Tevacombe Multichaler - instructions for use, dose, side effects, contraindications

active substances: salmeterol (in the form of salmeterol xinafoate) - 50.0 (72.6) μg / 50.0 (72.6) μg / 50.0 (72.6) μg; fluticasone propionate - 100.0 / 250.0 / 500.0 μg;

Excipients: lactose monohydrate (Respitose SV003) - 4913.7 / 5806.4 / 5656.4 μg, lactose monohydrate (Respitose ML003) - 4913.7 / 3871.0 / 3771.0 μg.

Description:The device is a multi-chaler containing inside a plastic cartridge in the form of a ring, covered with aluminum foil on top, with 30 or 60 uniformly located cells. Each cell is partially filled with white or almost white powder.

Pharmacotherapeutic group:bronchodilating agent combined (beta2-adrenomimetic selective + glucocorticosteroid local)

ATX: & nbsp

R.03.A.K Sympathomimetics in combination with corticosteroids or other drugs, excluding anticholinergic drugs

R.03.A.K.06 Salmeterol and fluticasone

Pharmacodynamics:

Tevacombe Multichaler is a combined preparation that contains salmeterol and fluticasone propionate, which possess different mechanisms of action.

Salmeterol prevents the appearance of symptoms of bronchospasm, fluticasone propionate improves pulmonary function and prevents the exacerbation of the disease. Tevacombe Multichaler may be an alternative for patients who simultaneously receive a beta agonist₂-adrenoceptors and inhaled glucocorticosteroid (GCS) from different inhalers.

Salmeterol is a selective long-acting (up to 12 h) beta agonist₂adrenoceptor, having a long side chain that binds to the outer domain of the receptor.

Pharmacological properties of salmeterol provide more effective protection against histamine-induced bronchoconstriction and longer bronchodilation (duration of at least 12 h) than beta agonists₂adrenoreceptors of short action.

In vitro The research showed that salmeterol is a potent inhibitor of the release from the human lungs of the mediators of mast cells, such as histamine, leukotrienes and prostaglandin D₂ and has a long period of validity.

Salmeterol depresses the early and late phases of the response to inhaled allergens. The inhibition of the late phase of the response persists for more than 30 hours after taking a single dose, while the bronchodilator effect is no longer present. Single administration of salmeterol weakens the hyperreactivity of the bronchial tree. This indicates that salmeterol in addition to bronchodilating activity has an additional effect, not associated with the expansion of bronchi, the clinical significance of which has not been finally established. This mechanism of action is different from the anti-inflammatory effect of GCS.

Fluticasone propionate belongs to the group of SCS for topical application and when inhaled at the recommended doses has a pronounced anti-inflammatory and anti-allergic effect in the lungs, which leads to a decrease in clinical symptoms, a decrease in the frequency of exacerbations of bronchial asthma.Fluticasone propionate does not cause undesirable phenomena, which are observed with systemic intake of corticosteroids.

With prolonged use of inhalation fluticasone propionate, the daily secretion of hormones in the adrenal cortex remains within normal limits in both adults and children, even when using the maximum recommended doses. After transferring patients receiving other inhaled glucocorticosteroids to the administration of fluticasone propionate, the daily secretion of adrenal cortex hormones gradually improves, despite the previous and current recurrent use of oral steroids. This indicates the restoration of the adrenal function against the background of the inhalation application of fluticasone propionate. With prolonged use of fluticasone propionate, the reserve function of the adrenal cortex also remains within normal limits, as evidenced by a normal increase in cortisol production in response to appropriate stimulation (it should be borne in mind that the residual decrease in adrenal reserve caused by previous therapy may persist for a long time).

Pharmacokinetics:

There is no evidence that when combined inhalation salmeterol and fluticasone propionate affect the pharmacokinetics of each other, and therefore the pharmacokinetic characteristics of each component of Tevacomb Multichaler can be considered separately.

A study conducted with the participation of 15 healthy volunteers who simultaneously received salmeterol (inhalation 50 μg twice daily) and an isoenzyme inhibitor CYP3A4 - ketoconazole (oral 400 mg once daily) for 7 days, showed a significant increase in salmeterol concentration in the blood plasma (an increase FROM_mOh in 1,4 times and AUC in 15 times). There was no increase in salmeterol accumulation when taking repeated doses. In 3 patients the treatment was canceled because of the lengthening of the interval QTc or rapid heart rate with sinus tachycardia. In the remaining 12 patients, simultaneous use of salmeterol and ketoconazole did not have a clinically significant effect on heart rate, blood potassium level or interval duration QTc (see the sections "With caution", "Special instructions", "Interaction with other medicinal products").

