Zafiron
Ukraine
Table of Contents
I N S T R U C T I O N for medical use of the medicinal product ZAFIRON (ZAFIRON)
Composition:
Active substance: formoterol;
1 capsule contains formoterol fumarate dihydrate 12.5 mcg, equivalent to formoterol fumarate 12 mcg;
Excipients: partially micronized monohydrate lactose, micronized monohydrate lactose, gelatin.
Pharmaceutical form. Powder-filled inhalation capsules.
Main physicochemical properties: hard transparent capsules of size "3" consisting of two cylindrical sections containing white powder.
Pharmacotherapeutic group. Adrenergic drugs for inhalation use. Selective beta2-adrenoceptor agonists. ATC code R03AC13.
Pharmacological properties.
Pharmacodynamics.
Formoterol fumarate is a selective beta2-adrenoceptor agonist. It exerts a bronchodilating effect in patients with reversible airway obstruction. The drug acts rapidly (onset of action within 1–3 minutes), and its effect lasts for 12 hours after inhalation. When used at therapeutic doses, the effect on the cardiovascular system is minimal and occurs only in isolated cases.
Formoterol inhibits the release of histamine and leukotrienes from passively sensitized human lungs. Formoterol effectively prevents bronchospasm induced by allergens, physical exertion, cold air, histamine, or methacholine. Since the bronchodilating effect of the drug lasts for 12 hours after inhalation, maintenance therapy with formoterol administered twice daily generally provides adequate control of bronchospasm in chronic lung diseases both during the day and at night.
Pharmacokinetics.
The therapeutic dose of the drug Zaphiron ranges from 12 to 24 mcg twice daily. Data on the pharmacokinetic properties of formoterol were obtained from studies involving healthy volunteers after inhalation of doses higher than therapeutic, and in patients with COPD after inhalation of therapeutic doses. The amount of formoterol excreted unchanged in urine is used as an indirect indicator of the total systemic exposure to the drug and correlates with data on plasma clearance. Elimination half-lives calculated from urinary and plasma data are similar.
Absorption.
After administration of formoterol at a dose exceeding the therapeutic dose (single dose of 120 mcg), maximum plasma concentration (Cmax) of 266 pmol/L was observed 5 minutes after inhalation. In patients with COPD receiving formoterol at doses of 12 or 24 mcg twice daily for 12 weeks, plasma concentrations measured 10 minutes, 2 hours, and 6 hours after inhalation were in the ranges of 11.5–25.7 pmol/L and 23.3–50.3 pmol/L, respectively.
Measurements of total excretion of formoterol and (or) its (R,R)- and (S,S)-enantiomers showed that the amount of formoterol in the bloodstream increased proportionally with the administered dose (12–96 mcg).
After repeated inhalation of 12 or 24 mcg of formoterol fumarate twice daily for 12 weeks, urinary excretion of unchanged formoterol increased from 63% to 73% (last dose compared to first dose) in asthmatic patients and from 19% to 38% in patients with COPD. These data indicate limited accumulation of formoterol in plasma after repeated dosing. No relatively greater accumulation of one enantiomer compared to the other was observed after repeated administration.
As with other drugs delivered via inhaler, it is expected that a significant portion of the formoterol dose from the inhaler will be swallowed by the patient and subsequently absorbed from the gastrointestinal tract. After oral administration of 80 micrograms of tritium-labeled formoterol fumarate to two healthy volunteers, at least 65% of the administered dose was absorbed.
Distribution.
Plasma protein binding of formoterol ranges from 61% to 64% (primarily to albumin — 34%). At concentrations achieved after therapeutic dosing, binding sites are not saturated.
Metabolism.
The main metabolic pathway of formoterol is direct glucuronidation. Another metabolic pathway is O-demethylation followed by glucuronidation. Other metabolic processes include conjugation of formoterol with sulfate and defunctionalization, followed by sulfate conjugation. O-demethylation and glucuronidation are catalyzed by multiple isoenzymes (UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, 2B15 and CYP2D6, 2C19, 2A6, respectively), indicating a low likelihood of drug interactions due to inhibition of specific isoenzymes involved in formoterol metabolism. Formoterol at therapeutic concentrations does not inhibit cytochrome P450 isoenzymes.
Excretion.
In patients with asthma or COPD treated for 12 weeks with 12 or 24 mcg of formoterol fumarate twice daily, approximately 10% and 7% of the dose, respectively, was excreted unchanged in urine. The (R,R) and (S,S) enantiomers accounted for approximately 40% and 60% of unchanged formoterol in urine, respectively, after a single dose (12 to 120 mcg) in healthy volunteers and after single and repeated doses in asthmatic patients.
