofagalny reflux. In isolated cases intestinal impassability, including paralytic Ilheus, a dysphagy.

Respiratory system: ≥0.1% and <1% - the Dysphonia. A bronchospasm, cough and local irritation, including irritation of a throat (as well as at reception of other inhalation means). ≥0.01% and <1% - Nasal bleeding.

Cardiovascular system: ≥0.01% and <1% - Tachycardia. Sertsebiyeniye. In isolated cases supraventricular tachycardia and a ciliary arrhythmia are registered.

Urinogenital system: ≥0.01% and <1% - the Complicated urination and a delay of an urination (at men with the contributing factors). Infections of an uric path.

Allergic reactions: ≥0.01% and <1% - Rash, urticaria, an itch, hypersensitivity reactions, including reactions of immediate type. Isolated cases of a Quincke's disease.

Nervous system: ≥0.1% and <1% - Dizziness.

The majority of the stated above side reactions can be connected with anticholinergic action of Spiriva. Also other anticholinergic effects - indistinct sight, increase in intraocular pressure (≥0.01% and <0.1%), glaucoma in isolated cases can meet.

Interaction with other medicines:

Use a tiotropiya in a combination with other drugs which are usually used for treatment of HOBL is possible: sympathomimetics, methylxanthines, peroral and inhalation glucocorticosteroids.

Limited information on combined use with anticholinergic drugs received from 2 clinical trials: the ipratropiya bromide against the background of constant reception of Spiriva at patients with HOBL (64 patients) and at healthy volunteers (20 people) did not lead one-time purpose of one dose to reduction of side reactions, change of vital parameters and electrocardiograms. However the constant combined use of anticholinergic drugs and Spiriva was not studied, and, therefore, it is not recommended.

Contraindications:

Raised by sensitivity to atropine or its derivatives (for example, an ipratropiya or an oksitropiya) or to other components of drug; in the 1st trimester of pregnancy; children up to 18 years.

With care. Closed-angle glaucoma, prostate hyperplasia, obstruction of a neck of a bladder.

Overdose:

At use of high doses manifestations of anticholinergic action are possible. However system anticholinergic side effects did not come to light after a single inhalation dose to 282 mkg a tiotropiya at reception by healthy volunteers.

Bilateral conjunctivitis in combination with dryness in a mouth were observed at healthy volunteers after repeated reception of a single daily dose of 141 mkg which disappeared at treatment continuation. At a research in which the effect of repeated doses a tiotropiya at patients from HOBL receiving at most 36 mkg of drug more than 4 weeks was studied dryness in a mouth was the only side effect.

The acute intoxication connected with accidental reception of capsules inside is improbable in connection with low bioavailability of drug.

Storage conditions:

At a temperature not above 25 °C. Not to subject to freezing. To store in the place, unavailable to children! Period of validity 24 months. Not to use after the expiry date specified on packaging. After opening to use the blister within 9 days.

Issue conditions:

According to the recipe

Packaging:

Capsules with powder for inhalations of 18 mkg. On 10 capsules in the blister from PVC / aluminum foil. 1,3 or 6 blisters complete with an inhaler HandiHaler, or without inhaler, with the application instruction are placed in a cardboard pack.