Beclomethasone + Formoterol - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Beta-adrenomimetics

Glucocorticosteroids

Included in the formulation

Foster

aerosol d / inhal.

Kiesi Pharmaceuticals SpA Italy

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

R.01.A.D.01 Beclomethasone

R.03.A.C.13 Formoterol

Pharmacodynamics:

The drug is a combination of beclomethasone dipropionate and formoterol. The substances have different mechanisms of action and show an additive effect in reducing the frequency of exacerbations of asthma.

Beclomethasone dipropionate is an inhaled glucocorticosteroid. In therapeutic doses has anti-inflammatory effect, reduces the severity of asthma symptoms and reduces the frequency of exacerbations of the disease, while it has fewer side effects than systemic glucocorticosteroids.

Formoterol is a selective beta agonist₂-adrenoreceptors, which exerts a relaxing effect on the smooth muscles of the bronchi in patients with reversible airway obstruction. Bronchodilator effect occurs within 1-3 minutes after the inhalation, and remains for 12 hours.

The combination of formoterol and beclomethasone dipropionate reduces the symptoms of bronchial asthma, improvesindicators of external respiration function and reduce the frequency of exacerbations of the disease.

Pharmacokinetics:

When inhaled, beclomethasone dipropionate is rapidly absorbed by the lungs. Systemic bio-suitability of beclomethasone-17-monopropionate is ensured by 36% at the expense of the lungs, and also due to absorption by the organs of the gastrointestinal tract of the swallowed part of the inhalation dose. There is an almost linear increase in systemic action with an increase in the inhalation dose. Absolute bioavailability after inhalation is about 2% and 62% of the nominal dose with respect to unchanged beclomethasone dipropionate and beclomethasone-17-monopropionate, respectively.

The bioavailability of swallowed beclomethasone dipropionate is negligible, however, the pre-systemic conversion of beclomethasone dipropionate to beclomethasone-17-monopropionate results in 41% of beclomethasone dipropionate being digested by the organism as beclomethasone-17-monopropionate.

The binding of the drug to plasma proteins is quite high.

Metabolism

In beclomethasone, high clearance rates from a large range of blood circulation due to the action of the enzyme-esterase, present in most tissues. Rol side metabolites in systemic exposure beclomethasone dipropionate is insignificant.

Excretion

Most of beclomethasone dipropionate is excreted through the gastrointestinal tract with fecal masses in the form of polar metabolites. Renal excretion beclomethasone dipropionate and its metabolites is insignificant. Half-life beclomethasone dipropionate and beclomethasone-17-monopropionate is 0.5 and 2.7 hours respectively.

Special clinical cases

With hepatic insufficiency, the pharmacokinetic properties and safety profile of the drug do not change due to the fact that beclomethasone is subject to rapid metabolism to polar metabolites when exposed to gastrointestinal tract, blood, lung and liver enzymes.

Beclomethasone dipropionate as and its metabolites with urine are practically not excreted. There are no grounds to assume an increased systemic effect on the body of patients with renal insufficiency.

Formoterol

Suction and distribution

With inhalation formoterol quickly absorbed in the lungs and in the gastrointestinal tract. Part of the inhalation dose is usually swallowed by the patient - depending on the method of inhalation and the device used.For example, when a multi-dose metered dose inhaler is used, the dose can be up to 90%, so the swallowed fraction should be taken into account when inhaling the route of administration of the drug.

About 65% of the oral dose of formoterol is absorbed through the gastrointestinal tract, with 70% of this volume being subjected to presystemic metabolism. Maximum concentration unchanged formoterol in blood plasma is observed for 0.5-1 hour after oral administration. The connection with plasma proteins in formoterol is 61-64%, while the affinity for albumin is 34%. In the range of therapeutic doses of saturation, affinity is not observed. With oral administration, the half-elimination (half-life) period is 2-3 hours. When inhaled 12-96 μg formoterol fumarate, the absorption of formoterol is linear.

Metabolism

Formoterol is metabolized by direct conjugation of the active phenol hydroxyl group.

Conjugates of glucuronic acid are not active. The second significant way of metabolizing formoterol is O-dimethylation by conjugation at the phenol-2-hydroxyl group level.Cytochrome P450 enzymes CYP2D6, CYP2C9, CYP2C19 participate in the O-demethylation of formoterol. There is reason to believe that the metabolism of formoterol is mainly carried out in the liver. Formoterol does not inhibit CYP450 enzymes at therapeutically significant concentrations.

Excretion

Only 67% of the oral dose of formoterol is excreted by the kidneys (mainly in the form of metabolites), the rest of the dose through the intestine. The renal clearance of formoterol is 150 ml per minute.