The active substance and its metabolites are completely eliminated from the body; approximately two-thirds of the orally administered dose is excreted in urine and one-third in feces. Renal clearance of formoterol is 150 mL/min.
In healthy volunteers, the elimination half-life of formoterol in plasma after a single 120 mcg dose of formoterol fumarate was 10 hours. In contrast, elimination half-lives of the (R,R) and (S,S) enantiomers, calculated based on urinary excretion data, were 13.9 and 12.3 hours, respectively.
Pharmacokinetic properties of formoterol in elderly patients and in patients with hepatic or renal impairment have not been studied.
Clinical characteristics.
Indications.
Prevention and treatment of bronchospasm in patients with bronchial asthma; prevention of bronchospasm induced by allergens, cold air, or physical exertion; prevention and treatment of bronchial airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
Contraindications.
Hypersensitivity to formoterol or to any of the excipients of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Concomitant use of Zafiron and medicinal products such as quinidine, disopyramide, procainamide, phenothiazines, antihistamines, tricyclic antidepressants, MAO inhibitors, macrolides, or drugs that prolong the QT interval requires caution, as their effects on the cardiovascular system may be potentiated (e.g., drugs that increase the QT interval increase the risk of ventricular arrhythmias).
Concomitant use of other sympathomimetic agents may potentiate the adverse effects of Zafiron.
Concomitant use of xanthine derivatives, corticosteroids, or diuretics may potentiate the potential hypokalemic effect of beta2-adrenergic stimulants.
Hypokalemia may increase the susceptibility to cardiac arrhythmias in patients treated with digoxin glycosides.
In patients receiving analgesic agents in the form of halogenated hydrocarbons, there is a risk of developing cardiac rhythm disturbances.
Beta-adrenergic blockers may attenuate or block the effect of Zafiron. Therefore, Zafiron should not be used concomitantly with beta-adrenergic blockers (including ophthalmic drops), unless no alternative is available.
Special precautions for use.
The lowest possible dose of Zafron that provides therapeutic effect should be selected according to individual patient needs. The maximum recommended dose should not be exceeded (see "Method of administration and dosage").
Anti-inflammatory treatment.
When treating patients with asthma, Zafron, a long-acting beta2-adrenergic agonist (LABA), should only be used as an adjunctive medication in combination with inhaled corticosteroids in patients whose asthma is not adequately controlled with inhaled corticosteroids alone, or in patients whose disease exacerbations warrant initiating treatment with inhaled corticosteroids and a long-acting beta2-adrenergic agonist.
In children aged 6 to 12 years, a combination product containing inhaled corticosteroids and a long-acting beta2-adrenergic agonist is recommended, except in cases where separate inhaled corticosteroids and long-acting beta2-adrenergic agonists are required.
Zafron should not be used concomitantly with other long-acting beta2-adrenergic agonists. During asthma treatment, Zafron should be used as an adjunctive medication in patients whose asthma is not adequately controlled with other therapies (e.g., low or moderate doses of inhaled corticosteroids) or in patients whose disease exacerbations justify initiating treatment with two maintenance medications, including Zafron.
For patients not receiving anti-inflammatory treatment, such therapy should be initiated simultaneously with the start of Zafron. Patients should be advised to continue anti-inflammatory therapy after starting Zafron, even if their condition improves.
If asthma symptoms decrease, gradual dose reduction of Zafron may be considered. It is important to regularly monitor patients during dose reduction. The lowest effective dose of Zafron should be used.
Exacerbations of asthma.
Clinical trials using Zafron have indicated a higher incidence of severe asthma exacerbations in patients receiving Zafron compared to those receiving placebo, particularly in children aged 5 to 12 years. These studies do not allow precise determination of differences in asthma exacerbation rates between the study groups.
If symptoms persist or the number of Zafron doses required to control disease symptoms increases, this usually indicates worsening of the underlying condition and the need for a physician to reassess the patient's baseline asthma therapy.
Initiating treatment with Zafron or increasing the dosage during an asthma exacerbation is not recommended.
Zafron should not be used to relieve acute asthma symptoms.
In case of an asthma attack, a short-acting beta2-adrenergic agonist should be used. Patients should be informed about the need for immediate medical assistance in case of sudden asthma exacerbation.
Frequent use of medication (i.e., prophylactic treatment), such as inhaled corticosteroids and long-acting beta2-adrenergic agonists, to prevent exercise-induced bronchospasm several times per week, despite ongoing maintenance therapy, may indicate inadequate asthma control and warrants reassessment of asthma treatment and evaluation of patient adherence to physician recommendations.
Concomitant diseases.
