Striverdi^® Respimat (Solution) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

Boehringer Ingelheim Pharma, GmbH & Co. KG (Germany)

ATC Code

R03AC19 (Olodaterol)

Active Substance

Olodaterol (Rec.INN registered by WHO)

Dosage Form

Striverdi® Respimat®

Metered dose inhalation solution 2.5 mcg/1 dose: cartridge 60 doses in set with Respimat® inhaler

Dosage Form, Packaging, and Composition

Metered inhalation solution clear, colorless or almost colorless.

Excipients : benzalkonium chloride – 0.0011 mg, disodium edetate – 0.0011 mg, anhydrous citric acid – 0.0003 mg, purified water – up to 11.05 mg.

60 doses (4 ml) – cartridges with a capacity of 4.5 ml (1), placed in an aluminum cylinder, in a set with a Respimat^® inhaler – cardboard packs.

Clinical-Pharmacological Group

Bronchodilator drug – beta₂-adrenergic agonist

Pharmacotherapeutic Group

Selective beta2-adrenomimetic

Pharmacological Action

Bronchodilator drug, beta₂-adrenomimetic. Olodaterol has high affinity and selectivity for β₂-adrenoceptors. Activation of β₂-adrenoceptors in the airways leads to stimulation of intracellular adenylate cyclase, which is involved in the synthesis of cyclic 3,5-adenosine monophosphate (cAMP). An increase in cAMP levels causes bronchodilation by relaxing smooth muscle cells in the airways.

Olodaterol is a long-acting selective β₂-adrenoceptor agonist, characterized by a rapid onset of action and a long duration of effect of at least 24 hours. β₂-adrenoceptors are present not only in airway smooth muscle but also on the surface of many other cells, including in the epithelium and endothelium of the lungs and heart.

The exact function of β₂-receptors in the heart is not known, but their presence indicates the possibility of effects on the heart even with highly selective beta₂-adrenergic agonists. It was found that a single application of olodaterol at doses of 10, 20, 30 and 50 mcg led to an increase (compared to placebo) in the QT interval (compared to baseline) within 20 min-2 hours, which on average increased with increasing dose from 1.6 ms (Olodaterol at a dose of 10 mcg) to 6.5 ms (Olodaterol at a dose of 50 mcg).

No trends were found in changes in mean heart rate or frequency and type of extrasystoles depending on the dose of the drug or time.

Studies have shown that the use of Striverdi^® Respimat^® at a dose of 5 mcg once daily (in the morning) led to a significant improvement (p<0.0001) in lung function within 5 minutes after the first dose (mean increase in FEV₁ was 0.130 L compared to a pre-treatment baseline of 1.18 L).

A significant improvement in lung function was maintained for 24 hours, the mean increase in AUC_0-3 FEV₁ was 0.162 L compared to placebo, p<0.0001; the mean increase in trough (24-hour) FEV₁ was 0.071 L compared to placebo (p<0.0001).

In two exercise tolerance studies, it was found that Striverdi^® Respimat^® compared to placebo increased the time to onset of fatigue (by 14% p=0.0002 and by 11.8% p=0.0018, respectively). Striverdi^® Respimat^® compared to placebo also reduced lung hyperinflation (functional residual capacity), leading to an increase in inspiratory capacity at rest and during exercise.

Pharmacokinetics

Olodaterol exhibits linear pharmacokinetics. After a single inhalation of doses ranging from 5 to 70 mcg, as well as after repeated once-daily administration of doses ranging from 2 to 20 mcg, systemic exposure increased proportionally with increasing dose.

After repeated once-daily administration, the steady-state pharmacokinetics of olodaterol were reached after 8 days, and the exposure increased by 1.8-fold compared to a single dose.

Absorption

Olodaterol is rapidly absorbed; after inhalation of the drug, C_max in plasma is usually reached within 10-20 minutes. In healthy volunteers after inhalation, the absolute bioavailability of olodaterol was about 30%, while the absolute bioavailability of olodaterol after oral administration as a solution was less than 1%.

Thus, the systemic exposure of olodaterol after inhalation is mainly realized through absorption in the lungs, and the contribution of the swallowed portion of the dose to systemic exposure is negligible.

Distribution

Olodaterol after inhalation and intravenous administration exhibits multicompartment distribution kinetics. V_d was high – 1110 L, indicating extensive distribution of the drug in tissues. The binding of olodaterol to human plasma proteins in vitro is concentration-independent and is approximately 60%.