Total renal excretion of formoterol after inhalation of a single dose through a metered powder inhaler increases linearly in the dose range of 12-96 μg. The excretion of unchanged and total formoterol is on average 8% and 25%, respectively. Based on measurements of plasma concentrations of formoterol after its single inhalation at a dose of 120 μg, a half-elimination (half-life) period of 10 hours was determined in 12 healthy volunteers. The ratio of (R, R) - and (S, S) -enantiomers of the unchanged drug in renal excretion is 40% and 60%, respectively. The relative ratio of these 2 indices does not change in the range of dosages being investigated; There is no evidence of the accumulation of one enantiomer relative to another after taking a second dose.

Indications:

Combined basic therapy of bronchial asthma (inhaled glucocorticosteroid and beta₂long-acting adrenomimetic).

In patients with symptoms of the disease, insufficiently controlled inhalation glucocorticosteroids and beta₂short-acting adrenomimetics,

In patients receiving effective maintenance doses of inhalation glucocorticosteroids and beta₂-adrenomimetics of long-acting.

ICD-10

X.J40-J47.J45 Asthma

Contraindications:

Children up to 12 years; increased sensitivity of the organism to the components of the drug.

Carefully:

FROM caution, the drug should be used for pulmonary tuberculosis, fungal, viral or bacterial infections of the respiratory system, thyrotoxicosis, pheochromocytoma.

Diabetes mellitus, uncontrolled hypokalemia, idiopathic hypertrophic subaortic stenosis, AV-blockade of the third degree, severe arterial hypertension, aneurysm of any site or other severe cardiovascular diseases (acute myocardial infarction, coronary heart disease, tachyarrhythmia, decompensated chronic heart failure, prolonged QT interval_from(reception of formoterol may cause prolongation of the QT interval_c) also require careful dose selection and use with caution.

Pregnancy and lactation:

There are no clinical data on the use of the drug during pregnancy. In the course of animal studies, embryotoxic or teratogenic effects were not identified.

At pregnancy the preparation should be used only in those cases when the benefit from application of a preparation exceeds potential risk for a fetus.

There is no data on the penetration of the drug into the breast milk of women. The drug can be given to nursing women only when the expected therapeutic effect for the mother exceeds the potential risk for the child.

Dosing and Administration:

For adults and teenagers over 12 years of age, 1-2 inhalations are indicated 2 times a day.

1) Patients should be under constant monitoring by a physician for an adequate dose selection.

2) The dose should be reduced to the lowest, against which the optimal control of symptoms of bronchial asthma remains.

3) At achievement of the full control over symptoms of a bronchial asthma against a minimum recommended dose of a preparation,At the next stage, you can try prescribing monotherapy with inhaled glucocorticosteroids.

There is no need for a specific dose selection for elderly patients.

No data on drug intake patients with renal or hepatic insufficiency.

The drug is not intended for the initial treatment of bronchial asthma. Selection of the dose of the drugs that make up the drug occurs individually and depending on the severity of the disease. This need to be taken into account not only at the beginning of treatment with combined preparations, but also with a change in the maintenance dose of the drug. In the event that individual patients require a different combination of doses of active components than in the preparation, a beta₂adrenomimetics and / or glucocorticosteroids in separate inhalers.

Side effects:

From the hemopoietic system: granulocytopenia, an increase in the number of platelets.

From the digestive system: dry mouth, burning sensation in the lips, dysphagia, indigestion, diarrhea.

From the musculoskeletal system: tremor, muscle cramps.

From the immune system: allergic dermatitis; increase in C-reactive protein.

Metabolic disorders: hypokalemia.

From the side of the central nervous system: often - a headache.

On the part of the respiratory system: often - the hoarseness of the voice; less often - rhinitis, dysphonia, cough, mild irritation in the throat, bronchospasm.

From the cardiovascular system: less often - heartbeat, prolongation of the QT interval, change of the electrocardiogram.

Infections: pharyngitis, flu, candidiasis of the oral mucosa, pharynx and esophagus, vaginal candidiasis, gastroenteritis, sinusitis.

Overdose:

Symptoms: with an overdose, nausea, vomiting, headache, tremor, drowsiness, severe palpitation, tachycardia, ventricular arrhythmia, lengthening of the interval QT_c, metabolic acidosis, hypokalemia, hyperglycemia.

Symptomatic treatment should be given. In severe cases, hospitalization is indicated. It is necessary to monitor the level of potassium in the blood plasma.

Inhaling doses of beclomethasone dipropionate above recommended may cause temporary suppression of adrenal cortex function. In most cases, the normal function of the adrenal gland is restored within a few days. It is recommended to monitor the level of cortisol in the blood plasma.