Zafron should be used with particular caution and under physician supervision, especially regarding adherence to the recommended dosage, in patients with: ischemic heart disease; cardiac arrhythmias and conduction disorders, particularly third-degree AV block; severe heart failure or severe uncompensated heart failure, idiopathic subaortic stenosis, severe hypertension, aneurysm, pheochromocytoma, hypertrophic obstructive cardiomyopathy; thyrotoxicosis; known or suspected QT interval prolongation (corrected QT > 0.44 sec).
Due to the hyperglycemic effect inherent to beta2-adrenergic agonists, additional monitoring of blood glucose levels is recommended for patients with diabetes mellitus.
Hypokalemia.
Beta2-adrenergic agonist therapy may lead to potentially serious hypokalemia. Since this effect may be potentiated by hypoxia and concomitant treatments, particular caution is required in patients with severe bronchial asthma. In such cases, regular monitoring of serum potassium levels is recommended.
Paradoxical bronchospasm.
As with other inhaled therapies, paradoxical bronchospasm should be considered as a possible adverse effect during treatment with Zafron. In such cases, the drug should be discontinued immediately and alternative therapy initiated.
The product contains lactose; therefore, patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome should not use this medication.
Use during pregnancy or breastfeeding.
The safety of Zafron during pregnancy and breastfeeding has not been established.
Animal studies have shown that formoterol causes embryolethality and reduces early postnatal survival and birth weight.
Zafron should be avoided during pregnancy unless no safer alternative is available. Formoterol, like other beta2-adrenergic agonists, may delay labor due to its tocolytic effect.
It is unknown whether formoterol is excreted in human breast milk. The substance has been detected in the milk of lactating rats. Women should discontinue breastfeeding during treatment.
Ability to affect reaction speed when driving or operating machinery.
Patients should refrain from driving or operating complex machinery if dizziness, tremor, or seizures occur during treatment.
Method of Administration and Dosage
Zafiron is intended for inhalation use in adults and children aged 6 years and older.
Adults.
Bronchial Asthma.
1–2 inhalation capsules (12–24 mcg) twice daily. The maximum recommended daily dose for maintenance therapy is 48 mcg per day. If necessary, an additional 1–2 capsules per day may be used to relieve symptoms. If the need for additional doses occurs more frequently than twice a week, the treatment regimen should be reviewed, as this may indicate worsening of the underlying disease.
Chronic Obstructive Pulmonary Disease (COPD).
1–2 inhalation capsules (12–24 mcg) twice daily.
The maximum daily dose for maintenance therapy is 48 mcg per day.
Prevention of bronchospasm induced by physical exertion, allergens, or cold air.
Inhale the contents of 1 capsule (12 mcg) 15 minutes before physical exertion or anticipated exposure to an allergen. Patients with severe bronchial asthma may require the use of 2 inhalation capsules (24 mcg) per day.
Children aged 6 years and older.
Bronchial Asthma.
1 inhalation capsule (12 mcg) twice daily.
The maximum recommended daily dose is 24 mcg per day.
Prevention of bronchospasm induced by physical exertion, allergens, or cold air.
Inhale the contents of 1 capsule (12 mcg) 15 minutes before exertion or anticipated allergen exposure.
How to Use the Inhaler
- Remove the cap from the inhaler.
- Holding the inhaler by the lower part, open it by twisting the mouthpiece (upper part) in the direction of the arrow.
- Place the capsule into the capsule-shaped chamber located in the lower part of the inhaler. The capsule should be removed from the packaging immediately before use.
- Close the mouthpiece by twisting it back into place.
- Press both buttons on the lower part of the inhaler fully and simultaneously (only once!), while holding the inhaler in an upright position.
WARNING! At this moment, the capsule may break apart, and small pieces of gelatin may enter the mouth or throat. The capsule is made of edible gelatin. The risk of capsule rupture is minimized if it is pierced only once, storage conditions are followed, and the capsule is unpacked immediately before use.
- Breathe out deeply.
- Place the mouthpiece in the mouth, tilt the head slightly backward, close lips around the mouthpiece, and perform several fast, steady, and deep inhalations. At this point, the capsule will begin to rotate in the chamber and disperse the powder, accompanied by a characteristic sound. If no sound is heard, the capsule may be stuck. In this case, open the inhaler and free the capsule. Do not attempt to free the capsule by repeatedly pressing the buttons.
- Upon hearing the characteristic buzzing sound, hold the breath as long as possible without discomfort, then remove the inhaler from the mouth and exhale. Then open the inhaler and check whether any powder remains in the capsule. If powder remains, repeat steps 6–8.
- Open the inhaler, remove the used empty capsule, close the mouthpiece, and replace the cap.
