Symbicort Turbuhaler, 320+9 mcg/dose 60 doses

Pharmacotherapeutic group: bronchodilator combined (b2-adrenomimetic selective + local glucocorticosteroid)

ATX code: R03AK07

Pharmacological properties Pharmacodynamics

Simbicort^® Turbuhaler^® contains formoterol and budesonide, which have different mechanisms of action and have an additive effect in reducing the frequency of exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD).

Budesonide. Budesonide is a glucocorticosteroid that has a rapid (within hours) and dose-dependent anti-inflammatory effect on the airways after inhalation, reducing the severity of symptoms and the frequency of exacerbations of bronchial asthma. When prescribing inhaled budesonide, there is a lower incidence of serious adverse effects than when using systemic glucocorticosteroids. It reduces the severity of bronchial mucosal edema, mucus production, sputum formation and airway hyperresponsiveness. The exact mechanism of anti-inflammatory action of glucocorticosteroids is unknown.

Formoterol. Formoterol is a selective b2-adrenergic receptor agonist that, after inhalation, causes rapid and prolonged relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The bronchodilator effect is dose-dependent, occurs rapidly, within 1-3 minutes after inhalation and persists for at least 12 hours after a single dose.

Clinical efficacy and safety Bronchial asthma

The addition of formoterol to budesonide reduces the severity of bronchial asthma symptoms, improves bronchial function and reduces the frequency of exacerbations.

The action of Simbicort ^® Turbukhaler on bronchial function is similar to that of the combination of budesonide and formoterol monotherapies and greater than that of budesonide alone. In all cases short-acting beta2-adrenostimulator was used for seizure control. No decrease of antiasthmatic effect with time was noted. The drug has good tolerability.

Chronic Obstructive Pulmonary Disease (COPD)

In two studies lasting 12 months in patients with moderate to severe COPD (baseline: prebronchodilatation SPH1 < 50% of proper; median postbronchodilatation SPH1 = 42% of proper) on Symbicort^® Turbuhaler^® there was a significant reduction in the frequency of exacerbations compared with patients treated with formoterol or placebo alone (mean exacerbation rate of 1.4 compared with 1.8-1.9 in the placebo/formoterol group). No differences were noted between Symbicort^® and formoterol on first-second forced expiratory volume (FEF1).

Pharmacokinetics Intake

Symbicort^® Turbuhaler^® is bioequivalent to the respective monotherapies with respect to the systemic effects of budesonide and formoterol. Despite this, a slight increase in cortisol suppression was noted after administration of Symbicort^® Turbuhaler compared to the monotherapies. This difference has no effect on clinical safety. There is no evidence of pharmacokinetic interaction between budesonide and formoterol.

Pharmacokinetic parameters for the respective substances are comparable after administration of budesonide and formoterol as monotherapy and as part of Symbicort^® Turbuhaler^®. For budesonide, when administered as part of a combination drug, the area under the concentration-time curve (AUC) is slightly greater, the drug is absorbed faster and the value of the maximum plasma concentration is higher.

For formoterol when given as part of a combination drug, the maximum plasma concentration is the same as for the mono drug.

Inhaled budesonide is rapidly absorbed and reaches maximum plasma concentration 30 minutes after inhalation. The average dose of budesonide delivered to the lungs after inhalation via Turbuhaler^® is 32-44% of the delivered dose. Systemic bioavailability is approximately 49% of the delivered dose. In children aged 6 to 16 years, the average dose of budesonide delivered to the lungs after inhalation via Turbuhaler^® is not different from that in adult patients (final plasma concentration of the drug was not determined).

Inhaled formoterol is rapidly absorbed and reaches maximum plasma concentration 10 minutes after inhalation. The average dose of formoterol delivered to the lungs after inhalation via Turbuhaler^® is 28-49% of the delivered dose. Systemic bioavailability is approximately 61% of the delivered dose.