With chronic administration of excessive doses of beclomethasone dipropionate, its systemic effect may manifest itself: a significant inhibition of the adrenal cortex can occur up to the adrenal crisis. 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 beclomethasone, which is part of the drug. In chronic overdose, it is recommended to monitor the reserve function of the adrenal cortex.

Interaction:

Co-administration with beta-adrenoreceptor blockers weakens the effect of formoterol.

Do not prescribe the drug at the same time with beta-blockers (including eye drops), with the exception of extreme necessity.

With the joint administration of the drug and other beta-adrenergic drugs may increase the side effect of formoterol.

When combined combination (beclomethasone and formoterol) and quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine),monoamine oxidase inhibitors and tricyclic antidepressants can prolong the QT intervalfrom and increase the risk of ventricular arrhythmias.

Such preparations as: levodopa, levothyroxine, oxytocin and alcohol reduce heart muscle tolerance to beta₂-adrenomimetics.

Co-administration of monoamine oxidase inhibitors, as well as drugs with similar properties, such as furazolidone and procarbazine, can cause an increase in blood pressure.

There is an increased risk of arrhythmia in patients with general anesthesia with preparations of halogenated hydrocarbons.

As a result of applying beta₂-adrenomimetics hypokalemia may occur, which may be enhanced by concomitant treatment with xanthine derivatives, mineral derivatives glucocorticosteroids, diuretics. Hypokalemia may increase predisposition to the development of arrhythmias in patients taking cardiac glycosides.

Due to the content of a small amount of ethanol, interaction in patients with hypersensitivity is possible, taking disulfiram or metronidazole.

Special instructions:

1) During the treatment period it is necessary to monitor the concentration of glucose in the blood in patients suffering from diabetes, due to the fact that inhalations of high doses of formoterol generally lead to an increase in blood glucose.

2) If anesthesia with halogenated hydrocarbon preparations is planned, the patient should be warned not to use the drug for 12 hours before the anesthesia begins.

3) As with the appointment of others glucocorticosteroids, the need to apply and dose of the drug in patients with active or inactive forms of pulmonary tuberculosis, fungal, viral or bacterial infections of the respiratory system should be reviewed.

4) There is a danger of developing an exacerbation if the drug is withdrawn - treatment with the drug is not recommended to be stopped abruptly, and the dose of the drug should be reduced gradually and under the supervision of the doctor.

5) When patients already undergo this course of treatment (inhalation or oral glucocorticosteroids), it must be continued without any changes, even if there is an improvement in symptoms.

6) Treatment with the drug should not be prescribed in the period of exacerbation of bronchial asthma.

7) As with any other inhalation therapy, the occurrence of paradoxical bronchospasm with immediate
increased rales after taking a dose of the drug. In this connection it is necessary to stop therapy with the drug, review the treatment tactics and, if necessary, prescribe alternative therapy.

8) Like any other inhalation glucocorticosteroid can cause systemic effects, especially with prolonged use in high doses; it should be noted, however, that the likelihood of developing such symptoms is much lower than when treated with oral glucocorticosteroids. Possible systemic effects include suppression of adrenal function, growth retardation in children and adolescents, reduction of bone mineral density, cataract and glaucoma. Given the above, the dose of inhalation glucocorticosteroid should be titrated to a minimum, which will ensure the maintenance of effective control.

With chronic administration of excessive doses of beclomethasone dipropionate, its systemic effect may manifest itself: a significant inhibition of the adrenal cortex can occur up to the adrenal crisis.The adrenal crisis is manifested by anorexia, abdominal pain, weight loss, fatigue, headache, nausea, vomiting, hypotension, 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 beclomethasone in the formulation. In chronic overdose, it is recommended to monitor the reserve function of the adrenal cortex.

If there is reason to believe that against the backdrop of previous systemic therapy glucocorticosteroid the adrenal gland function was disrupted, precaution should be taken when transferring patients to treatment with the drug.

The advantages of inhalation therapy, as a rule, minimize the need for oral glucocorticosteroids, but in patients who stop oral therapy glucocorticosteroids, an insufficient function of the adrenal gland may persist for a long time. Patients who in the past needed urgent high doses glucocorticosteroids or received long-term inhalation treatment glucocorticosteroids in a high dose, may also be at this risk group.

It is necessary to provide additional appointment glucocorticosteroids during periods of stress or surgery.

It is recommended that the patient be instructed to rinse the mouth with water after inhalation of maintenance doses in order to prevent the risk of developing candidiasis of the oral and pharyngeal mucosa.

The balloon is under pressure: do not expose to high temperatures, do not pierce, do not throw into the fire, even empty. To use within 3 months from the beginning of application.

Instructions

Beclomethasone + Formoterol (Beclomethasonum + Formoterolum)