Salmecort (Aerosol) Instructions for Use

Marketing Authorization Holder

Glenmark Pharmaceuticals, Ltd. (India)

Contact Information

GLENMARK IMPEX LLC (Russia)

ATC Code

R03AK06 (Salmeterol and fluticasone)

Active Substances

Fluticasone (Rec.INN registered by WHO)

Salmeterol (Rec.INN registered by WHO)

Dosage Forms

	Salmecort	Metered-dose inhalation aerosol 25 mcg+50 mcg/1 dose: canister of 120 doses with a metering valve and mouthpiece
		Metered-dose inhalation aerosol 25 mcg+125 mcg/1 dose: canister of 120 doses with a metering valve and mouthpiece
		Metered-dose inhalation aerosol 25 mcg+250 mcg/1 dose: canister of 120 doses with a metering valve and mouthpiece

Dosage Form, Packaging, and Composition

Metered-dose inhalation aerosol as a white or almost white suspension.

Excipients: 1,1,1,2-tetrafluoroethane (HFA-134a) – 73.099 mg, polyethylene glycol 1000 – 0.01464 mg.

120 doses – aluminum aerosol canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.

Metered-dose inhalation aerosol as a white or almost white suspension.

Excipients: 1,1,1,2-tetrafluoroethane (HFA-134a) – 73.024 mg, polyethylene glycol 1000 – 0.01464 mg.

120 doses – aluminum aerosol canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.

Metered-dose inhalation aerosol as a white or almost white suspension.

Excipients: 1,1,1,2-tetrafluoroethane (HFA-134a) – 72.9 mg, polyethylene glycol 1000 – 0.01464 mg.

120 doses – aluminum aerosol canisters (1) with a metering valve and a mouthpiece with a protective cap – cardboard packs.

Clinical-Pharmacological Group

Drug with anti-inflammatory and bronchodilator action

Pharmacotherapeutic Group

Bronchodilator agent (selective beta2-adrenomimetic + topical glucocorticosteroid)

Pharmacological Action

Mechanism of action

Salmecort is a combination drug containing 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. Due to a more convenient dosing regimen, Salmecort can be an alternative for patients who are simultaneously receiving a β₂-adrenoreceptor agonist and an inhaled corticosteroid from different inhalers.

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

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

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

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

Fluticasone propionate belongs to the group of topical corticosteroids and, when inhaled at recommended doses, exerts 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 reactions observed with systemic corticosteroid use.

With long-term inhalation use of fluticasone propionate, the daily secretion of adrenal cortex hormones remains within the normal range in both adults and children, even when used at the maximum recommended doses. After switching patients receiving other inhaled corticosteroids to fluticasone propionate, the daily secretion of adrenal cortex hormones gradually improves, despite prior and current periodic use of oral steroids. This indicates restoration of adrenal function during inhalation therapy with 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 considered that residual reduction of adrenal reserve caused by prior therapy may persist for a long time).

In a multicenter US study (SMART) investigating the use of salmeterol in asthma over 28 weeks, the safety of salmeterol added to usual therapy was assessed in adults and adolescents compared to placebo. Although there were no significant differences in the primary composite endpoint of respiratory-related deaths and life-threatening respiratory events, the study showed a significant increase in asthma-related deaths among patients receiving salmeterol (13 deaths among 13,176 patients receiving salmeterol compared to 3 deaths among 13,179 patients receiving placebo). The study did not assess the impact of concurrent inhaled corticosteroid use. Initially, only 47% of patients reported using inhaled corticosteroids.

Two multicenter 26-week studies were conducted to evaluate the safety and efficacy of the combination of salmeterol with fluticasone propionate and fluticasone propionate monotherapy in patients with asthma. One study involved adults and adolescents (AUSTRI study), and the other involved children aged 4-11 years (VESTRI study). Both studies included patients with persistent moderate or severe asthma with a history of hospitalizations or asthma exacerbations in the past year. The primary objective of each study was to determine whether the addition of a long-acting β₂-adrenoreceptor agonist to inhaled corticosteroid therapy (combination of salmeterol and fluticasone propionate) was non-inferior to inhaled corticosteroid monotherapy (fluticasone propionate) regarding the risk of serious asthma-related adverse events (asthma-related hospitalization, endotracheal intubation, and death). The secondary objective of these studies was to assess efficacy regarding the superiority of the combination of a long-acting β₂-adrenoreceptor agonist and an inhaled corticosteroid (combination of salmeterol and fluticasone propionate) over inhaled corticosteroid monotherapy (fluticasone propionate) on the development of severe asthma exacerbation (defined as a worsening of asthma requiring systemic corticosteroids for at least 3 days or hospitalization, or an emergency department visit for asthma requiring systemic corticosteroids).

