Seretide^® (Aerosol, Powder) Instructions for Use

ATC Code

R03AK06 (Salmeterol and fluticasone)

Active Substances

Salmeterol (Rec.INN registered by WHO)

Fluticasone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug with anti-inflammatory and bronchodilator action

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; adrenergics in combination with glucocorticoids or other agents, except anticholinergic agents

Pharmacological Action

Seretide^® Multidisk is a combination drug that contains salmeterol and fluticasone propionate, which have different mechanisms of action. Salmeterol prevents the occurrence of bronchospasm symptoms, and fluticasone propionate improves lung function and prevents disease exacerbation. Seretide^® Multidisk, due to a more convenient dosing regimen, can be an alternative for patients who are simultaneously receiving a β₂-adrenergic receptor agonist and an inhaled glucocorticosteroid from different inhalers.

Salmeterol is a selective long-acting (up to 12 hours) β₂-adrenergic receptor agonist with a long side chain that binds to the outer domain of the receptor.

The pharmacological properties of salmeterol provide more effective protection against histamine-induced bronchoconstriction and longer bronchodilation (lasting at least 12 hours) than short-acting β₂-adrenergic receptor agonists.

In vitro studies have shown that salmeterol is a potent inhibitor of the release of mast cell mediators from human lungs, such as histamine, leukotrienes, and prostaglandin D₂, and has a long duration of action.

Salmeterol inhibits the early and late phases of the response to inhaled allergens. Inhibition of the late-phase response persists for more than 30 hours after a single dose, at a time when the bronchodilating effect is no longer present. A single administration of salmeterol attenuates bronchial hyperreactivity. This indicates that salmeterol, in addition to bronchodilating activity, has an additional action not associated with bronchodilation, the clinical significance of which has not been definitively established. This mechanism of action differs from the anti-inflammatory effect of glucocorticosteroids.

Fluticasone propionate belongs to the group of topical glucocorticosteroids and, when inhaled at recommended doses, has a pronounced anti-inflammatory and anti-allergic effect in the lungs, leading to a reduction in clinical symptoms and a decrease in the frequency of asthma exacerbations. Fluticasone propionate does not cause adverse events observed with systemic corticosteroid use.

With long-term use of inhaled fluticasone propionate, the daily secretion of adrenal cortex hormones remains within the normal range in both adults and children, even when using the maximum recommended doses. After switching patients receiving other inhaled glucocorticosteroids to fluticasone propionate, the daily secretion of adrenal cortex hormones gradually improves, despite previous and current periodic use of oral steroids. This indicates the restoration of adrenal function during inhalation use of fluticasone propionate. With long-term use of fluticasone propionate, the reserve function of the adrenal cortex also remains within the normal range, as evidenced by a normal increase in cortisol production in response to appropriate stimulation (it should be taken into account that residual reduction of adrenal reserve caused by previous therapy may persist for a long time).

Pharmacokinetics

There is no evidence that when administered together by inhalation, salmeterol and fluticasone propionate affect each other’s pharmacokinetics, and therefore the pharmacokinetic characteristics of each component of Seretide^® Multidisk can be considered separately.

A study involving 15 healthy volunteers who simultaneously received salmeterol (inhaled 50 mcg twice daily) and the CYP3A4 isoenzyme inhibitor ketoconazole (oral 400 mg once daily) for 7 days showed a significant increase in plasma salmeterol concentrations (increase in C_max by 1.4 times and AUC by 15 times). No increase in salmeterol accumulation was observed with repeated doses. In three patients, treatment was discontinued due to prolongation of the QT_c interval or palpitations with sinus tachycardia. In the remaining 12 patients, the simultaneous use of salmeterol and ketoconazole did not have a clinically significant effect on heart rate, blood potassium levels, or the duration of the QT_c interval (see sections “With Caution”, “Special Instructions”, “Drug Interactions”).

Absorption

Salmeterol acts locally in lung tissues, so its plasma concentration is not an indicator of therapeutic effects. Data on its pharmacokinetics are very limited due to technical problems: when inhaled at therapeutic doses, its C_max in plasma is extremely low (about 200 pg/ml and below). After regular salmeterol inhalations, hydroxynaphthoic acid can be detected in the blood, with C_ss of about 100 ng/ml. These concentrations are 1000 times lower than the C_ss observed in toxicity studies. No adverse effects were observed with long-term regular use of the drug (for more than 12 months) in patients with airway obstruction.

