Formisonide, 160 mcg+4, 5 mcg/dose 120 pcs

Pharmacotherapeutic group:

Bronchodilator combined (β₂-adrenomimetic selective+glucocorticosteroid topical)

ATX code: R03AK07

Pharmacological properties

Pharmacodynamics

Formisonide® contains budesonide and formoterol, which have different mechanisms of action and have an additive effect in reducing the frequency of bronchial asthma exacerbations. The special properties of budesonide and formoterol make it possible to use their combination to relieve attacks/symptoms with an anti-inflammatory effect, or as maintenance therapy for bronchial asthma.

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 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 β₂ adrenoreceptor agonist whose inhalation is followed by rapid and prolonged relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The dose-dependent bronchodilator effect occurs within 1-3 minutes after inhalation and persists for at least 12 hours after a single dose.

Clinical efficacy of the combination of budesonide + formoterol as maintenance therapy

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

The effect of budesonide + formoterol combination therapy on lung function is consistent with the effect of budesonide and formoterol alone and greater than budesonide alone. In all cases, short-acting beta2-adrenostimulator was used for seizure control. No decrease of antiasthmatic effect with time was noted. The combination drug has good tolerability.

The combination of budesonide and formoterol as maintenance therapy in combination with a short-acting β₂-adrenoceptor. No decrease in anti-asthmatic effect with time has been observed. The drug has good tolerability.

The combination drug budesonide+formoterol as maintenance therapy in combination with a short-acting beta2-adrenoceptor to stop attacks was administered to patients aged 6 to 11 years for 12 weeks (two inhalations of 80/4.5 mcg/inhalation twice daily). Improved pulmonary function and good tolerability of therapy compared to a corresponding dose of budesonide were noted.

Clinical efficacy of budesonide and formoterol combination as maintenance therapy and for seizure/symptom control

The clinical effectiveness of budesonide and formoterol combination as maintenance therapy and for seizure/symptom control. A statistically and clinically significant reduction in the number of severe exacerbations was observed in 4,447 patients treated with budesonide and formoterol combination therapy as maintenance therapy and for attack/symptom management with anti-inflammatory effects for 6 to 12 months, an increase in the time to first exacerbation compared with the combination of budesonide combined with formoterol or budesonide as maintenance therapy and a beta2-adrenergic stimulant for seizure control. There was also effective control of disease symptoms, pulmonary function, and a reduction in the frequency of prescribing inhalation for seizure control. No development of tolerance to prescribed therapy was detected.

In patients who sought medical attention for the development of an acute asthma attack, symptom control (relief of bronchospasm) was as rapid and effective after inhalation of the combination of budesonide and formoterol as after prescription of salbutamol and formoterol.

Chronic Obstructive Pulmonary Disease (COPD)

In two studies lasting 12 months in patients with moderate to severe COPD (baseline: prebronchodilatation first-second forced expiratory volume (PEF₁) < 50% of proper; median postbronchodilatation PEF₁ = 42% of proper) there was a significant reduction in the rate of exacerbations with the budesonide and formoterol combination 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 difference was noted between taking budesonide in combination with formoterol and formoterol on the ROB ₁.

Pharmacokinetics

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The budesonide+formoterol combination drug is bioequivalent to the corresponding monotherapy drugs with respect to the systemic effects of budesonide and formoterol. In spite of this, a slight increase in cortisol suppression after budesonide and formoterol combination was observed compared with monotherapies. This difference has no effect on clinical safety. There is no evidence for pharmacokinetic interaction between budesonide and formoterol.

The pharmacokinetic parameters for the respective substances are comparable after administration of budesonide and formoterol as monotherapy and as part of budesonide+formoterol combination therapy. For budesonide when administered as part of the combination drug, the area under the curve “concentration-time” (AUC) is slightly greater, the drug is absorbed faster and the value of maximum plasma concentration is higher.

For formoterol when administered as part of a combination drug, the maximum plasma concentration is the same as that of the monotherapy.

