Advair Diskus

Composition

• salmeterol xinafoate, including salmeterol;
• fluticasone propionate (micronized).

Pharmacological Effect

Advair Diskus is a combined preparation which contains salmeterol and fluticasone propionate which have different mechanisms of action. Salmeterol prevents bronchospasm symptoms, fluticasone propionate improves respiratory function and prevents exacerbations. Advair Diskus due to more convenient dosage regimen may be an alternative for patients who are at the same time receiving beta2-adrenoreceptors agonists and inhaled glucocorticosteroids in different inhalers. Salmeterol is a selective long-acting (up to 12 h) beta2-adrenoreceptors agonist having a long side chain which binds to external receptor domain.

Salmeterol pharmacological properties offer more effective protection against histamine-induced bronchoconstriction and longer lasting bronchodilation (lasting at least 12 hours) than short-acting beta2-adrenoreceptors agonists.

In vitro studies showed that salmeterol is a potent inhibitor of mast cell mediators release from human lung, such as histamine, leukotriene and prostaglandin D2, and has a prolonged period of action. Salmeterol inhibits early and late phase response to inhaled allergens. Late phase response inhibition is maintained for more than 30 hours after a single dose administration when bronchodilatory effect is no longer present. Salmeterol single administration weakens bronchial tree hyperresponsiveness. This suggests that in addition to bronchodilatory activity salmeterol has additional effect, not associated with bronchiectasis, clinical significance of which is not completely established. This mechanism of action differs from GCS anti-inflammatory effect.

Fluticasone propionate belongs to group of glucocorticosteroids for topical, which at inhalational administration in recommended doses has a significant anti-inflammatory and anti-allergic action in lungs, resulting reduction of clinical symptoms and asthma exacerbations incidence. Fluticasone propionate doesn’t causes adverse events that occur with systemic glucocorticosteroids.

At prolonged use of inhaled fluticasone propionate, daily adrenal hormones secretion remains in normal range at both adults and children, even when using maximal recommended dosage. After transferring patients treated with other inhaled glucocorticosteroids to fluticasone propionate, daily adrenal hormones secretion is gradually improving, in spite of previous and current periodic use of oral steroids. This indicates to adrenal function recovery on the background of inhaled fluticasone propionate usage. At prolonged fluticasone propionate usage, adrenal cortex backup function also remains within normal limits, as evidenced by normal increase in cortisol production in response to appropriate stimulation (note that residual adrenal reserve reduction, caused by previous therapy, can be maintained for a long time).

Indications and Dosage Regimen

The drug is intended for regular asthma treatment, if combination therapy with long-acting beta2-adrenoreceptors agonists and inhaled glucocorticosteroids is indicated:

• at patients with poor disease control on the background of regular monotherapy with inhaled glucocorticosteroids with occasional short-acting beta2-adrenoreceptors agonists use;
• at patients with adequate disease control during therapy with inhaled glucocorticosteroids and long-acting beta2-adrenoreceptors agonists;
• as starting maintenance therapy at patients with persistent asthma in presence of indications for glucocorticosteroids to achieve control over disease.

The drug is intended for maintenance therapy at patients with COPD and FEV1 Bronchial asthma

Advair Diskus dosage should be reduced to lowest that provides effective control over symptoms.

If Advair Diskus drug intake 2 times a day provides symptoms control, in order to reduce dosage to lowest possible effective, administration frequency reduction to 1 times a day is possible.

A patient should be given such drug form, which contains fluticasone propionate dose, corresponding to disease severity.

If treatment with inhaled glucocorticosteroids does not provide adequate disease control, replacing them with Advair Diskus drug at dosage, therapeutically equivalent to administered glucocorticosteroids dosage, may improve control over bronchial asthma course. Patients who can control asthma only using inhaled glucocorticosteroids and their replacement with Advair Diskus may allow to reduce glucocorticosteroids dosage necessary for asthma control.

Recommended doses

• adults and children over 12 years: one inhalation (50 mcg of salmeterol and 100 mcg of fluticasone propionate) 2 times a day, or one inhalation (50 mcg of salmeterol and 250 mcg of fluticasone propionate) 2 times a day, or one inhalation (50 mcg of salmeterol and 500 mcg of fluticasone propionate) 2 times a day;
• children over 4 years: one inhalation (50 mcg of salmeterol and 100 mcg of fluticasone propionate) 2 times a day;
• there is currently no data on drug usage at children up to 4 years.