Fluticasone propionate the absolute bioavailability of inhaled fluticasone propionate in healthy individuals varies depending on the inhaler used; when administering the combination of salmeterol and fluticasone propionate using the “Multidisk” inhaler, it is 5.5%. Lower plasma concentrations of fluticasone propionate are observed in patients with bronchial asthma and COPD. Systemic absorption occurs primarily through the lungs. It is initially faster but then slows down.

Part of the inhaled dose may be swallowed, but this part contributes minimally to systemic absorption due to the low solubility of fluticasone propionate in water and due to its presystemic metabolism; bioavailability from the gastrointestinal tract is less than 1%. As the inhaled dose increases, a linear increase in the plasma concentration of fluticasone propionate is observed.

Distribution

There is no data on the distribution of salmeterol.

Fluticasone propionate has a large V_d at equilibrium (about 300 L) and has a relatively high degree of binding to plasma proteins (91%).

Metabolism

In vitro study results have shown that salmeterol is extensively metabolized by the CYP3A4 isoenzyme of the cytochrome P450 system to α-hydroxysalmeterol by aliphatic oxidation. A study with repeated dosing of salmeterol and erythromycin in healthy volunteers showed no clinically significant changes in pharmacodynamic effects when taking 500 mg of erythromycin three times daily. However, the drug interaction study of salmeterol and ketoconazole showed a significant increase in plasma salmeterol concentrations (see sections “Special Instructions”, “Drug Interactions”).

Fluticasone propionate is rapidly eliminated from the blood, mainly as a result of metabolism by the CYP3A4 isoenzyme of the cytochrome P450 system to an inactive carboxylic acid metabolite. Caution should be exercised when co-administering known CYP3A4 inhibitors and fluticasone propionate, as this may lead to an increase in its plasma concentration.

Excretion

There is no data regarding the excretion of salmeterol.

The disposition of fluticasone propionate is characterized by rapid clearance from plasma (1150 ml/min) and a terminal T_1/2 of approximately 8 hours. Renal clearance of unchanged fluticasone propionate is negligible (< 0.2%), less than 5% of the dose is excreted in the urine as a metabolite.

Indications

The drug is intended for the regular treatment of bronchial asthma when combination therapy with a long-acting beta₂-adrenergic agonist and an inhaled corticosteroid is indicated

• For patients with insufficient disease control on constant monotherapy with inhaled corticosteroids with periodic use of a short-acting beta₂-adrenergic agonist;
• For patients with adequate disease control on therapy with an inhaled corticosteroid and a long-acting beta₂-adrenergic agonist;
• As initial maintenance therapy in patients with persistent bronchial asthma when there are indications for the prescription of glucocorticosteroids to achieve disease control.

The drug is intended for maintenance therapy in patients with COPD with an FEV1 <60% of predicted (pre-bronchodilator) and a history of repeated exacerbations, in whom significant disease symptoms persist despite regular bronchodilator therapy.

ICD codes

Dosage Regimen

Aerosol

Seretide^® is intended for inhalation only.

The patient should be informed that to obtain the optimal effect, the drug should be used regularly, even in the absence of clinical symptoms of bronchial asthma and COPD.

The physician should regularly assess the effectiveness of the patient’s treatment.

Determining the duration of the course of therapy and changing the dose of the drug is possible only on the recommendation of a doctor.

Bronchial asthma

The dose of Seretide^® should be reduced to the lowest dose that provides effective symptom control.

If taking Seretide^® twice daily provides symptom control, as part of dose reduction to the minimum effective, it is possible to reduce the frequency of drug administration to once daily.

The patient should be prescribed the form of Seretide^® that contains a dose of fluticasone propionate appropriate to the severity of their disease.

If therapy with inhaled glucocorticosteroids does not provide adequate disease control, then replacing them with Seretide^® at a dose therapeutically equivalent to the dose of the administered glucocorticosteroids may improve asthma control. In patients whose asthma can be controlled solely with inhaled glucocorticosteroids, switching to Seretide^® may allow a reduction in the dose of glucocorticosteroids required to control asthma.

Recommended doses

Adults and children 12 years and older two inhalations (25 mcg salmeterol and 50 mcg fluticasone propionate) twice daily, or two inhalations (25 mcg salmeterol and 125 mcg fluticasone propionate) twice daily, or two inhalations (25 mcg salmeterol and 250 mcg fluticasone propionate) twice daily.

