Foradil Combi (Capsules) Instructions for Use

ATC Code

R03AK07 (Formoterol and Budesonide)

Active Substances

Budesonide (Rec.INN registered by WHO)

Formoterol (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Combined bronchodilator drug – selective beta₂-adrenomimetic + topical glucocorticosteroid

Pharmacotherapeutic Group

Bronchodilator agent (selective beta2-adrenomimetic + topical glucocorticosteroid)

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 is 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 compared to the use of 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 is a selective agonist of β₂-adrenergic receptors, which, 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 monotherapies and exceeds the effect of budesonide alone. In all cases, a short-acting beta₂-adrenergic stimulant was used to relieve attacks. No reduction in the anti-asthmatic effect over time was observed. 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 monotherapies 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 monotherapy.

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 is 90%. The V_d of formoterol is about 4 L/kg, budesonide is 3 L/kg.

Formoterol is inactivated by conjugation (active O-demethylated metabolites are formed, mainly as inactivated conjugates). Budesonide undergoes extensive biotransformation (about 90%) during first-pass metabolism through the liver, forming 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 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); the T_1/2 of the drug averages 17 hours.

Budesonide is metabolized primarily 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 treatment of 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

Determine the dosage individually based on disease severity and patient response.

For bronchial asthma, the usual adult and adolescent (12 years and older) dose is one or two capsules inhaled twice daily.

The maximum recommended daily dose is four capsules (two inhalations twice daily).

For COPD, the usual dose is two capsules inhaled twice daily.

Administer using the certified inhaler device only. Do not swallow the capsules.

Pierce the capsule only once, immediately before use.

Inhale the contents forcefully and deeply.

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

If a dose is missed, take it as soon as remembered, then continue the regular schedule. Do not double the dose.

An increased need for short-acting bronchodilators for symptom relief indicates deteriorating asthma control and requires medical review.

Do not abruptly discontinue therapy; taper the dose gradually under medical supervision.

Adverse Reactions

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

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

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

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

Dermatological reactions less common (>1/1000, <1/100) – bruising; rare (>1/10 000, <1/1000) – exanthema, itching, dermatitis.

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

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

Systemic effects 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 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 when the expected therapeutic benefit for the mother outweighs the potential risk to the fetus. Budesonide should be used at 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 at 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 to 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 for medical use of 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 stopping treatment, it is recommended to gradually reduce the dose. Abrupt discontinuation 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 strategy 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.

Attention should be drawn to the patient on 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, the treatment strategy should be reviewed, and, if necessary, alternative therapy should be prescribed.

Systemic effects 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 effects 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 should be provided during periods of stress or surgery.

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

When beta₂-adrenergic agonists are co-administered with drugs that can 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 a hypokalemic effect manifestation 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 ability to drive vehicles and operate machinery

The Budesonide/Formoterol combination may have a minor influence when adverse effects manifest. 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 3 mg) when co-administered, on average, by 6 times. When ketoconazole was administered 12 hours after budesonide intake, the plasma concentration of the latter increased, on average, by 3 times. Information on such interaction with budesonide during its inhalation use is lacking, but a significant increase in the plasma concentration of the drug should be expected. Since data for dose adjustment recommendations are lacking, the above combination of drugs should be avoided. If possible, the time intervals between the administration of ketoconazole and budesonide should be maximized. The possibility of reducing the dose of budesonide 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 the action of formoterol. The Formoterol + Budesonide combination should not be prescribed simultaneously with beta-blockers (including eye drops), except in forced cases.

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

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

Simultaneous 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 drugs.

When the Budesonide/Formoterol combination and other beta-adrenergic drugs are used simultaneously, an increase in the adverse effects of formoterol is possible. As a result of the use of beta₂-adrenergic agonists, hypokalemia may develop, which may be enhanced by concomitant treatment with xanthine derivatives, GCS, 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.