Suction

Salmeterol acts locally in the lung tissue, so its content in the blood plasma is not an indicator of therapeutic effects. Data on its pharmacokinetics are very limited due to technical problems: when inhaled in therapeutic doses, its maximum plasma concentration is extremely low (about 200 ng / ml and below). After regular inhalation with salmeterol, it is possible to detect hydroxynaphthoic acid in the blood, the equilibrium concentrations of which are about 100 ng / ml. These concentrations are 1000 times lower than the equilibrium concentrations observed in the toxicity studies. No adverse effects were observed with prolonged regular use of the drug (for more than 12 months) in patients with airway obstruction. Fluticasone propionate: the absolute bioavailability of a single dose inhalation fluticasone propionate in healthy people varies from about 5 to 11% of the nominal dose, depending on the inhaler used. In patients with bronchial asthma and chronic obstructive pulmonary disease (COPD), lower concentrations of fluticasone propionate in blood plasma are observed.Systemic absorption occurs mainly through the lungs. At first it is faster, but then its speed slows down.

Part of the inhalation dose can be swallowed, but this part contributes minimal contribution to systemic absorption due to the low solubility of fluticasone propionate in water and due to its pre-systemic metabolism; bioavailability from the gastrointestinal tract is less than 1%. As the inhalation dose increases, a linear increase in the concentration of fluticasone propionate in the blood plasma is observed.

Distribution

There is no data on the distribution of salmeterol.

Fluticasone propionate has a large volume of distribution in the equilibrium state (about 300 liters) and has a relatively high degree of binding to plasma proteins (91%).

Metabolism

Results of the study in vitro showed that salmeterol Extensively metabolized by isoenzyme CYP3A4 systems of cytochrome P450 to α-hydroxysalmeterol by aliphatic oxidation. In a study with repeated dosing of salmeterol and erythromycin, healthy volunteers did not have clinically significant changes in pharmacodynamic effects when taking 500 mg of erythromycin 3 times a day.However, the study of the interaction of salmeterol and ketoconazole showed a significant increase in the concentration of salmeterol in the blood plasma (see sections "Special instructions", "Interaction with other drugs").

Fluticasone propionate is rapidly eliminated from the blood, mainly as a result of metabolism under the action of the isoenzyme CYP3A4 systems of cytochrome P450 to the inactive carboxyl metabolite. Caution should be exercised while using known inhibitors CYP3A4 and fluticasone propionate, since in such situations it is possible to increase the content of the latter in plasma.

Excretion

There is no data on salmeterol excretion.

The distribution of fluticasone propionate is characterized by rapid clearance from the plasma (1150 ml / min) and a final half-life of about 8 hours. The renal clearance of unchanged fluticasone propionate is negligible (<0.2%), a metabolite with urine displays less than 5% of the dose.

Indications:

- Bronchial asthma (insufficiently controlled by the intake of inhaled glucocorticosteroids and beta₂-adrenomimetics of short-acting or adequately controlled by inhaled GCS and beta₂-adrenomimetics of long-acting) in children and adults who are shown combined therapy of beta₂-adrenomimetics and inhaled GCS.

- COPD in adults showing supportive combination therapy beta₂-adrenomimetics and inhaled GCS.

- As a starting maintenance therapy in patients with persistent asthma (daily occurrence of symptoms, daily use of tools for the rapid relief of symptoms) in the presence of indications for corticosteroids in order to achieve control of the disease.

Contraindications:

Hypersensitivity to fluticasone propionate, salmeterol and other components of the drug; hypersensitivity reactions to a milk protein in the anamnesis; children under 18 years of age with COPD; children under 4 years old with bronchial asthma; lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

Carefully:

Simultaneous application with inhibitors of isoenzyme CYP3A4 (ritonavir, ketoconazole), xanthine derivatives, monoamine oxidase (MAO) inhibitors, GCS, diuretics,tricyclic antidepressants; tuberculosis; fungal, viral or bacterial infections; pheochromocytoma; thyrotoxicosis; hypothyroidism; diabetes; uncontrolled hypokalemia; uncontrolled arterial hypertension; arrhythmias; cardiac ischemia; interval lengthening QT on the electrocardiogram; idiopathic hypertrophic subaortic stenosis; cataract; glaucoma; osteoporosis; pregnancy; the period of breastfeeding.