Distribution and metabolism

About 50% of formoterol and 90% of budesonide bind to plasma proteins. The volume of distribution for formoterol is about 4 l/kg and for budesonide 3 l/kg. Formoterol is inactivated by conjugation (active O-demethylated metabolites are formed, mostly as inactivated conjugates). Budesonide undergoes intensive biotransformation (about 90%) during the first passage through the liver to form metabolites with low glucocorticosteroid activity. Glucocorticosteroid activity of the main metabolites – 6-b-hydroxybudesonide and 16-a-hydroxyprednisolone – does not exceed 1% of similar activity of budesonide. There is no evidence of metabolite interaction or substitution reaction between budesonide and formoterol.

The bulk of the formoterol dose is metabolized in the liver and then excreted by the kidneys. After inhalation, 8-13% of the delivered dose of formoterol is excreted unchanged in the urine. Formoterol has a high systemic clearance (approximately 1.4 L/min); the half-life of the drug is on average 17 hours.

Budesonide is metabolized mainly with participation of CYP3A4 isoenzyme. Budesonide metabolites are excreted in the urine unchanged or as conjugates. Only small amounts of unchanged budesonide are detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 L/min).

The pharmacokinetics of formoterol in children and patients with renal impairment have not been studied. Plasma concentrations of budesonide and formoterol may be elevated in patients with liver disease.

Indications

Active ingredient

Composition

Each dose delivered contains:

The active ingredients:budesonide micronized 320 mcg and formoterol fumarate dihydrate 9 mcg.

Auxiliary substances: lactose monohydrate 491 µg.

How to take, the dosage

Symbicort® Turbukhaler® is not intended as an initial treatment for intermittent and mild persistent bronchial asthma. Selection of the dose of substances included in the drug Symbicort® Turbuhaler® is individual and depending on the severity of the disease. This must be taken into account not only when starting treatment with the combination drugs, but also when changing the dose of the drug.

In the event that individual patients require a different combination of active ingredient doses than in a fixed combination inhaler, b2-adrenomimetics and/or glucocorticosteroids should be prescribed in separate inhalers.

Patients should see their physician regularly to monitor the optimal dose of the drug. The dose should be reduced to the lowest dose against which optimal control of bronchial asthma symptoms is maintained. After achieving optimal bronchial asthma control with twice-daily dosing, it is recommended that the dose be titrated to the lowest effective dose, up to once-daily dosing, when the physician determines that the patient requires maintenance therapy with a long-acting bronchodilator in combination with an inhaled glucocorticosteroid.

An increase in the frequency of bronchodilator therapy as an acute care medication indicates a worsening of the underlying disease and warrants a review of bronchial asthma treatment.

Adults (18 years and older): 1 inhalation twice a day. If necessary, the dose may be increased to 2 inhalations twice a day. After achieving optimal control of bronchial asthma symptoms on the background of taking the drug twice a day, it is possible to reduce the dose to the lowest effective dose, up to taking once a day. Adolescents (12-17 years): 1 inhalation twice daily.

Children under 12 years of age: Symbicort® Turbuhaler® 320/9 mcg/dose is not recommended for children under 12 years of age due to lack of clinical data.

Symbicort® Turbuhaler® 320/9 mcg/dose is for maintenance therapy only.

Adults: 1 inhalation twice daily.

Special patient groups: There is no need for special selection of the dose of the drug for elderly patients. There are no data on the use of Symbicort® Turbukhaler in patients with renal or hepatic impairment. Because budesonide and formoterol are excreted primarily by the kidneys, with hepatic metabolism involved, a slower rate of drug excretion can be expected in patients with severe cirrhosis.

Interaction

The administration of 200 mg of ketoconazole once daily increased the plasma concentration of oral budesonide (single dose of 3 mg) when they were administered together by a factor of 6, on average. When administered ketoconazole 12 hours after budesonide administration, the plasma concentration of the latter increased, on average, by 3 times. There is no information about such interaction with inhaled budesonide, but a marked increase in plasma concentrations of the drug should be expected. Since no data are available for dose recommendations, the above-described combination of drugs should be avoided. If this is not possible, the time intervals between ketoconazole and budesonide should be maximized. A reduction in the dose of budesonide should also be considered. Other potent CYP3A4 inhibitors are also likely to significantly increase budesonide plasma concentrations.