Inhaled budesonide is rapidly absorbed and reaches maximum plasma concentration 30 minutes after inhalation. The average dose of budesonide delivered to the lungs by inhalation 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 by inhalation does not differ from those in adult patients (the final concentration of the drug in plasma 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 by inhalation is 28-49% of the delivered dose. Systemic bioavailability is about 61% of the delivered dose.

Distribution

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.

Metabolism, excretion

Formoterol is inactivated by conjugation (active O-demethylated metabolites are formed mainly 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-β-hydroxybudesonide and 16-α-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. 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 predominantly by the CYP3A4 isoenzyme. Budesonide metabolites are excreted by the kidneys 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).

Pharmacokinetics in special patient groups

The pharmacokinetics of formoterol and budesonide in patients with renal impairment have not been studied.

Plasma concentrations of budesonide and formoterol may be increased in patients with liver disease.

Indications

– Bronchial asthma, to achieve overall disease control, including prevention and relief of symptoms, and to reduce the risk of exacerbations.

Formisonide® is suitable for therapy of bronchial asthma of any severity, when inhaled glucocorticosteroids are appropriate.

– Chronic Obstructive Pulmonary Disease (COPD), as symptomatic therapy in patients with COPD with a post-bronchodilator BEP1 < 70% of proper and with a history of exacerbations despite regular bronchodilator therapy.

Active ingredient

Composition

Active ingredients:
Budesonide 160 mcg
Formoterol fumarate dihydrate 4.5 mcg
Excipients:
Sodium benzoate 0.02 mg
Lactose monohydrate up to 12.0 mg
Solid capsule*
Dye “caramel” –
Dye “copper chlorophyllin complex” –
Hypromellose up to 100%

How to take, the dosage

For inhaled use.

Bronchial asthma

The dose of Formisonide® is individualized and based 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 maintenance dose of the drug.

Patients must be constantly monitored by a physician for adequate dosage adjustment of Formisonide®.

Formisonide® can be used according to different approaches to therapy:

A. Formisonide® to control attacks/symptoms with anti-inflammatory effects (patients with mild bronchial asthma).

B. Formisonide® as maintenance therapy and for attack/symptom management with anti-inflammatory activity.

Alternatively, Formisonide® can be used as fixed-dose therapy:

C. Formisonide® as maintenance therapy (fixed dose).

A. Formisonide® For seizure/symptom management with anti-inflammatory action (patients with mild bronchial asthma)

Formisonide® is taken on demand to relieve bronchial asthma symptoms when they develop and to prevent bronchoconstriction caused by allergens or exercise (or to prevent symptoms in situations that the patient estimates could trigger a bronchial asthma attack). Formoterol, the active ingredient in Formisonide®, provides a rapid onset of action (within 1-3 minutes) with prolonged bronchodilation (at least 12 hours after a single dose) for reversible airway obstruction. The patient should have Formisonide® on hand at all times for symptomatic relief.

The physician should discuss allergen exposure and exercise volume with the patient and consider them when recommending the frequency of the drug.

Adults and adolescents (12 years and older):Patients should take 1 inhalation on demand when symptoms develop and to prevent bronchoconstriction caused by allergens or exercise to control bronchial asthma. If symptoms further escalate within a few minutes, 1 additional inhalation is prescribed, but no more than 6 inhalations to control 1 attack.

No more than 8 inhalations per day are usually required, but the number of inhalations may be increased to 12 per day for short periods of time. Patients receiving more than 8 inhalations per day are advised to seek medical attention for reassessment and review of therapy and bronchial asthma.

Dose-dependent and side effects in patients using large numbers of inhalations on demand require close monitoring.

Children under 12 years of age:The efficacy and safety of Formisonide® for seizure/symptom control with anti-inflammatory effects in children under 12 years of age has not been studied.

B. Formisonide® as maintenance therapy and for seizure/symptom management with anti-inflammatory effects

. If maintenance therapy with a combination of an inhaled glucocorticosteroid and a long-acting beta2-adrenoreceptor agonist is needed, the patient may take Formisonide® as maintenance therapy and in addition to anti-inflammatory seizure/symptom management. The patient should have Formisonide® on hand at all times for symptom relief. Formisonide® as maintenance therapy and for seizure/symptom relief with anti-inflammatory action is particularly indicated in patients with:

The physician should discuss allergen exposure and exercise volume with the patient and consider these in recommending the frequency of therapy.