Pregnancy and lactation:

The use of Tevacombe Multichaler during pregnancy and during breastfeeding is allowed only if the expected benefit of the use for the mother exceeds the possible risk to the fetus and the baby.

Dosing and Administration:

Inhalation.

Bronchial asthma

Adults and children over 12 years of age

1 inhalation (50 μg salmeterol + 100 μg fluticasone propionate / dose) twice daily or 1 inhalation (50 μg salmeterol + 250 μg fluticasone propionate / dose) twice daily or 1 inhalation (50 μg salmeterol + 500 μg fluticasone propionate / dose) 2 times a day.

Children from 4 to 12 years old

1 inhalation (50 μg salmeterol + 100 mcg fluticasone propionate / dose) 2 times a day.

COPD

Adults

1 inhalation (50 μg salmeterol + 250 μg fluticasone propionate / dose) 2 times a day or 1 inhalation (50 μg salmeterol + 500 μg fluticasone propionate / dose) 2 times a day. The drug Tevacombe Multichaler is used in a minimally effective dose, providing control of the symptoms of the disease. When the effect is achieved by using the Tevacombe Multichaler drug, it is advisable to reduce the dose to a minimally effective dose or to switch to a smaller dose twice a day, the frequency of application is 1 time per day. The selected dose of fluticasone propionate in Tevacombe Multichaler should correspond to the severity of the disease.

There is no need for dose adjustment in elderly patients and in patients with liver or kidney pathology.

Instructions for the patient to use the device "multihaler"

The multihaler device has an indicator window in which the number of remaining doses is indicated after the inhalation. The numbers go in descending order from 30 to 0 (or from 60 to 0). The numbers from 5 to 0 are red, warning that only a few doses remain in the device. Appearance of 0 in the indicator box means that the device is empty and unsuitable for future use.

Carrying out inhalations

1.Open the device "multihaler": With one hand, hold the casing so that the mouthpiece is at the face. Put the thumb of the other hand in a special groove; To open the cap of the device "multihaler", press your thumb against yourself until you hear a click.

The device "multihaler" is ready to work. By pressing the lever, another cell with powder for inhalation is opened. The lever must be pressed only before the inhalation, otherwise it will lead to a loss of the dose of the drug.

2. Inhale the dose of the drug: Hold the device "multihaler" horizontally, behind the body and at some distance from the mouth.

Take a deep breath without effort.

Tightly grasp the mouthpiece with your lips.

Take a slow and deep breath through your mouth (not through your nose). Take the mouthpiece out of your mouth.

Hold your breath for about 10 seconds or longer, as far as you can. Make a slow exhalation.

Never breathe out into the multihaler unit!

3. Close the multichihaler; Place your thumb in a special recess and push towards you until you hear a click.

The lever automatically returns to its original position, while the number of remaining doses decreases, which is indicated in the indicator window.

After inhalation, rinse your mouth with water without swallowing it.

Cleaning device "Multihaler"

After using the device "multihaler" the mouthpiece is wiped with a dry cloth. Never wash the device with a multihaler, it must be dry.

Additional Information

When using the multihaler, always keep it in a horizontal position. Do not disassemble the device "multihaler", it can not be reused after all doses are consumed.

Adults should help children when using the device, if necessary.

Side effects:

Due to the fact that the drug Tevacombe Multichaler contains salmeterol and fluticasone propionate, its use may be accompanied by side effects, the type and severity of which are characteristic for these active substances. Cases of additional side effects, developing due to the simultaneous introduction of two active substances there.

Undesirable effects are classified according to the frequency of their development: very often (≥ 1/10), often (≥ 1/100, <1/10), infrequently (≥ 1/1000, <1/100), rarely (≥ 1 / 10000, <1/1000), very rarely (<1/10000, including individual cases).

Allergic reactions: infrequently - hypersensitivity reactions, very rarely - angioneurotic edema of the face, mucous membranes of the mouth and throat, shortness of breath, bronchoconstriction, anaphylactoid reactions including anaphylactic shock.

From the side of metabolism and nutrition: often hypokalemia in patients with COPD; very rarely - hyperglycemia, a decrease in bone mineral density, a slowdown in growth children.

From the side of the organ of vision: very rarely - cataract, glaucoma.

From the endocrine system: very rarely - Cushing's syndrome, cushingoid symptoms, suppression of adrenal function.