A total of 11,679 and 6,208 patients were enrolled and treated in the AUSTRI and VESTRI studies, respectively. For the primary safety endpoint, non-inferiority was achieved in both studies. In the AUSTRI study, 5,834 patients received the combination of salmeterol and fluticasone propionate and 5,845 received fluticasone propionate monotherapy. Regarding the primary objective: during therapy, serious asthma-related adverse events were reported in 67 patients (34 patients in the combination therapy group and 33 patients in the monotherapy group). The hazard ratio was 1.029 (95% CI 0.638-1.662). No asthma-related deaths were identified during the study, and only 2 cases of endotracheal intubation were noted, both in the inhaled corticosteroid monotherapy group. Non-inferiority of the combination of salmeterol and fluticasone propionate compared to fluticasone propionate monotherapy was established if the 95% CI was less than 2.0. In the VESTRI study, 3,107 patients received the combination of salmeterol and fluticasone propionate and 3,101 received fluticasone propionate monotherapy. Serious adverse events were reported in 27 children in the combination therapy group and 21 children in the inhaled corticosteroid monotherapy group. The hazard ratio was 1.285 (95% CI 0.726-2.272). No deaths or cases of endotracheal intubation were observed in either group. Non-inferiority of the combination of salmeterol and fluticasone propionate compared to fluticasone propionate monotherapy was established if the 95% CI was less than 2.657.

Pharmacokinetics

There are no data indicating that salmeterol and fluticasone propionate affect each other’s pharmacokinetics when administered concurrently by inhalation; therefore, the pharmacokinetic characteristics of each component of Salmecort 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 (C_max increased 1.4-fold and AUC increased 15-fold). No accumulation of salmeterol was noted with repeated dosing. In 3 subjects, the drug was discontinued due to QT_c interval prolongation or palpitations with sinus tachycardia. In the remaining 12 subjects, concurrent use of salmeterol and ketoconazole had no clinically significant effect on heart rate, blood potassium levels, or QT_c interval duration.

Absorption

Salmeterol acts locally in lung tissues, so its plasma concentration is not an indicator of therapeutic effects. Data on the pharmacokinetics of salmeterol are very limited due to technical problems: when inhaled at therapeutic doses, its maximum plasma concentration is extremely low (about 200 pg/ml and below). After regular inhalation of salmeterol xinafoate, 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 (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 administered as a combination of salmeterol and fluticasone propionate via a metered-dose inhalation aerosol, it is 5.3%. Lower plasma concentrations of fluticasone propionate are observed in patients with asthma and COPD. Systemic absorption occurs primarily through the lungs. Initially, absorption is faster, but then its rate slows down.

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

Distribution

There are no data on the distribution of salmeterol.

Fluticasone propionate has a large volume of distribution at steady state (about 300 L) and a relatively high degree of binding to plasma proteins (91%).

Metabolism

In vitro study results indicate that salmeterol is extensively metabolized by the cytochrome P450 isoenzyme CYP3A4 to α-hydroxysalmeterol via aliphatic oxidation. A study with repeated dosing of salmeterol and erythromycin in healthy volunteers showed no clinically significant changes in pharmacodynamic effects with the administration of 500 mg erythromycin three times daily. However, the drug interaction study of salmeterol and ketoconazole showed a significant increase in plasma salmeterol concentrations.

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

Excretion

There are no data regarding the excretion of salmeterol.

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

Indications

Salmecort is intended for the regular treatment of bronchial asthma in patients who require combination therapy with a long-acting beta₂-adrenergic agonist and an inhaled corticosteroid

• In patients with insufficient disease control on constant inhaled corticosteroid monotherapy with intermittent use of a short-acting beta₂-adrenergic agonist;
• In 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 (daily occurrence of symptoms, daily use of quick-relief medications) when there is an indication for the use of corticosteroids to achieve disease control.