Adults and adolescents (12 years and older)Patients should take 1 inhalation on demand when symptoms develop and to prevent bronchoconstriction caused by allergens or exercise to control bronchial asthma. If symptoms further increase within a few minutes, 1 additional inhalation is prescribed, but no more than 6 inhalations to control 1 attack. Patients also take the recommended maintenance dose of 2 inhalations per day, 1 inhalation in the morning and evening or 2 inhalations once in the morning or evening only. For some patients, a maintenance dose of 2 inhalations twice daily may be prescribed.

It is not usually necessary to prescribe more than 8 inhalations per day, but the number of inhalations may be increased to 12 per day for short periods of time. Patients receiving more than 8 inhalations per day are advised to seek medical advice to reassess and review maintenance therapy.

Dose-dependent side effects in patients using large numbers of inhalations on demand require close monitoring.

Children under 12 years of age:Formisonide® as maintenance therapy and for relief of attacks/symptoms with anti-inflammatory effects is not recommended for children under 12 years of age.

C. Formisonide® as maintenance therapy (fixed dose)

. If maintenance therapy with a combination of an inhaled glucocorticosteroid and a long-acting beta2-adrenoreceptor agonist is needed, the patient may take Formisonide® in a fixed daily dose and use a separate short-acting bronchodilator for symptom relief.

Adults (18 years and older): 1 to 2 inhalations twice daily. If necessary, the dose may be increased to 4 inhalations twice a day.

Adolescents (12-17 years old): 1 to 2 inhalations twice daily.

Children aged 6-11 years:For children aged 6-11 years, a smaller dosage (80 mcg+4.5 mcg) is available.

Children under 6 years of age: Formisonide® is not recommended for children under 6 years of age.

The dose should be reduced to the lowest dose against which optimal control of bronchial asthma symptoms is maintained. After optimal control of bronchial asthma symptoms is achieved 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 believes the patient needs maintenance therapy with a long-acting bronchodilator in combination with an inhaled glucocorticosteroid.

When individual patients require a different combination of active ingredient doses than in Formisonide®, beta2-adrenomimetics and/or glucocorticosteroids should be prescribed in separate inhalers.

The increased frequency of use of short-acting beta2-adrenomimetics is an indication that overall disease control is worsening and requires a review of anti-asthmatic therapy.

COPD

Adults:2 inhalations twice daily.

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

Interaction

Taking 200 mg of ketoconazole once daily increases plasma concentrations (single oral dose of 3 mg) when they are administered together, on average, by 6 times. When using 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, however, a significant 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 interval between ketoconazole and budesonide should be maximized. A reduction in the dose of budesonide should also be considered. Other potent CYPCA4 inhibitors are also likely to significantly increase the plasma concentration of budesonide. Formisonide® for seizure management/symptoms with anti-inflammatory effects is not recommended in patients receiving potent CYPZA4 inhibitors.

The β-adrenergic receptor blockers may attenuate the effects of formoterol. Formosonide® should not be administered concomitantly with β-adrenal blockers (including eye drops) except in forced cases.

The co-administration of Formisonide® and quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants may prolong the QTc interval and increase the risk of ventricular arrhythmias.

In addition, levodopa, levothyroxine, oxytocin, and alcohol may decrease cardiac muscle tolerance to beta2-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.

The co-administration of Formisonide® and other β-adrenergic drug agonists may increase the side effect of formoterol.

The use of beta2-adrenomimetics may result in hypokalemia, which may be worsened 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

Dosing instructions

If bronchial asthma symptoms are manageable, the dose of Formisonide can be gradually reduced.sup>®, but it is important to monitor patients’ condition constantly.

The lowest effective dose of Formisonide® should be given (see section “Dosage and administration”).