Children 4 years and older: two inhalations (25 mcg salmeterol and 50 mcg fluticasone propionate) twice daily.

There are currently no data on the use of Seretide^® in children under 4 years of age.

Chronic obstructive pulmonary disease (COPD)

For adult patients the maximum recommended dose is two inhalations (25 mcg salmeterol and 250 mcg fluticasone propionate) twice daily.

Special patient groups

There is no need to reduce the dose of Seretide^® in elderly patients, as well as in patients with impaired renal or hepatic function.

Instructions for using the inhaler (for patients)

Checking the inhaler

Before using the inhaler for the first time, or if the inhaler has not been used for a week or more, remove the cap from the mouthpiece by gently squeezing the cap from the sides, hold the inhaler between the thumb and other fingers of one hand so that the thumb is on the base under the mouthpiece, shake the inhaler well and release two sprays into the air to make sure the inhaler is working.

Using the inhaler

1. Remove the cap from the mouthpiece by gently squeezing the cap from the sides.
2. Inspect the outside and inside of the inhaler, including the mouthpiece, for foreign objects.
3. Shake the inhaler well to ensure any foreign objects are removed and the contents of the inhaler are evenly mixed.
4. Hold the inhaler between the thumb and other fingers of one hand in an upright position with the bottom up, with the thumb on the base under the mouthpiece.
5. Exhale as deeply as possible, then place the mouthpiece in your mouth between your teeth, closing your lips around it, but do not bite the mouthpiece.
6. Immediately after starting to inhale through your mouth, press down on the top of the inhaler to release the Seretide^® spray, while continuing to inhale deeply and slowly.
7. Holding your breath, remove the inhaler from your mouth and remove your finger from the top of the inhaler. Continue to hold your breath for as long as possible.
8. To perform a second spray, hold the inhaler upright and after about 30 seconds repeat steps 3-7.
9. After using the inhaler, rinse your mouth with water and then spit it out.
10. Immediately close the mouthpiece cap by pressing and snapping it into place. If it does not snap, turn the mouthpiece cap and try to close the mouthpiece again. Do not press the cap hard.

The drug can also be used with a spacer. Attention! When performing steps 5, 6 and 7, do not rush.

You should start inhaling as slowly as possible, just before pressing the inhaler valve.

It is recommended to practice in front of a mirror the first few times.

If you see “mist” coming from the top of the inhaler or from the corners of your mouth, you should start over from step 2.

If your doctor has given you other instructions for using the inhaler, follow them strictly. Contact your doctor if you have difficulty using the inhaler.

Children

Young children may need help using the inhaler and should be assisted by an adult. Wait for the child to exhale and activate the inhaler at the moment of inhalation. Practice using the inhaler with the child. Older children and adults with weak hands should hold the inhaler with both hands. In this case, both index fingers should be on the top of the inhaler, and both thumbs should be on the base below the mouthpiece.

Cleaning the inhaler

The inhaler should be cleaned at least once a week.

1. Remove the protective cap from the mouthpiece.
2. Do not remove the metal canister from the plastic casing.
3. Wipe the mouthpiece and the inside and outside of the plastic casing with a dry cloth or cotton swab.
4. Close the mouthpiece with the protective cap.

Do not immerse the metal canister in water.

Powder

Seretide^® Multidisk is intended for inhalation only.

The patient should be informed that to obtain the optimal effect, the drug should be used regularly, even in the absence of clinical symptoms of bronchial asthma and COPD.

The physician should regularly assess the effectiveness of the patient’s treatment.

Determining the duration of the course of therapy and changing the dose of the drug is possible only on the recommendation of a doctor.

Bronchial asthma

The dose of Seretide^® Multidisk should be reduced to the lowest dose that provides effective symptom control.

If taking Seretide^® Multidisk twice daily provides symptom control, as part of dose reduction to the minimum effective, it is possible to reduce the frequency of drug administration to once daily.

The patient should be prescribed the form of Seretide^® Multidisk that contains a dose of fluticasone propionate appropriate to the severity of their disease.

If therapy with inhaled glucocorticosteroids does not provide adequate disease control, then replacing them with Seretide^® Multidisk at a dose therapeutically equivalent to the dose of the administered glucocorticosteroids may improve asthma control. In patients whose asthma can be controlled solely with inhaled glucocorticosteroids, switching to Seretide^® Multidisk may allow a reduction in the dose of glucocorticosteroids required to control asthma.

