Formoterol, 12 mcg/dose 60 pcs

Pharmacotherapeutic group

Bronchodilator agent – β2-adrenomimetic selective

ATC code

R03AC

Pharmacodynamics:

Formoterol is a selective beta2-adrenoreceptor agonist (beta2-adrenomimetic). It has a bronchodilator effect in patients with reversible airway obstruction. The action of the drug comes quickly (within 1-3 minutes) and lasts for 12 hours after inhalation. When using therapeutic doses, the effect on the cardiovascular system is minimal and only rarely observed.

Formoterol inhibits the release of histamine and leukotrysin from mast cells. In animal experiments some anti-inflammatory properties of formoterol have been shown, such as the ability to inhibit the development of edema and accumulation of inflammatory cells.

In in vitro animal experiments, racemic formoterol and its (R.R) and (S.S) enantiomers have been shown to be highly selective beta2 receptor agonists. The (S.S) enantiomer was 800-1000 times less active than the (RR) enantiomer and had no adverse effect on the activity of the (R.R) enantiomer with respect to effects on tracheal smooth muscle. There was no pharmacological evidence of an advantage of using one of these two enantiomers over the racemic mixture.

In studies in humans, formoterol has been shown to effectively prevent bronchospasm induced by inhaled allergens from physical activity with cold air histamine or methacholine. Since the bronchodilator effect of formoterol remains pronounced for 12 hours after inhalation, its administration 2 times a day for long-term maintenance therapy can in most cases provide the necessary control of bronchospasm in chronic lung diseases both during the day and at night.

In patients with stable chronic obstructive pulmonary disease (COPD) formoterol used as inhaled doses of 12 or 24 mcg twice daily is accompanied by improvement in quality of life parameters.

Pharmacokinetics:

Therapeutic dose range of formoterol is from 12 mcg to 24 mcg 2 times daily. Formoterol pharmacokinetic data were obtained in healthy volunteers after inhalation of formoterol at doses above the recommended range and in COPD patients after inhalation of formoterol at therapeutic doses.

Introduction

After a single inhalation of formoterol at a dose of 120 mcg in healthy volunteers, formoterol is rapidly absorbed into the blood plasma with a maximum plasma concentration (Cmax) of 266 pmol/L, reached within 5 minutes of inhalation. In COPD patients receiving formoterol at a dose of 12 or 24 micrograms twice daily for 12 weeks, the plasma concentrations of formoterol measured 10 minutes to 2 hours and 6 hours after inhalation were in the ranges of 115-257 lmol/L and 233-503 pmol/L, respectively.

Studies investigating the total urinary excretion of formoterol and its (R.R) and (S.S) enantiomers have shown that the amount of formoterol in the systemic bloodstream increases in proportion to the inhaled dose (12-96 µg).

After inhaled use of formoterol at a dose of 12 or 24 mcg twice daily for 12 weeks, urinary excretion of unchanged formoterol increased by 63-73% in patients with bronchial asthma (BA) and by 19-38% in patients with COPD. This indicates some cumulation of formoterol in blood plasma after repeated inhalations. No greater cumulation of one formoterol enantiomer than the other was observed after repeated inhalations.

The majority of formoterol administered by inhaler is swallowed and then absorbed from the gastrointestinal (GI) tract. When 80 μg of 3H-labeled formoterol was administered orally to two healthy volunteers, at least 65% of formoterol was absorbed.

Distribution

The binding of formoterol to plasma proteins is 61-64% binding to serum albumin is 34%. Saturation of binding sites is not achieved in the range of concentrations observed after administration of therapeutic doses of the drug.

Metabolism

The main route of metabolism of formoterol is direct conjugation with glucuronic acid. Another way of metabolism is O-demethylation with subsequent conjugation to glucuronic acid (glucuronidation).

Small metabolic pathways include conjugation of formoterol with sulfate followed by deformylation. Multiple isoenzymes are involved in the processes of glucuronidation (UGT1A1 1AZ 1A6 1A7 1A8 1A9 1A10 2B7 and 2B15) and O-demethylation (CYP2D6 209 2C9 and 2A6) of formoterol, which suggests a low possibility of drug interaction through inhibition of any isoenzyme involved in formoterol metabolism. At therapeutic concentrations, formoterol does not inhibit cytochrome P450 isoenzymes.

When formoterol is taken in a dose of 12 or 24 mcg 2 times daily for 12 weeks, 10 % and 15-18 % of the total dose in AD patients are excreted unchanged in the urine; 7 % and 6-9 % of the total dose in COPD patients, respectively.