Chronic obstructive pulmonary disease (COPD)

For adult patients, maximal recommended dosage is one inhalation (50 mcg of salmeterol and 500 mcg of fluticasone propionate) 2 times a day. For this drug dosage there has been demonstrated reduction in mortality from any cause.

Special patient groups

There is no need to reduce dosage for elderly patients and patients with impaired renal or hepatic function.

Instructions for Use

1. When you take Advair Diskus out of package, it is in closed position.
2. Advair Diskus preparation contains 28 or 60 doses in powder. Each dose is measured and hygienically protected. There is no need for any dosage level maintenance, or additional dosage refill.
3. Inhaler has an indicator, which after inhalation shows the number of remaining doses. Numbers go in descending order from 60 to 0 or from 28 to 0. Numbers from 0 to 5 are red, warning of the fact that only a few doses remain in inhaler. Number 0 in the window means that inhaler is empty and is not suitable for further use.

Overdose

It is not recommended to use the drug in doses higher than those specified in «Dosage» section. It is important to regularly review patient’s dosage regimen and reduce doses to lowest recommended for ensuring effective symptoms control.

Symptoms:

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

Acute fluticasone propionate overdose when inhaled can cause temporary hypothalamic-pituitary-adrenal system suppression. This does not usually require some extra measures because normal adrenal function is restored within a few days.

When receiving the drug in doses higher than above recommended for a long period of time, significant adrenocortical function inhibition is possible. There described rare cases of acute adrenal crisis, which occurred mostly at children treated with doses higher than recommended for a long time (months or years). Acute adrenal crisis manifest in hypoglycemia accompanied by confused consciousness and / or convulsions. Situations that can serve as triggering factors for acute adrenal crisis, include trauma, surgery, infection or any rapid reduction in dosage of fluticasone propionate.

Treatment:

There is no specific treatment for salmeterol and fluticasone propionate overdose. In case of overdose there should be conducted supportive therapy and patient’s condition control. At chronic overdose reserve adrenocortical function control is recommended.

Side Effects

All adverse effects reported below are characteristic of drug active ingredients – salmeterol and fluticasone propionate in particular. Adverse events profile of Advair Diskus doesn’t differ from adverse events profile of its active ingredients.

Adverse events reported below are listed in accordance with organs and systems defeat and frequency of their occurrence. Frequency is defined as follows: very often (≥ 1/10), often (≥ 1/100 and Data from clinical studies:

• Infectious and parasitic diseases:
  • often – oral candidiasis, pneumonia (at patients with COPD).
• Immune system: hypersensitivity reactions:
  • not often – skin hypersensitivity reactions, dyspnea;
  • rare – anaphylactic reactions.
• Endocrine system: possible systemic effects include:
  • not often – cataract;
  • rare – glaucoma.
• Metabolism and nutrition:
  • not often – hyperglycemia;
  • very rare – hypokalemia.
• Mental disorders:
  • not often – anxiety, sleep disorders;
  • rare – behavioral changes, including hyperactivity and irritability (especially at children).
• Nervous system:
  • very often – headaches;
  • not often – tremor.
• Cardiovascular system:
  • not often – heart palpitations, tachycardia, atrial fibrillation;
  • rare – arrhythmias, including ventricular arrhythmia, supraventricular tachycardia and extrasystoles.
• Respiratory system, thoracic and mediastinal organs:
  • often – hoarseness and / or dysphonia;
  • not often – throat irritation.
• Skin and subdermal tissues:
  • not often – bruising.
• Musculoskeletal and connective tissues:
  • often – muscle cramps, arthralgia.

Data from post-approval studies:

• Immune system: hypersensitivity reactions:
  • rare – angioedema (mainly facial and oropharynx swelling), bronchospasm.
• Endocrine system: possible systemic effects include:
  • rare – Cushing syndrome, cushingoid symptoms, adrenal suppression, growth retardation at children and adolescents, decrease in bone mineral density.
• Respiratory system, thoracic and mediastinal organs:
  • rare – paradoxical bronchospasm.

Contraindications

• age under 4 years;
• hypersensitivity to drug components.