Metabolism

Olodaterol is extensively metabolized by direct glucuronidation and O-demethylation of the methoxylated part of the molecule followed by conjugation. Of the six identified metabolites, only one unconjugated demethylated derivative (SOM 1522) binds to β₂-receptors, but this metabolite was not detected in plasma after long-term inhalation use of the drug at the recommended therapeutic dose or at doses 4 times the therapeutic dose.

In this regard, it is believed that the pharmacological action is due solely to olodaterol itself. The O-demethylation of olodaterol involves cytochrome P450 isoenzymes – CYP2C9 and CYP2C8, and (to a minor extent) CYP3A4. The formation of olodaterol glucuronides involves uridine diphosphate glucose-glucuronosyltransferase isoforms, UGT2B7, UGT1A1, 1A7 and 1A9.

Excretion

The total clearance of olodaterol in healthy volunteers is 872 ml/min, and renal clearance is 173 ml/min. The terminal T_1/2 after intravenous administration is 22 hours, while the terminal T_1/2 after inhalation is approximately 45 hours. It follows that in the latter case, elimination is more dependent on absorption.

The total isotopically labeled dose excreted via the kidneys (including the parent compound and all metabolites) was 38% after intravenous administration and 9% after oral administration. The total isotopically labeled dose of unchanged olodaterol excreted via the kidneys was 19% after intravenous administration. The total isotopically labeled dose excreted via the intestine was 53% after intravenous administration and 84% after oral administration.

More than 90% of the drug dose was excreted after intravenous administration within 5 days and after oral administration within 6 days. After inhalation administration, the excretion of unchanged olodaterol in urine over the dosing interval in healthy volunteers at steady-state pharmacokinetics was 5-7% of the dose.

Pharmacokinetics in special patient groups

Dose adjustment of Striverdi^® Respimat^® depending on body weight, gender and age is not required.

In patients with severe renal impairment (CrCl <30 ml/min), the systemic exposure of olodaterol increased on average by 1.4 times. This increase in exposure is not a safety concern, given the experience gained from the use of Striverdi^® Respimat^® in clinical studies.

In patients with mild and moderate hepatic impairment, the systemic exposure of olodaterol did not change. The systemic exposure of olodaterol in patients with severe hepatic impairment has not been studied.

Comparison of pharmacokinetic data obtained in clinical studies revealed a trend towards higher systemic exposure of olodaterol in Japanese patients and other patients of Asian race compared to Caucasian patients. In clinical studies of Striverdi^® Respimat^® used at doses that were 2 times the recommended therapeutic dose, no safety concerns were identified in Caucasian and Asian patients.

Indications

• For long-term maintenance therapy in patients with COPD, including chronic bronchitis and emphysema, to reduce airway obstruction, improve quality of life and exercise tolerance.

ICD codes

Dosage Regimen

The recommended therapeutic dose is 2 inhalations of spray from the Respimat^® inhaler (5 mcg/therapeutic dose) once daily, at the same time of day.

Elderly patients, patients with mild to moderate hepatic impairment and patients with renal impairment can use Striverdi^® Respimat^® at the recommended dose. There are no data on the use of Striverdi^® Respimat^® in patients with significant hepatic impairment.

COPD usually does not develop in children. The safety and efficacy of olodaterol in children have not been studied.

Instructions for Use

Insertion of the cartridge and preparation for use

Before first use of the inhaler, it is necessary to perform the actions listed below under numbers 1-6.

1. With the protective yellow cap closed, press the locking button and remove the transparent sleeve.
2. Remove the cartridge from the packaging and insert it with the thin end into the inhaler until it clicks.

To ensure that the cartridge is in place, press the cartridge firmly against a hard surface. The cartridge should not be completely immersed in the inhaler; the silver ring at its lower end should protrude from the inhaler.

Once the cartridge is inserted into the inhaler, it should not be removed.

1. Put on the transparent sleeve.

After this, the sleeve should not be removed again.

Preparation for first use of the Striverdi^® Respimat^® inhaler

1. Hold the Striverdi^® Respimat^® inhaler vertically with the protective yellow cap on.

Turn the transparent sleeve in the direction of the black arrow indicated on the label until it clicks (half a turn).

1. Fully flip open the yellow protective cap.
2. Point the Striverdi^® Respimat^® inhaler downwards, press the dose release button, then close the yellow protective cap.

Repeat steps 4, 5 and 6 until an aerosol cloud appears.

Then repeat steps 4, 5 and 6 another 3 times to complete the preparation of the inhaler for use.