From the nervous system: very often - headache; often - a tremor; very rarely - anxiety, sleep disorders, behavioral changes, including hyperactivity and irritability (mainly in children).

From the side of the cardiovascular system: often - a feeling of palpitations; infrequently - tachycardia; rarely - ventricular extrasystole; very rarely - violations of the heart rhythm, including atrial fibrillation, supraventricular tachycardia and extrasystole.

From the respiratory system, chest and mediastinum: very often - nasopharyngitis; often - irritation of the larynx, hoarseness of the voice, sinusitis, bronchitis and pneumonia in patients with COPD; very rarely - a paradoxical bronchospasm.

From the digestive system: often - candidiasis of the mucous membrane of the oral cavity and pharynx, irritation of the mucous membrane of the oral cavity and pharynx; rarely - pain in the abdomen, nausea, vomiting; very rarely - a violation of taste.

From the skin and subcutaneous tissues: often - a hemorrhage.

From the side of the musculoskeletal system: often - muscle cramps, traumatic fractures; very rarely - myalgia, arthralgia.

With prolonged use in doses exceeding the recommended, oppression of the function of the adrenal cortex is possible; it is extremely rare (mainly in children) to develop acute adrenal crisis (hypoglycemia, accompanied by a violation of consciousness and / or convulsions).

Overdose:

Symptoms: tremor, headache, tachycardia, increased blood pressure and hypokalemia caused by the action of salmeterol.

Temporary oppression of the hypothalamic-pituitary-adrenal system, which is due to the action of fluticasone propionate.

With prolonged inhalation of a combination of fluticasone propionate and salmeterol in excessively high doses, a noticeable inhibition of adrenal function is possible. There are rare reports of acute adrenal crises,which occurs predominantly in children receiving a combination of fluticasone propionate and salmeterol in excessively high doses for a long time (several months or years). Acute adrenal crisis is manifested by hypoglycemia, accompanied by confusion and / or convulsions. Situations that can serve as triggers for an acute adrenal crisis include trauma, surgery, infection, or a rapid reduction in the dose of fluticasone propionate.

Treatment: symptoms caused by the action of salmeterol, should be canceled by the introduction of an antidote - a cardioselective beta-blocker. In cases where the combination of fluticasone propionate and salmeterol is required due to an overdose of salmeterol, an appropriate replacement GCS is required.

Symptoms caused by the action of fluticasone propionate usually do not require emergency therapy, since in most cases the normal function of the adrenal glands is restored within a few days.

In chronic overdose, it is recommended to monitor the reserve function of the adrenal cortex.

Interaction:

In diseases accompanied by reversible airway obstruction, the use of both nonselective and cardioselective beta-blockers should be avoided, unless it is necessary and justified.

With inhalation application of fluticasone propionate, its concentration in the blood plasma is low due to intensive metabolism during primary passage through the liver under the influence of isoenzyme CYP3A4 and high system clearance. Due to this, clinically significant interaction with the participation of fluticasone propionate is unlikely. Care should be taken when using known inhibitors of the isoenzyme CYP3A4 and fluticasone propionate, because in such situations, an increase in the concentration of fluticasone propionate in plasma is possible.

Ritonavir (a highly active inhibitor of isoenzyme CYP3A4) can cause a significant increase in the concentration of fluticasone propionate in the blood plasma, as a result, serum cortisol concentrations are significantly reduced. There are reports of clinically significant drug interactions in patients,which simultaneously received fluticasone propionate and ritonavir, which was manifested by the development of the Itenko-Cushing syndrome and oppression of adrenal function. Given this, simultaneous use of fluticasone propionate and ritonavir should be avoided, unless the expected benefit of combination therapy for the patient exceeds the possible risk of developing systemic side effects of GCS.

Other inhibitors of isoenzyme CYP3A4 cause a negligible amount (erythromycin) and insignificant (ketoconazole) an increase in the concentration of fluticasone propionate in plasma, in which the concentrations of serum cortisol are practically not reduced. Despite this, it is advisable to use caution while using fluticasone propionate and strong inhibitors of isoenzyme CYP3A4 (eg, ketoconazole), since such combinations do not exclude the possibility of increasing the concentration of fluticasone propionate in plasma.

When used simultaneously with xanthine derivatives, GCS and diuretics, the risk of developing hypokalemia (especially in patients with exacerbation of bronchial asthma,with hypoxia); MAO inhibitors and tricyclic antidepressants increase the risk of developing side effects from the cardiovascular system.