The b-adrenergic receptor blockers may attenuate the effects of formoterol. The combination budesonide+formoterol should not be administered concomitantly with b-adrenoblockers (including eye drops) except when necessary.

The combined use of budesonide+formoterol and quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants may prolong QT interval and increase the risk of ventricular arrhythmias.

In addition, levodopa, levothyroxine, oxytocin, and alcohol may decrease cardiac muscle tolerance to b2-adrenomimetics.

The co-administration of MAO inhibitors, as well as drugs with similar properties, such as furazolidone and procarbazine, may cause an increase in blood pressure. There is an increased risk of arrhythmias in patients undergoing general anesthesia with preparations of halogenated hydrocarbons.

When using budesonide+formoterol combination together with other b-adrenergic drugs, an increased side effect of formoterol is possible.

The use of b2-adrenomimetics may result in hypokalemia, which may be increased by concomitant treatment with xanthine derivatives, mineral glucocorticosteroid derivatives or diuretics. Hypokalemia may increase the predisposition to develop arrhythmias in patients taking cardiac glycosides.

No interactions of budesonide and formoterol with other medications used to treat bronchial asthma have been noted.

Special Instructions

Inhaled powder containing budesonide and formoterol in an 80/4.5 mcg/dose ratio is not indicated for patients with severe bronchial asthma. It is not indicated for initial therapy selection in the initial stages of bronchial asthma treatment. Gradual reduction of the drug dose is recommended before discontinuing treatment.

An increase in the frequency of emergency bronchodilator administration indicates a worsening of the course of the underlying disease and serves as a reason to reconsider the treatment tactics for bronchial asthma. To minimize the possibility of developing oropharyngeal fungal lesions, rinse the mouth with water after each inhalation. There are no data on the use of the drug for acute attacks of bronchial asthma.

Patients should be strictly advised to have emergency medication with them at all times. Treatment should not be started during exacerbation of bronchial asthma. As with any other inhalation therapy, paradoxical bronchospasm may occur (in this case, the treatment tactic should be reviewed and if necessary, an alternative therapy should be prescribed). The manifestation of systemic action during inhalation therapy is less likely than when using oral GCS.

But it can occur with any inhaled GCS, especially when using high doses over a long period of time (it is important to use the lowest effective dose of inhaled GCS that provides optimal control of bronchial asthma symptoms). Physicians need to carefully monitor the growth of children and adolescents who take GCS in any dosage form for a long time, and assess the ratio of the benefit of GCS therapy to the possible risk of growth retardation.

If adrenal function was impaired during previous systemic GCS therapy, precautions should be taken when transferring patients to inhaled treatment with the drug (patients who discontinue oral GCS therapy may have insufficient adrenal function for a long time).

In stressful situations, the possibility of residual adrenal dysfunction in these patients should always be kept in mind. There are no clinical data on the use of the drug or combined use of formoterol and budesonide during pregnancy. In pregnant women, the drug should be used only if the expected benefit to the mother is greater than the potential risk to the fetus, and the lowest effective dose of budesonide necessary to maintain adequate control of bronchial asthma symptoms should be used.

It is not known whether formoterol or budesonide penetrates the breast milk of women (the drug may be prescribed to breastfeeding women only if the expected benefit to the mother is greater than any possible risk to the baby). During treatment, it is recommended to monitor serum K+ concentrations as well as glucose in diabetic patients. Contains lactose (less than 1 mg/dose). Usually this amount does not cause problems in patients with lactose intolerance.

Synopsis

Contraindications

– Hypersensitivity to budesonide, formoterol or inhaled lactose.

– Children under 12 years of age.

– Lactose intolerance, lactase deficiency or glucose-galactose malabsorption.