Maintenance therapy in patients with COPD who have a forced expiratory volume in one second (FEV1) <60% of predicted (pre-bronchodilator) with a history of repeated exacerbations, and in whom significant disease symptoms persist despite regular bronchodilator therapy.

ICD codes

Dosage Regimen

Inhalation. For inhalation use 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 asthma and COPD.

The physician should regularly assess the effectiveness of the patient’s treatment. Determination of the duration of the course of therapy and adjustment of the drug dose is possible only on the recommendation of a doctor.

The initial dose of the drug is determined based on the dose of fluticasone recommended for the treatment of the disease of this severity. Then the initial dose should be gradually reduced to the minimum effective dose. During treatment, the patient should be regularly monitored by a physician to select the optimal dose. The patient should not independently change the doses of the drug prescribed by the doctor.

Bronchial asthma

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

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

If therapy with inhaled corticosteroids does not provide adequate disease control, then switching to Salmecort at a dose therapeutically equivalent to the dose of the administered corticosteroids may improve asthma control. In patients whose asthma can be controlled solely with inhaled corticosteroids, switching to Salmecort may allow a reduction in the corticosteroid dose required for asthma control.

Recommended doses

Adults and children aged 12 years and older

• 2 inhalations (25 mcg salmeterol and 50 mcg fluticasone propionate) twice daily, or
• 2 inhalations (25 mcg salmeterol and 125 mcg fluticasone propionate) twice daily, or
• 2 inhalations (25 mcg salmeterol and 250 mcg fluticasone propionate) twice daily.

Children aged 4 years and older

• 2 inhalations (25 mcg salmeterol and 50 mcg fluticasone propionate) twice daily.

All patients taking the drug as maintenance therapy should be reviewed by a physician 6-12 weeks after the initial dose.

Chronic obstructive pulmonary disease

For adult patients, the maximum recommended dose is 2 inhalations (25 mcg salmeterol and 250 mcg fluticasone propionate) twice daily.

Special Patient Groups

There is no need to reduce the dose of Salmecort in elderly patients, nor in patients with impaired renal or hepatic function.

Instructions for Using the Inhaler

The inhaler must be shaken before each use.

Checking the Inhaler

1. Before the first use or if the inhaler has not been used for 2 days or more, it is necessary to test the inhaler. To do this, perform 4 presses (inhalations) into the air.

Using the Inhaler

2. Remove the protective cap from the mouthpiece. The mouthpiece must remain firmly attached to the canister (inhaler); if the inhaler was stored without the protective cap, it is necessary to check the mouthpiece for contamination.

3. Hold the inhaler in your hands with the mouthpiece facing down so that one finger is on the bottom of the inhaler and another finger or two are on the top end of the inhaler. Exhale and place the mouthpiece between your teeth.

4. Close your lips tightly around the mouthpiece and tilt your head back slightly. Begin to inhale slowly and simultaneously press down on the bottom of the canister. Continue inhaling to the end.

5. Remove the inhaler from your mouth and hold your breath for 10 seconds or as long as is comfortable. Exhale slowly.

Note

After each inhalation, it is necessary to rinse the mouth and/or throat with water. This will help reduce the dryness associated with taking the medication. The break between inhalations should be at least 1 minute. When performing a repeated inhalation, repeat steps 2-5. After use, close the mouthpiece with the protective cap.

It is recommended to perform the first few inhalations while watching yourself in a mirror. If you see that there is a “leak” of the medication through the mouth or from the hole between the mouthpiece and the inhaler body, this indicates incorrect inhalation technique.

Inhalations for young children should be performed under adult supervision.

Older children and adults with weak hands should hold the inhaler with both hands. In this case, both index fingers should be placed on the top part 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 day.

1. Remove the metal medication canister from the inhaler body. Remove the spray tip.

2. Rinse the mouthpiece and inhaler body under warm running water.

3. Wipe thoroughly with a dry cloth or cotton swab. Overheating should be avoided.

4. Assemble the inhaler.

After using all the doses indicated on the packaging, the metal canister should be discarded.

