Formisonid^® (Powder) Instructions for Use

Marketing Authorization Holder

Pharmstandard-Lexredstva OJSC (Russia)

ATC Code

R03AK07 (Formoterol and budesonide)

Active Substances

Budesonide (Rec.INN registered by WHO)

Formoterol (Rec.INN registered by WHO)

Dosage Forms

	Formisonid®	Powder for inhalation, dosed 80 mcg+4.5 mcg/1 dose: 30, 60 or 120 pcs. with or without an inhalation device; 60 pcs. in an inhalation device
		Powder for inhalation, dosed 160 mcg+4.5 mcg/1 dose: 30, 60 or 120 pcs. with or without an inhalation device; 60 pcs. in an inhalation device
		Powder for inhalation, dosed 320 mcg+9 mcg/1 dose: 30, 60 or 120 pcs. with or without an inhalation device; 60 pcs. in an inhalation device

Dosage Form, Packaging, and Composition

Powder for inhalation, dosed in hard capsules, No. 3, transparent, light brown; capsule contents – white or almost white powder.

Excipients: sodium benzoate – 0.02 mg, lactose monohydrate – up to 12 mg.

Capsule shell composition: dye “caramel” – 1.4388%, hypromellose – up to 100%.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (12) – cardboard packs.
10 pcs. – contour cell packs (3) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
10 pcs. – contour cell packs (6) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
10 pcs. – contour cell packs (12) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
60 pcs. (60 doses) – contour cell packs in a multi-dose inhalation device model Ostreahaler (1) – containers made of combined material (1) – cardboard packs.

Powder for inhalation, dosed in hard capsules, No. 3, transparent, colorless or with a slight yellowish tint; capsule contents – white or almost white powder.

Excipients: sodium benzoate – 0.02 mg, lactose monohydrate – up to 12 mg.

Capsule shell composition: hypromellose – up to 100%.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (12) – cardboard packs.
10 pcs. – contour cell packs (3) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
10 pcs. – contour cell packs (6) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
10 pcs. – contour cell packs (12) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
60 pcs. – contour cell packs in a multi-dose inhalation device model Ostreahaler (1) – containers made of combined material (1) – cardboard packs.

Powder for inhalation, dosed in hard capsules, No. 3, transparent, green; capsule contents – white or almost white powder.

Excipients: sodium benzoate – 0.02 mg, lactose monohydrate – up to 12 mg.

Capsule shell composition: dye “copper complex of chlorophyllins” – 0.2%, hypromellose – up to 100%.

10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
10 pcs. – contour cell packs (12) – cardboard packs.
10 pcs. – contour cell packs (3) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
10 pcs. – contour cell packs (6) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
10 pcs. – contour cell packs (12) with a single-dose inhalation device Inhaler CDM^® – cardboard packs.
60 pcs. – contour cell packs in a multi-dose inhalation device model Ostreahaler (1) – containers made of combined material (1) – cardboard packs.

Clinical-Pharmacological Group

Drug with anti-inflammatory and bronchodilator action

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; adrenergic agents for inhalation administration; adrenergic agents in combination with glucocorticoids or other drugs, except anticholinergic agents

Pharmacological Action

Combined bronchodilator agent. Budesonide and formoterol have different mechanisms of action and exhibit an additive effect in reducing the frequency of exacerbations of bronchial asthma and COPD.

The special properties of budesonide and formoterol allow their combination to be used simultaneously as maintenance therapy and for relief of attacks, or as maintenance therapy for bronchial asthma.

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

Formoterol – a selective β₂-adrenergic receptor agonist that, after inhalation, causes rapid and prolonged relaxation of bronchial smooth muscle in patients with reversible airway obstruction. The dose-dependent bronchodilatory effect occurs rapidly, within 1-3 minutes after inhalation, and lasts for at least 12 hours after a single dose.

The addition of formoterol to budesonide reduces the severity of bronchial asthma symptoms, improves bronchial function, and reduces the frequency of disease exacerbations. The effect of this fixed combination on bronchial function corresponds to the effect of the combination of budesonide and formoterol monodrugs and exceeds the effect of budesonide alone. In all cases, a short-acting beta₂-adrenergic stimulant was used to relieve attacks. No reduction in anti-asthmatic effect over time was noted. The combination is characterized by good tolerability.

Pharmacokinetics

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 monodrugs and as part of this combination. When administered as part of the combination, the AUC of budesonide is somewhat larger, absorption occurs faster, and the C_max in plasma is higher. The C_max of formoterol in plasma when administered as part of the combination coincides with that of the monodrug.

Inhaled Budesonide is rapidly absorbed and reaches C_max in plasma 30 minutes after inhalation. The average dose of budesonide reaching the lungs after inhalation is 32-44% of the delivered dose. Systemic bioavailability is approximately 49% of the delivered dose.

Inhaled formoterol is rapidly absorbed and reaches C_max in plasma 10 minutes after inhalation. The average dose of formoterol reaching the lungs after inhalation is 28-49% of the delivered dose. Systemic bioavailability is about 61% of the delivered dose.