With caution: pulmonary tuberculosis (active or inactive form); fungal, viral or bacterial respiratory infections, thyrotoxicosis, pheochromocytoma, diabetes mellitus, decreased adrenal cortex function, uncontrolled hypokalemia, hypertrophic obstructive cardiomyopathy, idiopathic hypertrophic subaortic stenosis, severe arterial hypertension, aneurysm of any localization or other severe cardiovascular diseases (coronary heart disease, tachyarrhythmia or severe heart failure), QT interval prolongation (formoterol administration may cause QT-s-interval prolongation), pregnancy, breast-feeding.

Side effects

An increase in the incidence of adverse reactions has not been observed with budesonide and formoterol. The most common adverse reactions associated with the use of the drug are adverse events pharmacologically expected for b2-adrenomimetics, such as tremor and palpitations, symptoms are usually of moderate severity and resolve on their own after a few days of treatment.

The adverse reactions associated with the use of budesonide or formoterol are listed below by organ system class and frequency of occurrence. The frequency of reactions is graded as follows: very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000), very rare (< 1/10000).

Infections and invasions: frequent – candidiasis of mucous membrane of oral cavity and throat, pneumonia (in patients with COPD)

Immune system disorders: frequently – immediate and delayed-type hypersensitivity reactions (e.g., dermatitis, exanthema, urticaria, skin itching, angioedema, and anaphylactic reaction)

Endocrine system disorders: very rarely – Cushing’s syndrome, depressed adrenal function, growth retardation, decreased bone mineral density Metabolic and nutritional disorders: frequently – hypokalemia; very rare – hyperglycemia Mental disorders: frequently – psychomotor agitation, anxiety, sleep disorders, aggression; very rare – depression, behavior disorders (mainly in children) Nervous system disorders: frequent – headache, tremor; infrequent – dizziness; very rare – taste disorders

Visual organ disorders: infrequent – blurred vision; very rare – cataracts, glaucoma

Cardiovascular disorders: frequent – palpitations; infrequent – tachycardia; rare – arrhythmia (e.g., atrial fibrillation, supraventricular tachycardia, extrasystole); very rare – angina pectoris, blood pressure fluctuations, QTc interval prolongation

Relatory system, chest and mediastinal organ disorders: frequently – cough, hoarseness, mild irritation of the pharyngeal mucosa; rarely – bronchospasm

Gastrointestinal tract disorders: infrequently – nausea

Skin and subcutaneous tissue disorders: infrequently – bruising

Skeletal, muscular and connective tissue disorders: infrequent – muscle cramps

Systemic effects of inhaled glucocorticosteroids may occur when high doses are used for prolonged periods of time.

The use of b2-adrenomimetics may increase blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Overdose

Symptoms of formoterol overdose: tremor, headache, palpitations. In some cases, tachycardia, hyperglycemia, hypokalemia, prolongation of the QT interval, arrhythmia, nausea and vomiting have been reported.

If Symbicort® Turbukhaler® has to be withdrawn because of an overdose of formoterol from the combination product, the appropriate glucocorticosteroid should be considered.

Treatment: supportive and symptomatic. In patients with acute bronchial obstruction, formoterol at a dose of 90 mcg for 3 hours was safe.

In acute overdose of budesonide, even at significant doses, no clinically significant effects are expected. In chronic overdoses, systemic glucocorticosteroid effects such as hypercorticism and suppression of adrenal function may occur.

Pregnancy use

There are no clinical data on the use of Simbicort® Turbukhaler® or the combined use of formoterol and budesonide during pregnancy.

In pregnancy, the drug should be used only when the benefits of using the drug exceed the potential risk to the fetus. The lowest effective dose of budesonide necessary to maintain adequate control of bronchial asthma symptoms should be used.

Inhaled budesonide is excreted with breast milk, but no effect on the child has been noted when used in therapeutic doses. It is not known whether formoterol penetrates into the breast milk of women. Simbicort® Turbuhaler® may be prescribed to breastfeeding women only if the expected benefit to the mother is greater than any possible risk to the baby.

Similarities