Adverse Reactions

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

The adverse reactions listed below are categorized by organ and organ system affected and by 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 (≥1/10000 and <1/1000), very rare (<1/10000, including isolated cases).

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

Immune system disorders: uncommon – hypersensitivity skin reactions, dyspnea; rare – anaphylactic reactions, angioedema (mainly facial and oropharyngeal edema), bronchospasm.

Endocrine system disorders: possible systemic effects include (see sections “Caution” and “Special Instructions”) rare – Cushing’s syndrome, cushingoid symptoms, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density.

Eye disorders: 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; uncommon – tremor (see section “Special Instructions”).

Cardiac disorders: uncommon – palpitations, tachycardia, atrial fibrillation; rare – arrhythmia, including ventricular extrasystole, supraventricular tachycardia, extrasystole.

Respiratory, thoracic and mediastinal disorders: common – hoarseness and/or dysphonia; uncommon – throat irritation; rare – paradoxical bronchospasm (see section “Special Instructions”).

Skin and subcutaneous tissue disorders uncommon – bruising.

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

Gastrointestinal disorders: very rare – dyspepsia, nausea.

Children and adolescents

The development of systemic reactions is theoretically possible, including Cushing’s syndrome, cushingoid symptoms, adrenal suppression, growth retardation in children and adolescents. Anxiety, sleep disorders, and behavioral disorders, including hyperactivity and irritability, may occur very rarely.

Contraindications

• Hypersensitivity to one or more components of the drug;
• Childhood (under 4 years of age).

Caution

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

Salmecort should be prescribed with caution in thyrotoxicosis.

Salmecort should be used with caution in fungal, viral, or bacterial respiratory tract infections.

Any inhaled corticosteroid can cause systemic effects, especially with long-term use at high doses. Therefore, the drug should be used with caution in glaucoma, cataract, osteoporosis.

There are very rare reports of increased blood glucose concentration, so patients with diabetes mellitus should use Salmecort with caution.

When taking any sympathomimetic drugs, especially at doses exceeding therapeutic ones, adverse cardiovascular reactions such as increased systolic blood pressure and heart rate may develop. For this reason, Salmecort should be prescribed with caution to patients suffering from 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 concentration. Therefore, Salmecort should be prescribed with caution to patients with uncontrolled hypokalemia or a predisposition to developing hypokalemia.

In drug interaction studies, it was found that the use of ketoconazole as concomitant systemic therapy increases the blood concentration of salmeterol. This can lead to prolongation of the QT_c interval. Caution should be exercised when co-administering strong CYP3A4 inhibitors (e.g., ketoconazole) and salmeterol.

Use in Pregnancy and Lactation

Pregnancy

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

According to the results of a retrospective epidemiological 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.

In reproductive toxicity studies in animals with administration of each component of the drug separately and their combination, an effect on the fetus from excessive systemic concentrations of the active beta₂-adrenergic agonist and corticosteroid was identified.

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

Breastfeeding period

The plasma concentration of salmeterol and fluticasone after inhalation of the drug at therapeutic doses is extremely low, so their concentration in breast milk should be equally low. This is confirmed by animal studies, in which low concentrations of the drug were detected in their milk.

There are no data regarding the concentration of salmeterol and fluticasone in the breast milk of women.

Use of the drug during breastfeeding is only permissible if the potential benefit to the mother outweighs the possible risk to the child.

Fertility

There are no data on the effect on human fertility. In animal studies, no effect of fluticasone or salmeterol on male or female fertility was identified.

Use in Hepatic Impairment

There is no need to reduce the dose of Salmecort in patients with impaired liver function.

Use in Renal Impairment

There is no need to reduce the dose of Salmecort in patients with impaired renal function.

Pediatric Use

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

Geriatric Use

There is no need to reduce the dose of Salmecort in elderly patients.

Special Precautions

Salmecort 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.

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

Sudden and progressive worsening of asthma control is potentially life-threatening; in such situations, the patient should also consult a doctor. The doctor should consider the possibility of a higher dose of corticosteroids. If the dose of Salmecort used does not provide adequate disease control, the patient should also consult a doctor.