Recommended doses

Adults and children 12 years and older one inhalation (50 mcg salmeterol and 100 mcg fluticasone propionate) twice daily, or one inhalation (50 mcg salmeterol and 250 mcg fluticasone propionate) twice daily, or one inhalation (50 mcg salmeterol and 500 mcg fluticasone propionate) twice daily.

Children 4 years and older: one inhalation (50 mcg salmeterol and 100 mcg fluticasone propionate) twice daily.

There are currently no data on the use of Seretide^® Multidisk in children under 4 years of age.

Chronic obstructive pulmonary disease (COPD)

For adult patients the maximum recommended dose is 1 inhalation (50 mcg salmeterol and 500 mcg fluticasone propionate) twice daily. For this dosage of Seretide^® Multidisk, a reduction in all-cause mortality has been demonstrated.

Special patient groups

There is no need to reduce the dose of Seretide^® Multidisk in elderly patients, as well as in patients with impaired renal or hepatic function.

Instructions for using the “Multidisk” inhaler

When you take Seretide^® Multidisk out of the box, it is in the closed position.

Seretide^® Multidisk contains 28 or 60 doses in powder form. Each dose is measured and hygienically protected. No dose level maintenance or additional filling is required.

The inhaler has an indicator that shows the number of doses remaining after each inhalation. The numbers go in descending order from 60 to 0 or from 28 to 0. The numbers from 5 to 0 are red, warning that there are only a few doses left in the inhaler. The appearance of the number 0 in the window means that the inhaler is empty and unsuitable for further use.

To perform an inhalation, follow five sequential actions:

1. open the inhaler;

2. press the lever;

3. inhale the dose of the drug;

4. close the inhaler;

5. rinse your mouth.

How the inhaler works

When the lever is turned, a small opening in the mouthpiece is revealed, and one dose is ready for inhalation. When the inhaler is closed, the lever automatically returns to its original position, thus remaining ready for the next required dose. The packaging protects the inhaler when it is not in use.

1. Open the inhaler. Hold the body with one hand, placing the thumb of your other hand in the special recess. To open the inhaler, push the thumb grip away from you as far as it will go until you hear a click.

2. Press the lever. Hold the inhaler with the mouthpiece facing you. The inhaler can be held in your right or left hand. Press the lever away from you as far as it will go until you hear a click. The inhaler is now ready for use. When you press the lever, the next blister containing the powder for inhalation is opened. The number of doses remaining decreases, which is indicated in the dose indicator window. Press the lever only immediately before inhalation, otherwise it will lead to a waste of the medication.

3. Inhale the dose of the medication. Before inhaling the medication, read this section carefully.

• Hold the inhaler away from your mouth and breathe out fully, but not forcefully. Remember: never exhale into the inhaler!
• Place the mouthpiece in your mouth and close your lips firmly around it. Take one steady, deep breath in through your mouth (not through your nose).
• Remove the inhaler from your mouth.
• Hold your breath for about 10 seconds or for as long as is comfortable.
• Breathe out slowly.

4. Close the inhaler. To close the inhaler, place your thumb in the special recess and push the thumb grip towards you as far as it will go until you hear a click. The lever automatically returns to its starting position. The inhaler is ready for use again.

5. Rinse your mouth. After using the inhaler, rinse your mouth with water and then spit it out.

Remember keep the inhaler dry. Keep it closed when not in use. Never exhale into the inhaler. Only press the lever when you are ready to take a dose. Do not exceed the prescribed dose. Keep the inhaler out of the reach of children.

Adverse Reactions

All adverse reactions listed below are characteristic of the active substances – salmeterol and fluticasone propionate individually. The adverse reaction profile of Seretide^® Multidisc does not differ from the adverse reaction profile of its active substances.

The adverse reactions listed below are presented according to the system organ class and frequency of occurrence. Frequency is defined as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000, including isolated cases). Frequency categories were formed based on data from clinical trials of the drug and post-marketing surveillance.

Clinical trial data

Frequency of adverse reactions

Infections and infestations common – oral and pharyngeal candidiasis, pneumonia (in patients with COPD); rare – esophageal candidiasis.

Immune system disorders hypersensitivity reactions: uncommon – skin hypersensitivity reactions, dyspnea; rare – anaphylactic reactions.