Patients are advised to have emergency medication or Formisonide® (for patients with bronchial asthma using Formisonide® at all timesfor relief of attacks/symptoms with anti-inflammatory action – therapy A or B), or short-acting beta2-adrenomimetics (for all patients using Formisonide® for maintenance therapy only – therapy C).

When using Formisonide® as maintenance therapy, patients should be advised to take regular maintenance doses of the drug according to the therapy chosen, even in cases without symptoms of the disease.

The patient should be instructed to rinse his mouth with water after inhaling maintenance doses to prevent the risk of oral candidiasis and pharyngeal candidiasis. It is also necessary to rinse the mouth with water after inhalation on demand if oral and pharyngeal candidiasis develops.

It is recommended that the maintenance dose of the drug be gradually reduced before discontinuing treatment, and abrupt withdrawal of treatment is not recommended. Inhaled glucocorticosteroids should not be completely withdrawn unless temporary withdrawal is necessary to confirm the diagnosis of bronchial asthma.

Formisonide® 80 mcg + 4.5 mcg/dose is not intended to treat patients with mild to severe bronchial asthma.

Enhancement of symptoms

An exacerbation and development of serious adverse events associated with bronchial asthma may occur during therapy with Formisonide®. Patients should continue treatment, but should seek medical attention if bronchial asthma symptoms are not controlled or if their condition worsens after starting therapy.

If therapy is not effective enough or the maximum recommended doses of Formisonide® are exceeded, the treatment regimen should be reconsidered. Unexpected and progressive worsening of bronchial asthma or COPD symptom control is a potentially life-threatening condition and requires urgent medical intervention. In this situation, consideration should be given to increasing the dose of glucocorticosteroids, such as prescribing a course of oral glucocorticosteroids, or antibiotic treatment if infection has set in. In severe exacerbations, monotherapy with a combination inhaled glucocorticosteroid and a long-acting beta2-adrenomimetic is insufficient.

Transfer from oral therapy

. If there is reason to believe that adrenal function has been impaired on prior systemic glucocorticosteroid therapy, precautions should be taken when transferring patients to treatment with Formisonide®.

The benefits of inhaled budesonide therapy generally minimize the need for oral glucocorticosteroids, but patients who discontinue oral glucocorticosteroid therapy may have long-term impaired adrenal function. Patients who in the past have required urgent high-dose glucocorticosteroids or have received long-term treatment with high-dose inhaled glucocorticosteroids may also be at risk. Additional glucocorticosteroids should be considered in times of stress or surgery.

Associates

Formisonide® contains lactose (< 1 mg/inhalation ). Usually this amount does not cause problems in patients with lactose intolerance.

Cautions for specific diseases

Precaution should be taken when treating patients with prolonged QTc intervals. Formoterol administration may cause prolongation of the QT interval.

In co-administration of beta2-adrenomimetics with drugs that may cause or exacerbate hypokalemic effects, such as xanthine derivatives, steroids, or diuretics, the hypokalemic effects of beta2-adrenomimetics may be enhanced. Special precautions should be observed in patients with unstable bronchial asthma who use short-acting bronchodilators to relieve attacks, in exacerbation of severe bronchial asthma, as the risk of hypokalemia increases against hypoxia and in other conditions, when the possibility of hypokalemic effect increases. In such cases it is recommended to control potassium content in serum.

The blood glucose concentration in diabetic patients should be monitored during treatment.

The necessity of use and dose of inhaled glucocorticosteroid should be reconsidered in patients with active or inactive pulmonary tuberculosis, fungal, viral or bacterial respiratory infections.

Systemic action

Systemic action can occur with any inhaled glucocorticosteroid, especially if high doses are taken over an extended period of time. Systemic effects are less likely to occur with inhaled therapy than with oral glucocorticosteroids. Possible systemic effects include suppression of adrenal function, growth retardation in children and adolescents, decreased bone mineral density, cataracts and glaucoma.

Because of the potential effect of inhaled glucocorticosteroids on bone mineral density, special attention should be paid to patients taking high doses of the drug over a long period of time with risk factors for osteoporosis. Studies of long-term use of inhaled budesonide in children at an average daily dose of 400 mcg (measured dose) or in adults at a daily dose of 800 mcg (measured dose) showed no marked effect on bone mineral density. There are no data regarding the effect of high doses of Formisonide® on bone mineral density.