The calculated urinary fractions (RR) and (SS) of unchanged formoterol enantiomers are 40% and 60%, respectively, after a single dose of formoterol (12-120 >1kg) in healthy volunteers and after single and repeated doses of formoterol in AD patients.

The active ingredient and its metabolites are completely eliminated from the body; about 2/3 of the orally administered dose is excreted with the urine 1/3 with the feces. Renal clearance of formoterol is 150 ml/min.

In healthy volunteers, the final half-life of formoterol from plasma after a single inhalation of formoterol 120 mcg is 10 hours; the final half-lives (RR) and (SS) of enantiomers calculated from urinary excretion are 139 and 123 hours, respectively.

Pharmacokinetics in selected patient groups

Performoterol pharmacokinetic parameters in men and women are not significantly different after adjustment for body weight.

Elderly patients (older than 65 years)

There is no evidence to support the need to change formoterol dosing in patients older than 65 years compared to younger patients.

Patients with hepatic and/or renal impairment

Pharmacokinetics of formoterol in patients with hepatic and/or renal impairment have not been studied.

Indications

Prevention and treatment of bronchial obstruction in patients with bronchial asthma (BA) as an adjunct to therapy with inhaled glucocorticosteroids.

Prevention of bronchospasm caused by inhalation of allergens in cold air or physical activity as an adjunct to therapy with inhaled glucocorticosteroids.

The prevention and treatment of bronchial obstruction in patients with chronic obstructive pulmonary disease (COPD) with both reversible and irreversible bronchial obstruction by chronic bronchitis and pulmonary emphysema.

Active ingredient

Composition

How to take, the dosage

Formoterol-Nativ is intended for inhaled use in patients over 18 years of age. The drug is not intended for oral administration.

The dose of Formoterol-Nativ is adjusted individually according to the patient’s needs. The lowest dose with therapeutic effect should be used. When achieving control of symptoms of bronchial asthma during therapy with Formoterol Nativ, the possibility of gradually reducing the dose of the drug should be considered. Dose reduction of Formoterol-nativ should be performed under regular medical supervision of the patient.

The drug is in capsules with the powder for inhalation, which should only be used with the special device – Inhaler CDM which is included in the package.

The dose of Formoterol Nativ for regular maintenance therapy is 12-24 mcg (1-2 capsule contents) 2 times daily.

Formoterol-Nativ should only be used as adjunctive therapy to inhaled glucocorticosteroids (GCS). The maximum recommended dose of 48 mcg (contents of 4 capsules) per day should not be exceeded.

As the maximum daily dose of Formoterol Nativ is 48 mcg, 12-24 mcg daily may be used to help with bronchial asthma symptoms if needed.

If the need for additional doses of Formoterol Nativ ceases to be episodic (eg more than 2 days/week), this may indicate a worsening of asthma. Formoterol-nativ should not be started or the dosage changed while bronchial asthma is exacerbating.

Formoterol-Nativ should not be used to relieve acute attacks of bronchial asthma.

Prevention of bronchospasm caused by exercise or unavoidable exposure to a known allergen

The dose of Formoterol-Nativ should be taken 12 mcg (1 capsule contents) 15 minutes before the intended exposure to the allergen or before exercise. Additional inhalations of the drug should not be administered within the next 12 hours.

Prevention of severe bronchospasm

Patients with a history of severe bronchospasm may require a single inhaled dose of 24 mcg (contents of 2 capsules).

CROPD

The dose of Formotrol-Napsv for regular maintenance therapy of COPD is 12-24 mcg (contents of 1-2 capsules) 2 times daily.

Inhalation Instructions

In order to ensure that the drug is used correctly, a physician or other health care professional should:

1. Warn the patient that the capsules are for inhalation use only and are not intended to be swallowed;

2. Explain to the patient that the powder inhalation capsules should only be used with the Inhaler CDM;

3. Show the patient how to use the inhaler.

Please remove the capsule from the carton immediately prior to use.

The instructions for use of the CDM Inhaler

The CDM powder inhaler is a plastic device with a sliding top and a retractable capsule compartment approximately 6 cm high.

The Inhaler CDM is a single-dose inhaler that allows you to dose and inhale the drug in very small doses. The Formoterol Nativ enters the patient’s airway with the air currents when you actively inhale through the mouthpiece of the device.

The CDM® Inhaler is very easy to use. You must follow the step-by-step instructions below:

Step 1: Remove the transparent cap from the CDM Insulator as shown in Figure 1.

Phase 2: Hold the device firmly in one hand with your index finger and open the capsule compartment with the thumb of your other hand, as shown in Fig. 2. To do so, use your index finger to push down on the PUSH on the movable portion of the CDM Inhaler, pushing it in the opposite direction.

