Zenhale^® (Aerosol) Instructions for Use

ATC Code

R03AK09 (Formoterol and Mometasone)

Active Substances

Formoterol (Rec.INN registered by WHO)

Mometasone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug with anti-inflammatory and bronchodilator action

Pharmacotherapeutic Group

Bronchodilator agent (selective beta2-adrenomimetic + topical glucocorticosteroid)

Pharmacological Action

Bronchodilator combination drug.

Mometasone furoate is a glucocorticosteroid with local anti-inflammatory action. Mometasone furoate significantly inhibits the release of leukotrienes from leukocytes. In cell culture, mometasone furoate markedly inhibits the synthesis and release of IL-1, IL-5, IL-6, and TNFα and is a potent inhibitor of TH2 cytokine production, IL-4 and IL-5, in human CD4+ T-cells.

Formoterol is a potent selective beta₂-adrenomimetic. On average, the bronchodilator effect in patients with reversible bronchial obstruction lasts 12 hours. Formoterol inhibits the release of histamine and leukotrienes in lung tissue. Preclinical studies have shown some anti-inflammatory properties, such as inhibition of edema development and accumulation of inflammatory cells.

Pharmacokinetics

Mometasone furoate

After inhalation of one or more doses, mometasone furoate (from 200 to 800 mcg) is rapidly absorbed, gradually transitioning into a prolonged absorption phase. The mean T_max is from 0.5 to 4 hours. Mometasone furoate is rapidly eliminated from plasma, with a mean clearance of about 12.5 ml/min/kg, independent of dose. The effective half-life T_1/2 is 25 hours. The absolute bioavailability is about 14% in healthy volunteers and from 5% to 7% in patients with bronchial asthma.

After intravenous bolus administration at steady-state concentration, the V_d is 152 L. In vitro studies have shown high protein binding of mometasone (from 98% to 99%) in the concentration range from 5 to 500 ng/ml.

No major metabolites have been identified. The portion swallowed during inhalation is absorbed in the gastrointestinal tract and undergoes metabolism to form a large number of metabolites. In hepatocyte microsomes, the drug is metabolized to a large number of metabolites, including 6-beta-hydroxymometasone furoate, which is formed by the action of the CYP3A4 isoenzyme.

The labeled drug, administered by inhalation, is primarily excreted via the intestine (74%) and to a lesser extent by the kidneys (8%).

Formoterol fumarate.

After administration, Formoterol is rapidly absorbed, with a mean T_max ranging from 0.17 to 1.97 hours. In the dose range from 10 to 40 mcg, exposure is directly proportional to the dose. The mean plasma T_1/2 is 9.1 hours. Formoterol binding to plasma proteins is 61-64%, binding to serum albumin is 34%. The drug is primarily metabolized by glucuronidation. Another pathway is O-demethylation followed by glucuronidation. Minor metabolic pathways include sulfate conjugation and deformylation followed by sulfate conjugation. Many isoenzymes catalyze the glucuronidation (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7 and 2B15) and O-demethylation (CYP2D6, 2C19, 2C9 and 2A6) of formoterol, suggesting a low potential for drug interactions associated with inhibition of specific enzymes. At therapeutic concentrations, the drug does not affect the cytochrome P450 system isoenzymes.

After oral administration of 80 mcg of labeled formoterol fumarate, it was found that within 104 hours, from 59% to 62% of the drug is excreted by the kidneys, and from 32% to 34% via the intestine. After inhalation administration of the drug, the renal clearance of formoterol was 217 ml/min. After a single inhalation of 10 to 40 mcg of formoterol as part of the drug, approximately 6.2% to 6.8% of formoterol is excreted unchanged by the kidneys.

Indications

For continuous use as maintenance therapy for bronchial asthma, including to reduce the severity of asthma exacerbations in adults and children over 12 years of age: for patients whose disease is not controlled using only inhaled glucocorticosteroids and inhaled short-acting beta₂-adrenomimetics for relief of attacks (on an “as needed” basis); for patients whose disease severity requires the prescription of two types of maintenance therapy.

ICD codes

Dosage Regimen

Administer by inhalation only. The regimen is individualized based on disease severity and prior therapy.

For maintenance therapy of asthma in patients 12 years and older, the usual starting dose is two inhalations twice daily.

For patients not adequately controlled on inhaled corticosteroids, the dose is two inhalations of Zenhale 100/5 mcg twice daily.

For patients requiring a higher strength, use Zenhale 200/5 mcg at a dose of two inhalations twice daily.

The maximum recommended daily dose is four inhalations of Zenhale 200/5 mcg.

After asthma stability is achieved, titrate to the lowest effective dose to maintain control.

Rinse the mouth with water after each use to reduce the risk of oropharyngeal candidiasis.

This product is not indicated for the initial treatment of acute asthma symptoms. Use a short-acting beta2-agonist for acute relief.

If a previously effective dosage regimen fails to provide relief, immediately seek medical advice.

Adverse Reactions

Nervous system disorders: headache, tremor, dizziness.

Eye disorders: lens opacities, increased intraocular pressure.

Allergic reactions: bronchospasm, atopic dermatitis, urticaria.

Nervous system disorders: insomnia, nervousness, anxiety, agitation.

Cardiovascular system disorders: tachycardia, palpitations, increased blood pressure.