Endocrine disorders possible systemic effects (see section “Special Precautions”): uncommon – cataract; rare – glaucoma.

Metabolism and nutrition disorders: uncommon – hyperglycemia; very rare – hypokalemia.

Psychiatric disorders uncommon – anxiety, sleep disorders; rare – behavioral changes, including hyperactivity and irritability (especially in children).

Nervous system disorders very common – headache (see section “Special Precautions”); uncommon – tremor (see section “Special Precautions”).

Cardiac disorders uncommon – palpitations (see sections “Use with Caution” and “Special Precautions”), tachycardia, atrial fibrillation; rare – arrhythmia, including ventricular extrasystole, supraventricular tachycardia and extrasystole.

Respiratory, thoracic and mediastinal disorders common – hoarseness and/or dysphonia; uncommon – pharyngeal irritation.

Skin and subcutaneous tissue disorders: uncommon – contusion.

Musculoskeletal and connective tissue disorders common – muscle cramps, arthralgia.

Post-marketing surveillance data

Frequency of adverse reactions

Immune system disorders hypersensitivity reactions: rare – angioedema (mainly facial and oropharyngeal edema), bronchospasm.

Endocrine disorders possible systemic effects (see section “Special Precautions”) rare – Cushing’s syndrome, cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density.

Respiratory, thoracic and mediastinal disorders: rare – paradoxical bronchospasm (see section “Special Precautions”).

Contraindications

• Hypersensitivity to the components of the drug;
• Children under 4 years of age.

Use with caution

Like all other inhaled drugs containing corticosteroids, Seretide^® Multidisc should be used with caution in patients with active or latent pulmonary tuberculosis.

Seretide^® Multidisc should be prescribed with caution in thyrotoxicosis.

Seretide^® Multidisc should be used with caution in fungal, viral or bacterial infections of the respiratory tract.

When taking any drugs from the sympathomimetic group, especially when exceeding therapeutic doses, the development of cardiovascular events such as increased systolic blood pressure and heart rate is possible. For this reason, Seretide^® Multidisc should be prescribed with caution to patients with cardiovascular diseases, including arrhythmias such as supraventricular tachycardia and extrasystole, ventricular extrasystole, atrial fibrillation.

All sympathomimetic drugs in doses exceeding therapeutic ones can cause a transient decrease in serum potassium levels. Therefore, Seretide^® Multidisc should be prescribed with caution to patients with hypokalemia.

Seretide^® Multidisc should be used with caution in individuals with a history of allergic reaction to lactose and milk protein, as residual amounts of protein may be part of the lactose.

Any inhaled corticosteroid can cause systemic effects, especially with long-term use in high doses. Therefore, the drug should be used with caution in glaucoma, cataract, osteoporosis (see section “Special Precautions”).

There are very rare reports of increased blood glucose levels, so patients with diabetes mellitus should use Seretide^® Multidisc with caution (see section “Adverse Reactions”).

Use in Pregnancy and Lactation

Fertility

There are no data on the effect on fertility in humans. Studies in animals have revealed no effect of fluticasone propionate or salmeterol xinafoate on fertility in males or females.

Pregnancy

Data on the use of the drug in pregnant women are limited. Use during pregnancy is only acceptable if the potential benefit to the mother outweighs the possible risk to the fetus.

According to the results of a retrospective study, no increased risk of serious congenital malformations was identified after exposure to fluticasone propionate during the first trimester of pregnancy compared to other inhaled corticosteroids.

Reproductive toxicity studies in animals with the administration of each component of the drug separately, as well as their combination, revealed an effect on the fetus due to excessive systemic concentrations of the active beta₂-adrenergic agonist and corticosteroid.

Extensive clinical experience with drugs of this class indicates that at therapeutic doses, the described effects are not clinically significant.

Breastfeeding period

The plasma concentration of salmeterol and fluticasone propionate after inhalation of the drug in therapeutic doses is extremely low, so their concentration in breast milk should be equally low. This is confirmed by studies in animals, in whose milk low concentrations of the drug were determined. There are no concomitant data regarding human breast milk.

The use of the drug during breastfeeding is only acceptable if the potential benefit to the mother outweighs the possible risk to the child.

Use in Hepatic Impairment

In patients with impaired liver function, dose reduction is not required.

Use in Renal Impairment

In patients with impaired renal function, dose reduction is not required.

Pediatric Use

It is recommended to monitor the growth dynamics of children receiving long-term therapy with inhaled corticosteroids.

