Spiolto Respimat, 2.5 mcg+2, 5 mcg/dose 4 ml cartridges, complete with respimat inhaler

Bronchodilator.

Olodaterol – a long-acting beta2-adrenomimetic – and tiotropium bromide – an m-cholinoblocker – provide complementary bronchodilation as a result of the different mechanism of action of the active substances and the different localization of the target receptors in the lungs.

Olodaterol has high affinity and selectivity for beta2-adrenoreceptors. Activation of beta2-adrenoceptors in the respiratory tract leads to stimulation of intracellular adenylate cyclase, which is involved in the synthesis of cAMP. Increased levels of cAMP cause bronchodilation, relaxing the smooth muscle cells of the airways.

Olodaterol is a selective long-acting beta2-adrenoceptor agonist with rapid onset of action and long (at least 24 hours) retention of effect. Beta2-adrenoceptors are present not only in smooth muscle cells, but also in many other cells, including epithelial and endothelial cells of the lungs and heart. The exact function of beta2-receptors in the heart is not fully understood, but their presence indicates that even highly selective beta2-adrenergic agonists can affect the heart.

Tiotropium bromide is a long-acting muscarinic receptor antagonist, often referred to in clinical practice as an m-cholin blocker. It has the same affinity for m1-m5-subtypes of muscarinic receptors. The result of inhibition of m3-receptors in the respiratory tract is relaxation of smooth muscles.

The bronchodilator effect is dose-dependent and persists for at least 24 hours. The considerable duration of action is probably due to the very slow dissociation of tiotropium bromide from m3-receptors: the half-dissociation period is significantly longer than that of ipratropium bromide.

When administered by inhalation, tiotropium bromide, as an N-quaternary ammonium derivative, has a local selective effect (on the bronchi), while not causing systemic m-cholinoblocking side effects at therapeutic doses. Dissociation from m2-receptors is faster than from m3-receptors, indicating the predominance of selectivity for m3-subtype receptors over m2-receptors. High affinity for receptors and slow dissociation of tiotropium bromide from bonding to receptors cause a pronounced and prolonged bronchodilator effect in patients with COPD.

The bronchodilation that develops after inhalation of tiotropium bromide is due primarily to local action (on the airways) rather than systemic action.

Indications

SPIOLTO RESPIMAT, taken once daily, is indicated for long-term maintenance therapy in patients with chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary emphysema, to reduce airway obstruction and associated shortness of breath; reduce exacerbations frequency; improve exercise tolerance and quality of life.

Active ingredient

Composition

1 dose contains:

olodaterol hydrochloride – 2.736 mcg, which corresponds to the content of olodaterol – 2.5 mcg

tiotropium bromide monohydrate – 3.124 mg, which corresponds to the content of tiotropium – 2.5 mg

Excipients:

benzalkonium chloride solution – 0.0022 mg (respectively benzalkonium chloride – 0.0011 mg),

dinatrium edetate – 0.0011 mg,

citric acid anhydrous 1M – to pH 2.9,

purified water – to 11.05 mg.

How to take, the dosage

The recommended therapeutic dose is 2 inhalations of Respimat inhaler spray (5 mcg/therapeutic dose of tiotropium bromide and 5 mcg/therapeutic dose of olodaterol) once daily, at the same time of day (see Instructions for Use).

In elderly patients, Spiolto Respimat can be used in the recommended dose.

In patients with mild to moderate hepatic impairment, Spiolto Respimat can be used in the recommended dose.

There are no data on the use of olodaterol in patients with severe hepatic impairment.

In patients with impaired renal function, Spiolto Respimat can be used in the recommended dose.

Patients with moderate to severe renal impairment using Spiolto Respimat should be under close medical supervision.

Interaction

While no specific studies of drug interactions have been conducted, tiotropium bromide has been coadministered with other COPD drugs, including methylxanthines, oral steroids, and inhaled steroids, with no clinical evidence of drug interactions.

The long-term co-administration of tiotropium bromide with other m-cholinoblocking drugs has not been studied. Therefore, long-term co-administration of the drug Spiolto Respimat with other m-cholinoblocking drugs is not recommended.

The concomitant use of other adrenergic drugs may increase the undesirable effects of Spiolto Respimat.

The concomitant use of xanthine derivatives, steroids, or diuretics (non-caliber) may increase the hypokalemic effects of adrenomimetics.

Beta-adrenoblockers may weaken or counteract the effect of olodaterol. In this case, the use of bega1-adrenoblockers is preferable, although they should also be used with caution.

MAO inhibitors, tricyclic antidepressants, or other drugs that can prolong the QTc interval may increase the cardiovascular effects of Spiolto Respimat.

The co-administration of olodaterol with ketoconazole resulted in a 1.7-fold increase in systemic exposure to olodaterol. However, this did not affect safety. No dose changes are required.

Special Instructions

The drug Spiolto Respimat should not be used in bronchial asthma. Efficacy and safety of the drug Spiolto Respimat in bronchial asthma have not been studied.