Respiratory system disorders: dysphonia, oropharyngeal pain, pharyngeal irritation.

Gastrointestinal system disorders: nausea, dry mouth, oral candidiasis, dyspepsia, increased body weight.

Musculoskeletal system disorders: muscle spasms.

Systemic reactions: suppression of the hypothalamic-pituitary-adrenal system, growth retardation in children and adolescents, bone demineralization, steroid diabetes.

Contraindications

Children under 12 years of age; hypersensitivity to the active substances.

With caution

Patients with tuberculosis or latent tuberculosis infection, as well as with untreated fungal, bacterial, systemic viral diseases or ocular herpes simplex, with coronary artery disease, cardiac arrhythmias (especially third-degree AV block), severe chronic heart failure, idiopathic hypertrophic subaortic stenosis, severe arterial hypertension, aneurysm, pheochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, QT interval prolongation (corrected QT > 0.44 sec); patients being switched from systemic glucocorticosteroid therapy to inhaled therapy.

Use in Pregnancy and Lactation

Used during pregnancy and breastfeeding only if the expected benefit to the mother outweighs the potential risk to the fetus.

Pediatric Use

Contraindicated in children under 12 years of age.

Children receiving glucocorticosteroid therapy or other immunosuppressants should be warned about the possible danger of contact with patients with certain infectious diseases (e.g., chickenpox or measles), and about the need to consult a doctor if such contact occurs.

Special Precautions

Stressful situations, such as trauma, surgery, infectious diseases, or asthma attacks, may require the prescription of a short course of replacement therapy with systemic glucocorticosteroids, which subsequently must be discontinued by gradually reducing their dose as symptoms disappear. Such patients are advised to always carry a supply of glucocorticosteroids in tablet form and an information card stating that the patient needs to take glucocorticosteroids orally in stressful situations and the recommended doses. This group of patients is also recommended to periodically monitor adrenal cortex function, in particular, measuring plasma cortisol levels in the morning.

Switching patients from systemic glucocorticosteroid therapy to inhaled therapy may lead to the manifestation of pre-existing symptoms of some allergic diseases that were suppressed by previous systemic glucocorticosteroid therapy. In such cases, symptomatic treatment is indicated.

Patients should be instructed by a doctor or medical staff on the rules of use.

Serious side effects and complications associated with bronchial asthma may develop during the use of the drug. Patients should not interrupt the course of treatment, but if the disease is not controlled or symptoms worsen, they should immediately consult a doctor.

Treatment should not be initiated in patients with a sudden increase in asthma symptoms, as well as in life-threatening exacerbations.

The physician should reconsider asthma therapy if asthma symptoms persist, if constant dose increases of the drug are required to achieve disease control, if bronchodilators no longer relieve asthma attacks, or if peak expiratory flow decreases, as these signs usually indicate worsening asthma. In the above cases, the possibility of using additional glucocorticosteroid therapy should be considered.

It is not a means for rapid relief of bronchospasm or any other manifestations of an asthma attack. In such cases, short-acting beta₂-adrenomimetics should be used. In addition, the patient should be informed of the need to consult a doctor immediately in case of worsening asthma.

During clinical trials, the development of oropharyngeal candidiasis associated with the use of glucocorticosteroids was noted in some patients. Such complications generally require a special course of treatment with antifungal drugs, and in some cases, discontinuation of the drug. The patient should be advised to rinse the mouth after using the drug.

Cases of cataract and glaucoma development while taking mometasone furoate are rarely described.

Serious hypokalemia may develop during the use of beta₂-adrenomimetics. Hypokalemia may increase the likelihood of arrhythmia.

Caution should be exercised in patients with severe asthma, as the development of hypokalemia may be potentiated by hypoxia and concomitant treatment. In such situations, continuous monitoring of serum potassium levels is recommended.

Beta₂-adrenomimetics, including Formoterol, have a hyperglycemic effect, so patients with diabetes mellitus are recommended to have additional monitoring of blood glucose levels.

Effect on ability to drive vehicles and operate machinery

If side effects from the nervous system develop, one should refrain from driving vehicles or working with mechanisms during the period of drug use.

Drug Interactions

Concomitant use of inhaled mometasone furoate with a potent inhibitor of the CYP3A4 enzyme, ketoconazole, leads to a significant increase in the plasma concentration of mometasone.

Concomitant use with sympathomimetics may increase the frequency of formoterol side effects.

Concomitant use with xanthine derivatives and non-potassium-sparing diuretics may enhance the hypokalemic effect of beta₂-adrenomimetics.

Formoterol, like other beta₂-adrenomimetics, should be prescribed with caution to patients taking quinidine, disopyramide, procainamide, phenothiazines, terfenadine, astemizole, macrolides, MAO inhibitors, tricyclic antidepressants or any drugs that prolong the QT interval, because the listed drugs may enhance the adrenergic effect of the drug on the cardiovascular system. Drugs that prolong the QT interval increase the risk of ventricular arrhythmia.

Beta-adrenergic blockers may weaken or completely block the effect of formoterol. Therefore, drugs of these groups (including eye drops) should not be prescribed simultaneously, except in cases where there are compelling reasons for this.

There is an increased risk of arrhythmias in patients with concomitant use of anesthesia with halogenated hydrocarbons.

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.