The use of the drug is contraindicated in children under 4 years of age.

Geriatric Use

There is no need to reduce the dose of the drug for elderly patients.

Special Precautions

Seretide^® Multidisc is not intended for the relief of acute symptoms, as a fast- and short-acting inhaled bronchodilator (e.g., salbutamol) should be used in such cases. Patients should be informed to always have a medication for relieving acute symptoms on hand.

The combination of salmeterol and fluticasone propionate can be used for initial maintenance therapy in patients with persistent bronchial asthma (daily occurrence of symptoms or daily use of relief medications) when there are indications for the prescription of corticosteroids and when determining their approximate dosage.

More frequent use of short-acting bronchodilators to relieve symptoms indicates a worsening of disease control, and in such situations, the patient should consult a doctor.

Sudden and increasing deterioration in the control of bronchial asthma is potentially life-threatening, and in such situations, the patient should also consult a doctor. The doctor should consider prescribing a higher dose of corticosteroids. If the dose of Seretide^® Multidisc used does not provide adequate disease control, the patient should also consult a doctor.

Patients with asthma should not abruptly stop treatment with Seretide^® Multidisc due to the risk of exacerbation; the dose of the drug should be reduced gradually under medical supervision.

In patients with COPD, discontinuation of the drug may be accompanied by symptoms of decompensation and requires medical supervision.

Clinical trial data have shown an increased incidence of pneumonia in patients with COPD receiving Seretide^® Multidisc (see section “Adverse Reactions”). Physicians should be aware of the possibility of pneumonia in COPD, as the clinical picture of pneumonia and COPD exacerbation is often similar.

Any inhaled corticosteroid can cause systemic effects, especially with long-term use in high doses; it should be noted, however, that the likelihood of such symptoms is much lower than with treatment with oral corticosteroids (see section “Overdose”). Possible systemic effects include Cushing’s syndrome, cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract and glaucoma. Therefore, in the treatment of bronchial asthma, it is important to reduce the dose to the lowest dose that provides effective symptom control.

In emergency and planned situations that can cause stress, it is always necessary to remember the possibility of adrenal suppression and be prepared to use corticosteroids (see section “Overdose”).

During resuscitation or surgical interventions, assessment of the degree of adrenal insufficiency is required.

It is recommended to regularly measure the height of children receiving long-term therapy with inhaled corticosteroids.

Due to the possibility of adrenal suppression, patients transferred from oral corticosteroids to inhaled therapy with fluticasone propionate should be treated with particular caution and their adrenal cortex function should be regularly monitored. When transferring patients from systemic corticosteroids to inhaled therapy, allergic reactions (e.g., allergic rhinitis, eczema) that were previously suppressed by systemic corticosteroids may appear. In such situations, symptomatic treatment with antihistamines and/or topical medications, including topical corticosteroids, is recommended.

After starting treatment with inhaled fluticasone propionate, systemic corticosteroids should be discontinued gradually, and such patients should carry a special patient card containing instructions about the possible need for additional administration of corticosteroids in stressful situations.

In patients with exacerbation of bronchial asthma, hypoxia, plasma K⁺ ion concentrations should be monitored.

There are very rare reports of increased blood glucose levels, and this should be kept in mind when prescribing the combination of salmeterol and fluticasone propionate to patients with diabetes mellitus (see section “Adverse Reactions”).

During the post-marketing period, reports have been received of clinically significant drug interactions between fluticasone propionate (intranasally or by inhalation) and ritonavir, leading to systemic effects of corticosteroids, including Cushing’s syndrome and adrenal suppression. Therefore, the concomitant use of fluticasone propionate and ritonavir should be avoided, except in cases where the potential benefit to the patient outweighs the risk of systemic side effects of corticosteroids (see section “Drug Interactions”).

Data from a clinical safety study of salmeterol added to ongoing therapy for bronchial asthma compared with placebo showed that the frequency of asthma-related deaths was higher in the salmeterol group. When taking salmeterol compared with placebo, the risk of serious adverse respiratory events or death in patients of African American descent is presumably higher than in other patients. The significance of pharmacogenetic factors or other causes is unknown. The effect of concomitant use of corticosteroids was not studied in this trial.

Like other inhaled medications, Seretide^® Multidisc may cause paradoxical bronchospasm, manifested by increasing shortness of breath immediately after use. In this case, a short-acting inhaled bronchodilator should be used immediately, Seretide^® Multidisc should be discontinued, and, if necessary, alternative therapy should be initiated.