Plasma protein binding of formoterol is 50%, budesonide – 90%. The V_d of formoterol is about 4 L/kg, budesonide – 3 L/kg.

Formoterol is inactivated by conjugation (active O-demethylated metabolites are formed, mainly as inactivated conjugates). Budesonide undergoes intensive biotransformation (about 90%) during the “first pass” through the liver with the formation of metabolites with low glucocorticoid activity. The glucocorticoid activity of the main metabolites, 6-β-hydroxybudesonide and 16-α-hydroxyprednisolone, does not exceed 1% of the similar activity of budesonide. There is no evidence of metabolite interaction or substitution reaction between budesonide and formoterol.

The main part 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); T_1/2 of the drug averages 17 hours.

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

Indications

Bronchial asthma insufficiently controlled by inhaled GCS and short-acting beta₂-adrenergic stimulants or adequately controlled by inhaled GCS and long-acting beta₂-adrenergic stimulants.

Symptomatic therapy for patients with severe COPD (FEV1 <50% of the predicted estimated level) and with a history of repeated exacerbations who have pronounced symptoms of the disease despite therapy with long-acting bronchodilators.

ICD codes

Dosage Regimen

Select the appropriate dosage strength based on disease severity and prior therapy.

For bronchial asthma, administer one inhalation once or twice daily.

The maximum daily dose is two inhalations for the 80 mcg/4.5 mcg and 160 mcg/4.5 mcg strengths.

The maximum daily dose for the 320 mcg/9 mcg strength is one inhalation twice daily.

For severe COPD, administer one inhalation of the 160 mcg/4.5 mcg or 320 mcg/9 mcg strength twice daily.

Use the lowest effective dose to maintain symptom control.

Individualize the dose based on the patient’s clinical response.

Do not exceed the prescribed maximum daily dose.

Rinse the mouth with water after each inhalation to reduce the risk of oral candidiasis.

Instruct patients on the proper use of the inhalation device.

Regularly reassess the patient’s dosage requirements.

Adverse Reactions

Nervous system disorders frequently (>1/100, <1/10) – headache; less frequently (>1/1000, <1/100) – psychomotor agitation, anxiety, nausea, dizziness, sleep disorders; very rarely (<1/10 000) – depression, behavioral disorders (mainly in children), taste disorders.

Cardiovascular system disorders frequently (>1/100, <1/10) – palpitations; less frequently (>1/1000, <1/100) – tachycardia; rarely (>1/10 000, <1/1000) – atrial fibrillation, supraventricular tachycardia, extrasystole; very rarely (<1/10 000) – angina pectoris, blood pressure fluctuations.

Musculoskeletal system disorders frequently (>1/100, <1/10) – tremor; less frequently (>1/1000, <1/100) – muscle cramps.

Respiratory system disorders frequently (>1/100, <1/10) – candidiasis of the oral and pharyngeal mucosa, mild throat irritation, cough, hoarseness; rarely (>1/10 000, <1/1000) – bronchospasm.

Dermatological reactions less frequently (>1/1000, <1/100) – bruising; rarely (>1/10 000, <1/1000) – exanthema, pruritus, dermatitis.

Allergic reactions rarely (>1/10 000, <1/1000) – urticaria, angioedema, anaphylactic reactions.

Metabolic disorders: rarely (>1/10 000, <1/1000) – hypokalemia; very rarely (<1/10 000) – hyperglycemia, symptoms of systemic action of GCS (including adrenal hypofunction).

Systemic action of inhaled GCS may be observed when taking the drug in high doses for a long time.

The use of beta₂-adrenergic agonists may lead to an increase in the blood levels of insulin, free fatty acids, glycerol, and ketone derivatives.

Contraindications

Hypersensitivity to budesonide, formoterol, or inhaled lactose; childhood (depending on the dosage form used).

With caution

Pulmonary tuberculosis (active or inactive form), fungal, viral or bacterial respiratory tract infections, thyrotoxicosis, pheochromocytoma, diabetes mellitus, uncontrolled hypokalemia, idiopathic hypertrophic subaortic stenosis, severe arterial hypertension, aneurysm of any location or other severe cardiovascular diseases (coronary artery disease, tachyarrhythmia or severe heart failure), QT interval prolongation.

Use in Pregnancy and Lactation

During pregnancy, the Budesonide/formoterol combination should be used only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus. Budesonide should be used in the minimum effective dose necessary to maintain adequate control of bronchial asthma symptoms.

Inhaled Budesonide is excreted in breast milk, but no effects on the child have been observed when used in therapeutic doses. It is not known whether formoterol is excreted in breast milk in women. The Budesonide/formoterol combination can be prescribed to nursing women only if the expected benefit for the mother outweighs any possible risk for the child.

Pediatric Use

Use in children of appropriate age categories is possible strictly according to indications, in recommended doses and dosage forms. It is necessary to strictly follow the instructions in the medical use instructions for drugs containing the fixed combination Budesonide + formoterol regarding contraindications in children of different ages for specific dosage forms of this combination.

Geriatric Use

No special dose adjustment of the drug is required for elderly patients.