The Striverdi^® Respimat^® inhaler is now ready for use.

Performing these steps does not reduce the number of doses of the drug.

After preparation, the Striverdi^® Respimat^® inhaler allows for the release of 60 inhalations of the drug (30 therapeutic doses).

Daily use of the Striverdi^® Respimat^® inhaler

Use the Striverdi^® Respimat^® inhaler only once daily. Each time, it is necessary to take 2 inhalations.

I. Hold the Striverdi^® Respimat^® inhaler vertically with the yellow protective cap on to prevent accidental release of medicine. Turn the transparent sleeve in the direction of the black arrow indicated on the label until it clicks (half a turn).

II. Fully flip open the yellow protective cap. Exhale slowly and deeply, then tightly enclose the end of the mouthpiece with your lips. The air vent in the inhaler must be free. Point the Striverdi^® Respimat^® inhaler towards the back of your throat.

While inhaling slowly and deeply through your mouth, press the dose release button and continue to inhale for as long as possible. Hold your breath for 10 seconds or as long as is comfortable for the patient.

III. Repeat steps I and II to get the full dose.

Close the yellow protective cap of the Striverdi^® Respimat^® inhaler until the next use.

If the Striverdi^® Respimat^® inhaler has not been used for more than 7 days, release 1 dose from it towards the floor. If the Striverdi^® Respimat^® inhaler has not been used for more than 21 days, repeat steps 4-6 until a visible aerosol cloud appears, then repeat steps 4-6 another 3 times.

How to determine when to use a new Striverdi^® Respimat^® inhaler

The Striverdi^® Respimat^® inhaler contains 60 inhalations (30 therapeutic doses). The dose indicator shows approximately how much medicine is left. When the inhaler indicator points to the red area of the scale, this means that there is approximately 7 days of medicine left (14 inhalations). During this period, it is necessary to get a prescription for a new Striverdi^® Respimat^® inhaler.

When the dose indicator reaches the end of the red scale, this means that the Striverdi^® Respimat^® inhaler is empty (i.e., all 30 doses have been used). The inhaler will automatically lock. From this point on, turning the transparent sleeve will be impossible.

The Striverdi^® Respimat^® inhaler should be disposed of no later than 3 months after use, even if not all of the drug has been used.

How to care for the inhaler

Wipe the mouthpiece, including its inner metal part, using only a damp soft cloth, at least once a week. A slight discoloration of the mouthpiece does not affect the functioning of the Striverdi^® Respimat^® inhaler. If necessary, you can also wipe the outside of the Striverdi^® Respimat^® inhaler with a damp cloth.

Adverse Reactions

Adverse reactions were identified based on data obtained from clinical studies of Striverdi^® Respimat^®.

Olodaterol belongs to the group of long-acting beta-adrenomimetics. Therefore, the possibility of adverse effects characteristic of the entire class of beta-adrenomimetics should be taken into account, such as tachycardia, arrhythmia, palpitations, myocardial ischemia, angina, hypertension or hypotension, tremor, headache, nervousness, insomnia, dizziness, dry mouth, nausea, muscle spasm, fatigue, malaise, hypokalemia, hyperglycemia and metabolic acidosis.

From the respiratory system nasopharyngitis.

From the nervous system dizziness.

From the cardiovascular system arterial hypertension.

From the skin rash.

From the musculoskeletal system: arthralgia.

The occurrence of a rash may be considered as a hypersensitivity reaction to Striverdi^® Respimat^®. Other hypersensitivity reactions are possible (as with the topical use of any absorbed drugs).

Contraindications

• Hypersensitivity to olodaterol or to any component of the drug;
• Childhood and adolescence under 18 years of age (due to lack of data on efficacy and safety).

Use with caution in cardiovascular diseases, including unstable coronary artery disease, cardiac arrhythmia, QT interval prolongation, hypertrophic obstructive cardiomyopathy, arterial hypertension, thyrotoxicosis, convulsions, as well as in patients with a history of diseases such as myocardial infarction or hospitalization for heart failure (within the previous year), life-threatening arrhythmia, paroxysmal tachycardia with heart rate >100.

Use in Pregnancy and Lactation

There are no clinical data on the effect of Striverdi^® Respimat^® on the course of pregnancy. In preclinical studies, when using olodaterol in high doses, several times higher than therapeutic doses, effects typical of beta-adrenomimetics were found.

The drug should be used during pregnancy only if the probable benefit to the mother outweighs the potential risk to the fetus.