Patients with asthma should not abruptly discontinue treatment with Salmecort due to the risk of exacerbation; the drug dose 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 studies have provided data on an increased incidence of pneumonia in COPD patients receiving Salmecort. Physicians should be aware of the possibility of pneumonia in COPD patients, as the clinical picture of COPD exacerbation and pneumonia is often similar.

Any inhaled corticosteroid can cause systemic reactions, especially with long-term use at high doses; however, the likelihood of such symptoms is much lower than with oral corticosteroid treatment. Possible systemic reactions include Cushing’s syndrome, cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma, central serous chorioretinopathy, psychomotor hyperactivity, sleep disorder, anxiety, depression, or aggression (especially in children). Therefore, when treating asthma, it is important to reduce the dose to the lowest one that provides effective symptom control.

In emergency and planned situations that can cause stress, the possibility of adrenal suppression should always be considered, and readiness to administer corticosteroids should be maintained.

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 cortical function should be regularly monitored.

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

There are very rare reports of increased blood glucose concentration, and this should be kept in mind when prescribing the combination of salmeterol with fluticasone propionate to patients with diabetes mellitus.

During the post-registration period, reports have been received of clinically significant drug interactions between fluticasone propionate and ritonavir, leading to systemic corticosteroid effects, 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 associated with systemic corticosteroid effects.

Like other inhaled drugs, Salmecort can cause paradoxical bronchospasm, manifested by increasing shortness of breath immediately after use. In this case, a fast- and short-acting inhaled bronchodilator should be used immediately, Salmecort should be discontinued, the patient should be examined, and, if necessary, alternative therapy should be initiated.

There are reports of adverse reactions associated with the pharmacological action of beta₂-adrenergic receptor agonists, such as tremor, palpitations, and headache. However, these reactions are short-lived, and their severity decreases with regular therapy.

Effect on ability to drive vehicles and operate machinery

Clinical studies have not provided data on the effect of the drug on the ability to drive vehicles and operate other machinery; however, the adverse reactions 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 disease 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 of fluticasone propionate by inhalation may provoke temporary suppression of the hypothalamic-pituitary-adrenal axis. 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, significant suppression of adrenal cortical 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 manifests as hypoglycemia accompanied by confusion and/or seizures. Situations that can serve as triggers for acute adrenal crisis include trauma, surgery, infection, or any rapid reduction in the dose of inhaled fluticasone propionate contained in Salmecort.

Treatment

There is no specific treatment for overdose of salmeterol and fluticasone propionate. In case of overdose, supportive therapy should be provided and the patient’s condition should be monitored.

When using the drug in doses exceeding those indicated in the instructions for a long time, suppression of adrenal cortical function may be observed.

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.

Salmeterol

Concomitant use with ketoconazole should be avoided unless the benefit of use outweighs the potential risk of systemic side effects from salmeterol treatment. There is a similar risk of interaction with other strong CYP3A4 inhibitors (itraconazole, telithromycin, ritonavir).

Fluticasone propionate

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 isoenzyme CYP3A4 in the intestine and liver. This makes clinically significant interactions involving fluticasone propionate unlikely.

Ritonavir, as a highly active inhibitor of the CYP3A4 enzyme, can cause a sharp increase in the plasma concentration of fluticasone propionate, resulting in a significant decrease in serum cortisol concentrations. Concomitant use with ritonavir causes side effects such as Cushing’s syndrome and adrenal suppression. Given this, the simultaneous use of fluticasone propionate and ritonavir should be avoided, except in cases where the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

Other inhibitors of the CYP3A4 isoenzyme cause a negligible (erythromycin) and 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 strong CYP3A4 inhibitors (e.g., ketoconazole), as such combinations may increase the plasma concentration of fluticasone propionate.

Xanthine derivatives, corticosteroids, and diuretics increase the risk of hypokalemia (especially in patients with asthma exacerbation, under hypoxic conditions).

MAO inhibitors and tricyclic antidepressants increase the risk of cardiovascular side effects.

Compatible with cromoglicic acid.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F), and should not be frozen.

Shelf Life

The shelf life is 2 years. Do not use the drug after the expiration date.

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.