Paradoxical bronchospasm

As with any other inhalation therapy, paradoxical bronchospasm may occur with immediate increase in rales after taking the drug dose. Therefore, treatment with Formisonide® should be discontinued, the therapy should be reconsidered and, if necessary, alternative therapy should be indicated.

population of pediatric patients

The growth of children receiving long-term inhaled glucocorticosteroid therapy should be monitored regularly. If growth retardation is established, therapy should be revised to reduce the dose of inhaled glucocorticosteroid. The ratio of the benefit of glucocorticosteroid therapy to the possible risk of growth retardation should be carefully evaluated. It is recommended that a pediatric pulmonologist be consulted when choosing therapy.

Based on limited research data on long-term glucocorticosteroid therapy, it is reasonable to assume that most children and adolescents receiving inhaled budesonide therapy will eventually achieve growth rates normal for adults. However, minor short-term growth retardation has been reported, mostly in the first year of treatment.

Patient populations with COPD

Data from clinical trials of Formisonide® in patients with COPD with prebronchodilator OEF 1 > 50% of proper and with post-bronchodilatation ROP1 < 70% of proper are not available (see Pharmacodynamics section).

Clinical studies and meta-analyses have shown that the use of inhaled glucocorticosteroids in COPD can lead to an increased risk of pneumonia. However, the absolute risk with budesonide is small. A meta-analysis of 11 double-blind studies involving 10570 patients with COPD showed no statistically significant increase in the risk of pneumonia in patients receiving budesonide (including in combination with formoterol) compared to patients receiving therapy without budesonide (placebo or formoterol). The incidence of serious adverse event pneumonia was 1.9% per year for therapy including budesonide and 1.5% per year for therapy without budesonide. The pooled risk ratio when comparing therapy including budesonide with therapy without budesonide was 1.15 (95% confidence interval (CI:) 0,83, 1,57). The pooled risk ratio when comparing budesonide/formoterol to formoterol or placebo was 1.00 (95% CI: 0.69, 1.44). A causal relationship in the development of pneumonia with the use of budesonide-containing drugs has not been established.

Influence on the ability to drive vehicles, mechanisms

Formisonide® has no effect on the ability to drive vehicles and mechanisms. It may affect the ability to drive or operate machinery if there is an adverse effect.

Contraindications

-High sensitivity to budesonide, formoterol or inhaled lactose.

-Lactose intolerance, lactase deficiency or glucose-galactase malabsorption.

-Children under 6 years of age (for 80 mcg+4.5 mcg dosage).

-Children under 12 years of age (for doses of 160 mcg + 4.5 mcg and 320 mcg + 9 mcg).

Cautions

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 disease (coronary artery disease, tachyarrhythmia, or severe heart failure), QT interval prolongation (formoterol administration may cause QT-interval prolongation).

Side effects

Overdose

Symptoms of formoterol overdose: tremor, headache, palpitations. The development of tachycardia, hyperglycemia, hypokalemia, prolongation of the QT-s interval, arrhythmia, nausea and vomiting has been reported in individual cases. Supportive symptomatic treatment may be prescribed. The use of formoterol at a dose of 90 mcg for 3 hours in patients with acute bronchial obstruction was safe.

If Formisonide® has to be withdrawn due to an overdose of formoterol, which is part of the combination drug, the prescription of an appropriate glucocorticosteroid should be considered.

Budesonide overdose: In acute overdose of budesonide, even in significant doses, clinically significant effects are not expected. In chronic overdose, systemic glucocorticosteroid effects such as hypercorticism and suppression of adrenal function may occur.

Treatment: supportive and symptomatic.

Pregnancy use

There are no clinical data on the use of Formisonide® or concomitant use of budesonide and formoterol in pregnancy.

Pregnancy During pregnancy, Formisonide® 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.

Period of breastfeeding. 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. Formosonide® may be prescribed to women during breastfeeding only if the expected benefit to the mother is greater than any possible risk to the baby.

Similarities