There are reports of side effects associated with the pharmacological action of beta₂-agonists, such as tremor, subjective palpitations and headache. However, these phenomena are short-term, and their severity decreases with regular therapy.

Effect on ability to drive and use machines

Clinical trials have not provided data on the effect of the drug on the ability to drive vehicles and other mechanisms, but the side effects that the drug may cause should be taken into account.

Overdose

Prescribing the drug in doses exceeding those indicated in the “Dosage Regimen” section is not recommended. It is very important to regularly review the patient’s dosage regimen and reduce the dose to the lowest of the recommended doses that provides effective symptom control.

Symptoms

Expected symptoms and signs of salmeterol overdose are typical of excessive beta₂-adrenergic stimulation and include tremor, headache, tachycardia, increased systolic blood pressure and hypokalemia.

Acute overdose with inhaled fluticasone propionate may provoke temporary suppression of the hypothalamic-pituitary-adrenal system. This usually does not require any emergency measures, as normal adrenal function recovers within a few days.

When taking the drug in doses higher than recommended over a long period of time, significant suppression of adrenal cortex function is possible. Rare cases of acute adrenal crisis have been described, occurring mainly in children who received doses of the drug higher than recommended for a long time (several months or years). Acute adrenal crisis is manifested by hypoglycemia, accompanied by confusion and/or convulsions. Situations that can serve as triggers for acute adrenal crisis include trauma, surgery, infection, or any rapid reduction in the dose of fluticasone propionate contained in Seretide^® Multidisc.

Treatment

There is no specific treatment for overdose with salmeterol and fluticasone propionate. In case of overdose, supportive therapy should be provided and the patient’s condition should be monitored. In case of chronic overdose, it is recommended to monitor the reserve function of the adrenal cortex.

Drug Interactions

Due to the risk of bronchospasm, the use of selective and non-selective beta-blockers should be avoided, except in cases where they are absolutely necessary for the patient.

Under normal circumstances, inhalation of fluticasone propionate is accompanied by low plasma concentrations due to intensive first-pass metabolism and high systemic clearance under the influence of the cytochrome P450 system isoenzyme CYP3A4 in the intestine and liver. This makes clinically significant interactions involving fluticasone propionate unlikely.

A drug interaction study has shown that ritonavir, a highly active inhibitor of the CYP3A4 isoenzyme, can cause a sharp increase in the plasma concentration of fluticasone propionate, resulting in a significant decrease in serum cortisol concentrations.

During post-marketing surveillance, reports have been received of clinically significant drug interactions in patients who were simultaneously receiving fluticasone propionate (intranasally or by inhalation) and ritonavir. This interaction caused side effects such as Cushing’s syndrome and adrenal suppression. Therefore, the concomitant use of fluticasone propionate and ritonavir should be avoided, except in cases where the potential benefit to the patient outweighs the risk of systemic side effects of corticosteroids.

Studies have shown that other inhibitors of the CYP3A4 isoenzyme cause a negligible (erythromycin) and a slight (ketoconazole) increase in the plasma content of fluticasone propionate, with virtually no decrease in serum cortisol concentrations. Nevertheless, caution is recommended when co-administering fluticasone propionate and potent CYP3A4 inhibitors (e.g., ketoconazole), as such combinations may potentially increase the plasma concentration of fluticasone propionate, which could potentially increase the systemic effects of fluticasone propionate.

During the investigation of drug interactions, it was found that the use of ketoconazole as concomitant systemic therapy significantly increases the plasma concentration of salmeterol (an increase in C_max by 1.4 times and AUC by 15 times). This may lead to a prolongation of the QTc interval. Caution should be exercised when co-administering strong CYP3A4 inhibitors (e.g., ketoconazole) and salmeterol.

Xanthine derivatives, corticosteroids, and diuretics increase the risk of hypokalemia (especially in patients with exacerbation of bronchial asthma, under hypoxia). MAO inhibitors and tricyclic antidepressants increase the risk of adverse effects on the cardiovascular system.

The drug Seretide^® Multidisk is compatible with cromoglicic acid.

Storage Conditions

The drug should be stored out of the reach of children at a temperature below 30°C (86°F).

Shelf Life

The shelf life is 2 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

RU/SFC/0039/16 23.12.2016

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.