Special instructions:

To obtain the optimum effect, Tevacombe Multichaler is used regularly, even in the absence of symptoms of bronchial asthma and COPD. The doctor determines the course of treatment and the dose individually.

The drug Tevacombe Multichaler should not be used to treat asthmatic status or other acute attacks of bronchospasm in bronchial asthma and COPD. It should be recommended to the patient to always have a drug for cupping bronchospasm (short-acting bronchodilators). The increased demand for short-acting bronchodilators indicates a worsening of the course of the disease. Tevacombe Multichaler is contraindicated in patients with allergic reactions to milk proteins in history because of the increased risk of developing anaphylactic reactions.

Sudden and increasing bronchospasm poses a potential threat to the life of the patient. In this situation, you need to see a doctor, becauseThe dose of Tevacomb Multichaler may not be sufficient to adequately control the disease.

Any inhaled GCS can cause systemic effects, especially with prolonged use in high doses. The likelihood of such symptoms is much lower than when taking GCS inside. The dose of inhaled glucocorticosteroids during application should be reduce to a minimum, which ensures the maintenance of effective disease control.

Treatment of bronchial asthma is recommended to be performed under the supervision of a physician, assessing the patient's clinical condition and lung function.

The patient needs to be trained in the correct use of the multihaler device.

When carrying out resuscitation measures or surgical operations, it is required to determine the degree of adrenal insufficiency.

In connection with the possibility of developing adrenal insufficiency, one should be careful and regularly monitor the indices of adrenal cortex function when transferring patients taking SCS for oral administration to treatment with fluticasone propionate for ingestion.In such situations, allergic reactions may occur (for example, allergic rhinitis, eczema), which were previously suppressed by GCS for oral administration, and there may be a need for symptomatic treatment with antiallergic and / or topical agents (including SCS for topical use ).

Because of the risk of developing an exacerbation, sudden withdrawal of Tevacombe Multichaler should be avoided. The dose of Tevacombe Multichaler should be reduced gradually under the supervision of a doctor.

The abolition of GCS for oral administration against the background of inhalations of fluticasone propionate should be carried out gradually. Patients should carry a card indicating that they may require additional use of GCS for oral administration in a variety of stressful situations.

It is recommended to monitor the growth dynamics of children who receive long-term inhaled glucocorticosteroids.

At present, there is no data on the use of Tevacombe Multichaler in children under 4 years of age.

In patients with exacerbation of bronchial asthma, hypoxia, it is necessary to monitor the potassium concentration in the blood plasma.

There are very rare reports of an increase in the concentration of glucose in the blood, this should be remembered by using a combination of salmeterol and fluticasone propionate in patients with diabetes mellitus.

When taking salmeterol, the risk of serious unwanted reactions in the treatment of bronchial asthma from the respiratory system or death in patients of African American origin is presumably higher than in other patients. The importance of pharmacogenetic factors or other causes is unknown. The effect of concomitant use of inhaled glucocorticosteroids on the risk of lethal outcomes in patients with bronchial asthma has not been studied.

Like other inhaled drugs, Tevacombe Multichaler can cause a paradoxical bronchospasm, manifested by the increase of dyspnea immediately after use. In this case, a short-acting inhaled bronchodilator should be immediately used, Tevacom Multihaler should be canceled and alternative therapy should be started, if necessary.

Unwanted reactions beta₂-adrenomimetics, such as palpitations and tremors, with regular treatment tend to fade.

To reduce the manifestations of such side effects of fluconazole propionate, like candidiasis of the oral and pharyngeal mucosa, hoarseness, it is necessary to rinse the mouth and throat with water after inhalation of Tevacombe Multichaler.

Effect on the ability to drive transp. cf. and fur:

There is no need for special precautions for the management of transport or work with technology.

Form release / dosage:Powder for inhalation dosed 50 + 100 μg / dose, 50 + 250 μg / dose, 50 + 500 μg / dose.

Packaging:

Inside the device "multihaler" there is a plastic cartridge in the form of a ring, covered with aluminum foil on top, with 30 or 60 uniformly located cells.

Each cell contains one dose of the drug in the form of a powder for inhalation.

On the device "multihaler" there is a counter of doses.

The device is placed in a bag of laminated foil.

For 1 device "multihaler" in the package along with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature of no higher than 30 ° C, in a dry, dark place.

Keep out of the reach of children.

Shelf life:2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003552

Date of registration:11.04.2016