With Caution:

• as with all inhaled medications containing glucocorticosteroids, Advair Diskus should be used with caution at patients with acute or latent pulmonary tuberculosis;
• at thyrotoxicosis;
• at fungal, viral or bacterial respiratory system infections;
• when you receive any drug of sympathomimetic group, particularly excessing therapeutic doses, cardiovascular events are possible, such as increase in systolic blood pressure and heart rate. For this reason, Advair Diskus should be used with caution at patients with cardiovascular diseases, including arrhythmias, such as supraventricular tachycardia and extrasystole, ventricular arrhythmia, atrial fibrillation;
• all sympathomimetic drugs in doses exceeding therapeutic, may cause transient decrease in serum potassium level. Therefore, Advair Diskus should be used with caution at patients with hypokalemia;
• at allergic reactions to milk protein and lactose in anamnesis as residual amounts of protein may be a part of lactose;
• any inhaled glucocorticosteroid may cause systemic effects, especially at prolonged use in high doses. Therefore, the drug should be used with caution at glaucoma, cataracts, osteoporosis;
• there are very rare reports of increased blood glucose levels, so diabetics should also use the drug with caution.

Pregnancy and Lactation Period

Pregnant and lactating women should be prescribed the drug only if expected benefit for the mother outweighs any possible risk for the fetus or child.

There are insufficient data on salmeterol and fluticasone propionate usage during pregnancy and lactation period.

Pregnancy

Reproductive toxicity of the drug and its components was studied during preclinical studies. Excessive systemic concentration of active β2- adrenoreceptors agonists and GCS has effects on fetus.

Extensive clinical experience with this drugs of this class shows that when in therapeutic doses of these effects are not clinically significant. Salmeterol and fluticasone propionate have no genotoxicity.

Lactation Period

Salmeterol and fluticasone propionate concentration in blood plasma after drug inhalation in therapeutic doses is extremely low, so concentration in human milk should be as low. This is confirmed by studies in animals, in milk of which low concentrations of salmeterol and fluticasone propionate were estimated. No data on salmeterol and fluticasone propionate concentrations in breast milk of women during breastfeeding.

Drug and Alcohol Interactions

Because of bronchospasm risk, patients should avoid selective and nonselective beta-blockers, except cases when they are essential to the patient.

In normal situations fluticasone propionate inhalations are accompanied by low concentrations in blood plasma due to intensive metabolism during «first pass» and high systemic clearance under influence CYP3A4 isoenzyme of P450 cytochrome system in gut and liver. Due to this clinically significant interactions involving fluticasone propionate are unlikely.

Research on drug interactions has shown that ritonavir – highly active CYP3A4 isoenzyme inhibitor – can cause a sharp increase in fluticasone propionate concentration in blood plasma, resulting in significantly reduced serum cortisol concentrations. During post-approval studies there have been received reports about clinically significant drug interactions at patients who are concurrently receiving fluticasone propionate (intranasally or by inhalation) and ritonavir. This interaction causes side effects such as Cushing syndrome and adrenal suppression. Given this, you should avoid simultaneous use of fluticasone propionate and ritonavir, unless expected benefit to the patient outweighs risk of glucocorticosteroids systemic side effects.

Studies have shown that other CYP3A4 inhibitors cause negligible (erythromycin) and minor (ketoconazole) increased content of fluticasone propionate in blood plasma, which almost doesn’t decrease serum cortisol concentrations. Despite this, it is advisable to be careful while applying fluticasone propionate and potent CYP3A4 inhibitors (e. g., ketoconazole), since such combinations do not exclude probability of increasing fluticasone propionate concentration in blood plasma, which could potentially increase systemic effects of fluticasone propionate.

When studying drug interactions, it was found that ketoconazole as concomitant systemic therapy significantly increases salmeterol concentration in blood plasma (Cmax increase by 1,4 times and AUC – by 15 times). This can lead to QTc interval lengthening. Caution must be taken at concomitant use of strong CYP3A4 inhibitors (e. g., ketoconazole) and salmeterol.

Xanthine derivatives, glucocorticosteroids and diuretics increase risk of hypokalemia (especially at patients with acute bronchial asthma exacerbation, at hypoxia).

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

Advair Diskus is compatible with cromoglicic acid.