The inhibitory effect of olodaterol on uterine contractility should be taken into account.

There are no clinical data on the use of olodaterol during lactation. The drug should be used during breastfeeding only if the probable benefit to the mother outweighs the potential risk to the child.

Use in Hepatic Impairment

In patients with mild to moderate hepatic impairment, Striverdi^® Respimat^® can be used at the recommended dose. There are no data on the use of the drug in patients with significant hepatic impairment.

Use in Renal Impairment

In patients with renal impairment, Striverdi^® Respimat^® can be used at the recommended dose.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age (due to lack of data on efficacy and safety).

Geriatric Use

In elderly patients, Striverdi^® Respimat^® can be used at the recommended dose.

Special Precautions

Striverdi^® Respimat^® is intended for maintenance treatment of patients with COPD. Since in the general population COPD is significantly predominant in patients over 40 years of age, when prescribing the drug to patients under 40 years of age, spirometric confirmation of the diagnosis of COPD is required.

Striverdi^® Respimat^® should not be used for bronchial asthma. The long-term efficacy and safety of olodaterol in bronchial asthma have not been studied.

The drug Striverdi^® Respimat^® is not intended for the treatment of acute episodes of bronchospasm, i.e., as a rescue medication.

Following the use of Striverdi^® Respimat^®, immediate-type hypersensitivity reactions may occur (as with the use of any medicinal product).

The use of Striverdi^® Respimat^®, like other inhaled medicinal products, can lead to paradoxical bronchospasm, which is sometimes life-threatening. In the event of paradoxical bronchospasm, the use of the drug should be discontinued immediately and alternative therapy should be instituted.

Long-acting beta-adrenergic agonists should be used with caution in patients with unusual reactions to sympathomimetic amines.

Olodaterol, like other beta-adrenergic agonists, can have clinically significant effects on the cardiovascular system in some patients (increased heart rate, elevated blood pressure, and/or the appearance of corresponding symptoms). If such effects occur, discontinuation of treatment may be necessary. Furthermore, it has been reported that beta-adrenergic agonists can lead to ECG changes such as T-wave flattening and ST-segment depression, although the clinical significance of these changes is unknown.

Beta-adrenergic agonists can cause significant hypokalemia in some patients, which may predispose them to adverse cardiovascular effects. The decrease in serum potassium is usually transient and does not require supplementation. In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant therapy, and may increase the risk of arrhythmias.

Inhalation of high doses of beta-adrenergic agonists can lead to an increase in plasma glucose levels.

Striverdi^® Respimat^® should not be used in combination with any other medicinal product containing long-acting beta-adrenergic agonists. Patients who frequently use short-acting inhaled beta-adrenergic agonists (e.g., 4 times/day) should be informed that such drugs are used only for the relief of acute bronchospasm symptoms.

Effect on the ability to drive vehicles and operate machinery

Studies on the effect on the ability to drive vehicles and operate machinery have not been conducted. Caution should be exercised when engaging in these activities, as dizziness may occur.

Overdose

Symptoms: an overdose of olodaterol may lead to pronounced effects typical of beta-adrenergic agonists, such as myocardial ischemia, arterial hypertension or hypotension, tachycardia, arrhythmia, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis.

Treatment: discontinue the drug and provide supportive and symptomatic therapy. In severe cases, hospitalization is necessary. The use of cardioselective beta-adrenergic blockers is recommended, but only with extreme caution, as the use of these drugs may cause bronchospasm.

Drug Interactions

Concomitant use of other adrenergic drugs may enhance the adverse effects of Striverdi^® Respimat^®.

Concomitant use of xanthine derivatives, steroids, or diuretics (not belonging to the potassium-sparing group) may enhance the hypokalemic effect of beta-adrenergic agonists.

Beta-adrenergic blockers may weaken the effect of Striverdi^® Respimat^® or counteract this effect. Therefore, Striverdi^® Respimat^® should be used together with beta-adrenergic blockers (including eye drops) only when absolutely necessary. In this case, the use of cardioselective beta-adrenergic blockers is preferable, although they should also be used with caution.

MAO inhibitors, tricyclic antidepressants, or other drugs capable of prolonging the QTc interval may enhance the effect of Striverdi^® Respimat^® on the cardiovascular system.

Concomitant use of Striverdi^® Respimat^® with ketoconazole led to a 1.7-fold increase in the systemic exposure of olodaterol; however, this did not affect safety; no dose adjustment is required.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F). The drug must be used within 3 months after the first inhalation.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.