Special Precautions

Before discontinuing treatment, it is recommended to gradually reduce the dose. Abrupt withdrawal of treatment is not recommended.

The Budesonide/formoterol combination is not used for initial therapy selection in the early stages of bronchial asthma treatment.

Taking formoterol may cause QT interval prolongation.

An increase in the frequency of use of bronchodilators as emergency medications indicates a worsening of the underlying disease and is a reason to review the treatment tactics for bronchial asthma. 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, the possibility of increasing the dose of GCS or adding systemic anti-inflammatory therapy, for example, a course of oral GCS or antibiotic treatment in case of infection, should be considered. Patients are advised to always carry emergency medications (short-acting beta₂-adrenergic agonists) with them.

The patient’s attention should be drawn to the need for regular intake of the drug containing the Budesonide/formoterol combination according to the selected dose, even in the absence of disease symptoms.

Treatment should not be started during an exacerbation or significant worsening of bronchial asthma.

As with any other inhalation therapy, paradoxical bronchospasm with immediate worsening of wheezing after taking a dose of the combined drug may occur. In this regard, therapy should be discontinued, treatment tactics reviewed, and, if necessary, alternative therapy prescribed.

Systemic action may occur with the use of any inhaled GCS, especially when taking drugs in high doses for a long period of time. The manifestation of systemic action is less likely with inhalation therapy than with the use of oral GCS. Possible systemic effects include suppression of adrenal function, decreased bone mineral density, cataracts, and glaucoma.

Due to the potential effect of inhaled GCS on bone mineral density, special attention should be paid to patients taking high doses of the drug for a long period with risk factors for osteoporosis. Long-term studies of inhaled budesonide use in children at an average daily dose of 400 mcg (metered dose) or in adults at a daily dose of 800 mcg (metered dose) did not show a significant effect on bone mineral density.

If there is reason to believe that adrenal function was impaired during previous systemic GCS therapy, precautions should be taken when transferring patients to treatment with the Budesonide/formoterol combination.

The benefits of inhalation therapy with budesonide generally minimize the need for oral steroids; however, in patients discontinuing oral GCS therapy, insufficient adrenal function may persist for a long time. Patients who previously required emergency use of high doses of GCS or received long-term treatment with inhaled GCS in high doses may also be in this risk group. Additional prescription of GCS during stress or surgery should be considered.

The necessity of use and the dose of inhaled GCS should be reviewed in patients with active or inactive forms of pulmonary tuberculosis, fungal, viral, or bacterial respiratory tract infections.

When beta₂-adrenergic agonists are co-administered with drugs that may cause or enhance the hypokalemic effect, for example, xanthine derivatives, steroids, or diuretics, the hypokalemic effect of beta₂-adrenergic agonists may be enhanced.

Special precautions should be observed in patients with unstable bronchial asthma using short-acting bronchodilators to relieve attacks during exacerbation of severe bronchial asthma, as the risk of hypokalemia increases against the background of hypoxia and in other conditions where the likelihood of manifestation of the hypokalemic effect increases. In such cases, it is recommended to monitor serum potassium levels.

During treatment, blood glucose concentration should be monitored in patients with diabetes mellitus.

Effect on the ability to drive vehicles and mechanisms

The combination of Budesonide/formoterol may have a minor effect on the manifestation of side effects. Caution should be exercised when driving vehicles and operating machinery during treatment.

Drug Interactions

Taking ketoconazole at a dose of 200 mg once daily increases the plasma concentration of orally administered budesonide (single dose of 3 mg) by an average of 6 times when co-administered. When ketoconazole was administered 12 hours after budesonide intake, the plasma concentration of the latter increased by an average of 3 times. Information on such an interaction with inhaled budesonide is not available, but a significant increase in the plasma concentration of the drug should be expected. Since data for dose adjustment recommendations are lacking, the aforementioned drug combination should be avoided. If possible, the time intervals between the administration of ketoconazole and budesonide should be maximized. The possibility of reducing the budesonide dose should also be considered. Other potent CYP3A4 inhibitors are also likely to significantly increase the plasma concentration of budesonide.

Beta₂-adrenergic receptor blockers can reduce the intensity of formoterol’s action. The formoterol + Budesonide combination should not be prescribed concurrently with beta-blockers (including eye drops), except in compelling circumstances.

Concomitant administration of the formoterol+Budesonide combination with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), MAO inhibitors, and tricyclic antidepressants may prolong the QT interval and increase the risk of ventricular arrhythmias.

In addition, levodopa, levothyroxine, oxytocin, and alcohol can reduce the tolerance of the heart muscle to beta₂-adrenergic agonists.

Concomitant use 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 halogenated hydrocarbon agents.

When the Budesonide/formoterol combination is used concomitantly with other beta-adrenergic drugs, the side effects of formoterol may be enhanced. The use of beta₂-adrenergic agonists can lead to hypokalemia, which may be potentiated by concomitant treatment with xanthine derivatives, corticosteroids, or diuretics. Hypokalemia may increase the predisposition to the development of arrhythmias in patients taking cardiac glycosides.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.