Hypersensitivity

Possible immediate hypersensitivity reactions after using Spiolto Respimat.

Acute bronchospasm

Spiolto Respimat is not indicated for the treatment of acute episodes of bronchospasm, i.e. as an emergency treatment.

Paradoxic bronchospasm

The use of Spiolto Respimat, like other inhaled medicines, may lead to paradoxic bronchospasm, sometimes life-threatening. If paradoxical bronchospasm develops, the use of Spiolto Respimat should be immediately discontinued and alternative therapy should be prescribed.

Patients with impaired renal function

Because tiotropium bromide is primarily excreted by the kidneys, patients with moderate to severe renal impairment (CK <50 ml/min) using Spiolto Respimat should be under close medical supervision.

Visual disturbances

Patients should be advised of the correct use of Spiolto Respimat. The solution or aerosol should not be allowed into the eyes. Pain or discomfort in the eyes, blurred vision, and visual halos around light sources combined with red eyes caused by swelling of the conjunctiva and cornea may be symptoms of acute closed angle glaucoma. If any combination of these symptoms develops, see a specialist immediately. Myotic eye drops are not considered an effective treatment.

Cardiovascular effects

Olodaterol, like other beta-adrenomimetics, may have clinically significant cardiovascular effects in some patients (increased heart rate, increased BP and/or associated symptoms). Discontinuation of treatment may be required if such symptoms occur. In addition, beta2-adrenomimetics have been reported to cause ECG changes such as T-wave flattening and ST-segment depression, although the clinical significance of these changes is unknown.

Hypokalemia

Beta2-adrenomimetics in some patients may lead to hypokalemia, setting the stage for adverse cardiovascular effects. Decrease of serum potassium concentration is usually short-term and does not require its replenishment. In patients with severe COPD, hypokalemia may be worsened by hypoxia and concomitant treatment and increase the risk of arrhythmias.

Hyperglycemia

Inhaled use of high doses of beta2-adrenomimetics may increase plasma glucose concentrations.

Spiolto Respimat should not be used in combination with any other medication containing long-acting beta2-adrenomimetics.

Patients who frequently use short-acting inhaled beta2-adrenomimetics (e.g., 4 times/day) should be instructed that these medications are only used to relieve acute symptoms of bronchospasm.

The drug Spiolto Respimat is intended as a maintenance treatment for COPD patients. Because of the fact that in the general population of COPD patients over 40 years of age are significantly predominant, spirometric confirmation of the diagnosis of COPD is required when prescribing the product in patients younger than 40 years of age.

Influence of the drug on the ability to drive and operate vehicles

There have been no studies to study the effect on the ability to operate vehicles and machinery. Caution should be exercised when performing these activities as dizziness or blurred vision may occur.

Contraindications

Patients with hypersensitivity to olodaterol, tiotropium bromide or any component of the drug are contraindicated;

Patients with a history of hypersensitivity to atropine or its derivatives, such as ipratropium and oxytropium;

It is not recommended for use in children under 18 years of age (due to lack of efficacy and safety data).

Side effects

Nervous system disorders: dizziness, insomnia.

Metabolism and nutrition: dehydration.

Visual system disorders: increased intraocular pressure, glaucoma; blurred vision.

Cardiovascular system: atrial fibrillation, palpitations, tachycardia, supraventricular tachycardia, increased BP.

Respiratory, chest and mediastinal organs: cough, nasal bleeding, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis.

Gastrointestinal disorders: minor dry mouth, constipation, oral candidiasis, dysphagia, gastroesophageal reflux, gingivitis, glossitis, stomatitis; intestinal obstruction, including paralytic intestinal obstruction.

Skin disorders: skin infections and skin ulcers, dry skin.

Allergic reactions: rash, itching, angioedema, urticaria, hypersensitivity, including immediate type reactions.

Muscular system and related connective tissue disorders: arthralgia, swollen joints, back pain.

Renal and urinary system disorders: dysuria, urinary retention (more common in men with predisposing factors), urinary tract infection.

Infections and invasions: nasopharyngitis.

Overdose

Olodaterol overdose may result in marked effects typical of beta2-adrenomimetics, such as myocardial ischemia, increased or decreased BP, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, restlessness, headache, tremor, dry mouth, muscle spasm, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis.

When using high doses of tiotropium bromide, m-cholinoblocking effects may occur. After 14-day inhalation use of tiotropium bromide in doses as high as 40 mcg, no significant adverse events were observed in healthy subjects, except for a feeling of dryness of mucous membranes of the nose and oropharynx, the frequency of which depended on the dose value (10-40 mcg/day). The exception was a distinct decrease in salivation starting on day 7 of the drug.

Treatment

The administration of Spiolto Respimat should be discontinued. Supportive and symptomatic treatment is indicated. Hospitalization is necessary in severe cases. Beta1-adrenoblockers may be recommended, but with extreme caution, as they can cause bronchospasm.