Step 3: Hold the device with one hand and push the drug capsule into the slot (Fig. H).

Please make sure the capsule is seated correctly (Fig. 4).

Please hold the CDM Tool upright and close the slot by pushing back with the thumb as far as it will go until a “click” sound is heard (Fig. 5).

Please hold the Inhaler CDM strictly vertically (Figure 6).

Step 7: Place it in its working position, as shown in Fig. 7. To do this, firmly press the mouthpiece so that the arrow marked on the housing disappears beyond the boundaries of the bottom of the unit to the top line. Then release the mouthpiece to return it to its original position. This will puncture the capsule allowing the medication to enter the mouthpiece.

Please note: Due to the destruction of the gelatin capsule, small pieces of gelatin may enter the mouth or throat as a result of inhalation. To minimize this phenomenon, do not pierce the capsule more than once.

Please note: Breathe out before inhaling (Fig. 8). Do not exhale through the mouthpiece!

Phase 9: Gently grasp the CDM InsHLER mouthpiece with your teeth and breathe in through your mouth firmly (Fig. 9). You will hear a vibrating sound inside the capsule compartment as the capsule rotates and disperses the medicine. Caution: The mouthpiece should not be chewed or heard strongly with your teeth! Do not press on the mouthpiece when inhaling. This may block the movement of the capsule. Hold your breath for approx. 10 seconds or as long as possible.

Remove the inhaler from your mouth. Breathe out slowly. Then breathe normally.

Repeat steps 8-9 again to ensure that the dose of medicine is inhaled.

Step 10. After the inhalation, open the capsule compartment remove the empty capsule and then close it as shown in Fig. 5.

Please note: When inhaling, try not to cover the holes on the sides of the mouthpiece. This may obstruct the free flow of air inside the inhaler and thereby decrease dispersion of the capsule contents.

Always close the Inhaler CDM with the cap tightly after use to keep the mouthpiece clean.

Clean the outside of the mouthpiece with a dry cloth at regular intervals (once a week).

There have been isolated reports of patients accidentally swallowing entire capsules without using the inhaler. Most of these cases are not associated with adverse events. The healthcare professional should explain to the patient how to use the medication correctly, especially if the patient does not get better breathing after inhalation.

Interaction

Formoterol-Nativ as well as other beta2-adrenomimetics should be prescribed with caution in patients receiving such drugs as: quinidine disopyramide procainamide phenothiazines macrolides monoamine oxidase inhibitors (MAOIs) tricyclic antidepressants antihistamines and other drugs known to prolong the QT interval, as in these cases, the effects of adrenstnormers on the cardiovascular system may increase and the risk of ventricular arrhythmias increases. Concomitant use of other sympathomimetic agents may worsen the adverse reactions of Formoterol Nativ.

The concomitant use of xanthine derivatives of glucocorticosteroids or diuretics may increase the potential hypokalemic effect of Formoterol-Nativ.

Patients receiving anesthesia with halogenated hydrocarbons have an increased risk of arrhythmias.

The drugs relating to beta2-adrenoblockers may decrease the effects of Formoterol-inativ, and may cause serious bronchospasm in patients with bronchial asthma. Therefore, Formoterol-on-tiv should not be used in combination with beta2-adrenoblockers (including eye drops), unless there are extraordinary reasons to use such a combination.

Special Instructions

In patients with bronchial asthma, Formoterol-Nativ should be used only as adjunctive therapy when symptoms are not adequately controlled with inhaled GCS monotherapy or when the disease is severe and a combination of inhaled GCS and a long-acting beta2-adrenoceptor agonist is required. Formoterol-nativ should not be used with other long-acting beta2-adrenoreceptor agonists.

When Formoterol-Nativ is prescribed, the patients’ condition should be evaluated in relation to the adequacy of the anti-inflammatory therapy they receive. After initiation of treatment with Formoterol-Nativ, patients should be advised to continue anti-inflammatory therapy without change, even if improvement is noted.

Beta2-adrenoceptor agonists should be used to control an acute attack of bronchial asthma. Patients should seek medical attention immediately if there is a sudden worsening of the condition.

Hypokalemia

A consequence of therapy with beta2-adrenomimetics including Formoterol-nativ may be the development of potentially serious hypokalemia. Hypokalemia may increase the risk of arrhythmias. Since this action of Formoterol-Nativ may be enhanced by hypoxia and concomitant treatment, special caution should be observed in patients with bronchial asthma of severe course. In these cases, regular monitoring of serum potassium concentration is recommended.

Paradoxical bronchospasm

Like other inhaled drugs, Formoterol-nativ may cause paradoxical bronchospasm. In this case, the drug should be discontinued immediately and an alternative treatment should be prescribed.