Cleaning the Inhaler: To remove residual powder, wipe the mouthpiece and capsule chamber with a dry cloth or clean soft brush.
Children.
Formoterol should not be used in children under 6 years of age due to insufficient clinical experience in this patient group.
Overdose.
Symptoms: Zafiron overdose may cause effects typical of excessive action of other β₂-adrenergic agonists, such as nausea, vomiting, headache, tremor, drowsiness, palpitations, tachycardia, ventricular arrhythmias, metabolic acidosis, hypokalemia, hyperglycemia, QT interval prolongation on ECG, and arterial hypertension.
Treatment: supportive and symptomatic therapy is indicated. Hospitalization is required in severe cases.
Beta-blockers may be considered, but only with extreme caution, as their use may provoke bronchospasm.
In cases of severe intoxication, serum electrolyte levels (e.g., potassium) and acid-base balance should be monitored.
Side effects
Severe exacerbation of asthma.
Placebo-controlled clinical studies, in which formoterol was administered for at least 4 weeks, indicate a higher incidence of severe asthma exacerbations in patients receiving formoterol (0.9% with a dose of 10–12 mcg twice daily, 1.9% with a dose of 24 mcg twice daily) compared to patients receiving placebo (0.3%), particularly in children aged 6 to 12 years.
Experience in adolescents and adults with asthma
In two large-scale controlled studies conducted over 12 weeks for the registration of a formoterol-containing product in the U.S. market, which included 1095 patients aged 12 years and older, severe asthma exacerbations (asthma exacerbations requiring hospitalization) occurred more frequently with formoterol 24 mcg twice daily (9/271, 3.3%) than with formoterol 12 mcg twice daily (1/275, 0.4%), placebo (2/277, 0.7%), or albuterol (2/277, 0.7%).
In a subsequent clinical trial addressing the above observations, 2085 patients were enrolled. The study compared serious asthma-related adverse events between groups receiving higher and lower drug doses. Results from this 16-week study did not demonstrate a clear dose-related relationship regarding the occurrence of this effect. The percentage of patients experiencing severe asthma exacerbations was slightly higher in the formoterol groups compared to placebo (in three double-blind groups: formoterol 24 mcg twice daily (2/527, 0.4%), formoterol 12 mcg twice daily (3/527, 0.6%), and placebo (1/514, 0.2%); and in the open-label group: formoterol 12 mcg twice daily plus up to two additional doses per day (1/517, 0.2%).
Experience in children aged 6 to 12 years with asthma
The safety of a formoterol-containing product administered at a dose of 12 mcg twice daily, a product at a dose of 24 mcg twice daily, and placebo was compared in one large, multicenter, randomized, double-blind clinical trial conducted over 52 weeks in a group of 518 children (aged 6 to 12 years) with asthma requiring daily treatment with bronchodilators and anti-inflammatory agents. Severe asthma exacerbations occurred more frequently in children receiving formoterol 24 mcg twice daily (11/171, 6.4%) or formoterol 12 mcg twice daily (8/171, 4.7%) than in those receiving placebo (0/176, 0.0%).
The frequency of adverse reactions was defined as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), and very rare (<1/10,000).
| Immune system disorders |
Rare: hypersensitivity reactions, including arterial hypotension, bronchospasm, urticaria, angioneurotic edema, pruritus, exanthema |
| Metabolism and nutrition disorders |
Rare: hypokalemia Very rare: hyperkalemia |
| Nervous system disorders |
Common: headache, tremor Uncommon: excitement, feeling of anxiety, nervousness, insomnia, dizziness Very rare: taste disturbance |
| Cardiovascular disorders |
Common: palpitations Uncommon: tachycardia Rare: arrhythmia, e.g., atrial fibrillation, supraventricular tachycardia, extrasystole Very rare: angina pectoris, prolonged QT interval on electrocardiogram, peripheral edema |
| Respiratory, thoracic and mediastinal disorders |
Uncommon: paradoxical bronchospasm, cough, rash, increased blood pressure (including hypertension), allergic reactions, throat irritation |
| Gastrointestinal disorders |
Very rare: nausea |
| Musculoskeletal and connective tissue disorders |
Uncommon: cramps, myalgia |
Shelf life.
2 years.
Storage conditions.
Store in the original packaging, in a place inaccessible to children, at a temperature not exceeding 25 ºC.
Packaging.
10 capsules in a Pa-Al-PVC blister; 6 or 12 blisters together with the inhaler and instructions for medical use in a cardboard box.
Prescription status.
Prescription only.
Manufacturer (responsible for batch release).
Adamed Pharma S.A., Poland.
Manufacturer's address and location of operations.
5 Józefa Piłsudskiego Marshal Street, 95-200 Pabianice, Poland.