The use of formoterol in a dose greater than 54 mcg/day (over 4 inhalations) may lead to positive doping tests.

There are no data on the effect of Formoterol-Pativ on driving and mechanic ability. In case of such adverse reactions as dizziness, tremor cramps or muscle spasm one should refrain from driving vehicles and operating machinery as well as from performing other potentially dangerous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

Hypersensitivity and/or intolerance of any of the ingredients of the drug.

Age under 18 years.

Breastfeeding.

Rare hereditary conditions such as lactose intolerance lactase deficiency or glucose-galactose malabsorption.

If you have any of these conditions, please talk to your doctor before taking this medicine.

Particular caution should be exercised with Formoterol Nativ (especially with regard to dose reduction) and patients should be closely monitored in the presence of the following comorbidities coronary heart disease; cardiac rhythm and conduction disorders especially grade III atrioventricular block; severe heart failure; idiomatic hypertrophic subaortic stenosis; severe arterial hypertension; aneurysm of any localization; fsochromocytoma; ketoacidosis; hypertrophic obstructive cardiomyopathy; thyrotoxicosis; known or suspected QTc interval prolongation (QT corrected > 0.44 sec);

With consideration of the hyperglycemic effect of β2-adrenomimetics in diabetic patients taking Formoterol-Nativ, additional and regular monitoring of blood glucose concentrations is recommended.

Side effects

The undesirable reactions are categorized according to the frequency of occurrence. The following criteria were used to assess frequency: very common (>1/10) common (1/100 to 1/10) infrequent (1/1000 to 1/100) rare (1/10000 to 1/1000) very rare (< 1/10000) (including individual reports).

Infectious and parasitic diseases: often – pharyngitis acute respiratory viral infection.

Immune system disorders: very rare – anaphylactic reactions urticaria angioedema (Quincke’s edema) itching rash.

Mechanism and nutrition disorders: very rare – metabolic acidosis. Mental disorders: infrequent – agitation anxiety hyperexcitability insomnia; very rare – fatigue.

Nervous system disorders: frequently – headache tremor; infrequently – dizziness; very rarely – change of taste.

Chronic disorders: frequently – palpitations, chest pain; infrequent – tachycardia; very rare – peripheral edema; angina pectoris disorders of heart rhythm (including atrial fibrillation ventricular extrasistoles tachyarrhythmia).

Vascular disorders: very rarely – decrease of blood pressure (hypotension) increase of blood pressure (hypertension).

Respiratory system disorders of the thorax and mediastinum: frequently – sinusitis increased sputum production; infrequently – bronchospasm including paradoxical dysphonia; very rarely – cough.

Gastrointestinal disorders: infrequent – dry mouth; very rare – nausea.

Muscular and connective tissue disorders: often – back pain leg cramps; infrequent – muscle spasm myalgia.

General disorders and disorders at the site of administration: frequently – fever; infrequently – irritation of the mucous membrane of the pharynx and larynx.

Laboratory and instrumental data: infrequent – flattening or inversion of the T waveform ST segment depression and prolongation of the QT interval on electrocardiogram; very rare – hypokalemia hyperglycemia.

If any of the adverse reactions listed in the instructions worsen, or if you notice any other adverse reactions not listed in the instructions, tell your doctor.

Overdose

Symptoms. Formoterol overdose is likely to lead to the development of phenomena characteristic of beta2-adrenomimetics overdose or increased manifestation of side effects: pain behind the chest feeling palpitations tachycardia up to 200 beatsmin ventricular arrhythmias increased or decreased blood pressure dry mouth nausea headache dizziness tremors nervousness weakness anxiety sleepiness metabolic acidosis hypokalemia hyperglycemia seizures. As with all inhaled beta2-adrenomimetics, formoterol overdose can lead to cardiac arrest and death.

Treatment. Supportive and symptomatic therapy is indicated. Hospitalization is necessary in severe cases.

The use of cardioselective beta2-adrenoblockers may be considered, but only under close medical supervision and with extreme caution, since their use may cause bronchospasm. Cardiac monitoring is recommended.

Pregnancy use

The safety of formoterol administration during pregnancy and breastfeeding has not yet been established.

The use in pregnancy is possible only if the estimated benefit to the mother exceeds the potential risk to the fetus. Formoterol as well as other beta2-adrenomimetics may delay the process of labor due to the tocolytic action (relaxing effect on uterine smooth muscle).

It is not known whether formoterol penetrates into breast milk. Therefore, breastfeeding should be stopped if it is necessary to use formoterol.

There are no data on the effect of the drug on fertility. Studies in experimental animals did not reveal any effect on fertility when using formoterol orally.