SERETIDE DISKUS 0.50 mcg. / 100 mcg. 60 doses 

Qualitative and quantitative composition
With each breath adopted Seretide Diskus 50 ug salmeterol ( as salmeterol xinafoate) and respectively 100 , 250 and 500 ug fluticasone propionate.
For excipients, see section 6.1 .
 
 
3 . formulation
Powder for inhalation.
 
 
4 . clinical data
4.1. witness
asthma
 
Seretide Diskus is indicated for the regular treatment of asthma where it is appropriate to use a combination of long-acting beta -2- agonist and inhaled corticosteroid :
- Patients inadequately controlled on the background of treatment with inhaled corticosteroids and short -acting B-2 agonist as needed.
or
- Patients with adequately controlled on concomitant inhaled corticosteroid and long-acting B2 - agonist.
 
Note: Use the lowest concentration of Seretide Diskus (salmeterol / fluticasone propionate 50 mcg / 100 ug) is not suitable for adults and children with severe asthma.
 
Chronic obstructive pulmonary disease
Seretide is indicated for the symptomatic treatment of patients with COPD expressed ( with FEV1 <50 % of normal intended ) with a history of repeated exacerbations with significant symptoms despite regular bronchodilator therapy.
 
4.2 . Dosage and method of administration
Seretide Diskus is intended for inhalation .
Patients should be advised that for optimal effect Seretide Diskus should be used daily , even in the absence of symptoms .
Patients should be regularly reassessed by a doctor in order to maintain optimal dosage of Seretide and dosage can be changed only with a prescription. The dosage should be adjusted to achieve the optimum smallest dose which is maintained effective control of symptoms .
In cases where adequate control of symptoms is maintained with the lowest a concentration of Seretide Diskus, given twice daily , the next step in treatment could include a sample application only inhaled corticosteroid. Alternatively , if , at the discretion of the attending physician which would provide adequate control of the symptoms of the disease in patients who require administration of a long acting beta - agonist , can be switched to Seretide Diskus, administered once daily . Where Seretide Diskus administered once daily if the patient has a history of nocturnal seizures , the drug is inhaled in the evening and in patients with symptoms mainly during the day the dose is to be inhaled in the morning .
Depending on the severity of the disease apply such a concentration of Seretide Diskus, which contain appropriate dose fluticasone propionate. Doctors who prescribe the drug should be aware that patients with asthma, fluticasone propionate is as effective as other inhaled steroids at approximately halved daily dose in micrograms . For example, 100mg fluticasone propionate is approximately equivalent to 200 mcg beclomethasone dipropionate or budesonide. If necessary dosage outside of Seretide Diskus recommended regimens may be used appropriate doses of beta - agonists and / or corticosteroids.
 
Recommended dosage:
asthma
Adults and adolescents over 12 years:
one inhalation (50 ug salmeterol and 100 ug fluticasone propionate) or twice daily
one inhalation ( 50 mcg salmeterol and 250 mcg fluticasone propionate) twice daily or
one inhalation (50 mcg and 500 mcg salmeterol fluticasone propionate) twice daily.
 
Children over 4 years :
one inhalation (50 mcg and 100 mcg salmeterol fluticasone propionate) twice daily. Maximum licensed dose of fluticasone propionate in children Seretide Diskus 100 mcg twice dnevno.Nyama information on the use of Seretide in children under 4 years of age.
 
COPD :
 
adults:
one inhalation (50 mcg and 500 mcg salmeterol fluticasone propionate) twice daily.
 
 
Special populations:
In elderly patients or those with renal impairment is not necessary to adjust the dosage. There are no data on the use of Seredite Diskus in patients with hepatic impairment.
 
Using the Diskus
The device is opened and is activated by sliding the plunger , after which the applicator is placed in the mouth and the lips are concluded around it. Inhale the dose , and the device is closed.
 
 
4.3 . Contraindications
Seretide Diskus is contraindicated in patients with hypersensitivity to any of the drugs or the excipients (see 6.2 . List of excipients and their amounts ) .
 
 
4,4 . Special warnings and precautions for use
Normal treatment of asthma should follow a stepwise program. It is the response of the patient to be monitored both clinically and by functional assays of the respiratory function .
Seretide Diskus should not be used to arrest an acute asthma attack , which requires the use of fast-and short bronchodilator. Patients should be advised to have available such a relief vehicle at any time. Seretide Diskus is not for initial therapy of asthma to establish the need and the approximate dose corticosteroid.
Increased use of short-acting bronchodilators to arrest seizures showed worsening of disease control and requires examination of the patient.
Sudden and progressive deterioration in asthma control is potentially life-threatening and the patient should be consulted urgently by a doctor . In this case, should consider increasing the dosage of corticosteroids. Where Seretide Diskus in current dosage did not provide adequate control of asthma , the patient should also be consulted by lekar.V case of need should be given additional corticosteroid treatment in patients with asthma or COPD.
Treatment with Seretide should not be suddenly interrupted when the patients with asthma because of the risk of exacerbation . Dose reduction should be done under medical supervision . In patients with COPD cessation of therapy may also be accompanied by worsening of symptoms , so it is necessary to be carried out under medical supervision.
And all other inhaled drugs containing corticosteroids , Seretide Diskus should be used with caution in patients with pulmonary tuberculosis.
Seretide Diskus should be used with caution in patients with severe cardiovascular disease , incl. arrhythmias , diabetes mellitus, untreated hypokalaemia or tireotoksikoza.Mnogo rarely reported increase in blood sugar levels (see section 4.8 . Undesirable effects ), but this should be considered when prescribing to patients with a history of diabetes mellitus .
Potentially serious hypokalaemia may result from systemic therapy with B2 - agonists. Upon inhalation therapy at therapeutic doses , however , plasma levels of salmeterol are very niski.Kakto with any other inhalation therapy may develop paradoxical bronchospasm with sudden increase in wheezing after dosing . Therapy with Seretide Diskus should be discontinued immediately, the patient should be reviewed and , if necessary, to be his alternative therapy .
Seretide contains lactose in amounts 12,5 mg / dose. This amount does not normally cause problems in patients with lactose intolerance .
When switching to treatment with Seretide need special attention , especially when suspicion that adrenal function is impaired due to systemic steroid therapy in the past.
As with all corticosteroids , particularly at high doses for prolonged periods of time , it is possible to systemic reactions occur , the occurrence of these events is less likely than with oral corticosteroids .
Possible systemic effects include Cushing's syndrome and features kashingoidni adrenal suppression , growth retardation in children and adolescents , decrease in bone mineral density , cataract and glaucoma. It is therefore important that the patient pass regular reviews and dose of inhaled corticosteroid is adjusted to achieve the smallest possible dose at which effective control of asthma symptoms .
Recommended to regularly measure the height of children receiving long with inhaled corticosteroids.
Continuous treatment with high doses of corticosteroids may result in suppression of the function of the adrenal glands and acute adrenal crisis . Especially increased the risk in children and adolescents aged under 16 years who received high doses of fluticasone propionate ( typically > 1000 ug per day). Described are also very rare cases, suppression of adrenal function and acute adrenal crisis , and at doses of between 500 and less than 1000 ug. Factors that can trigger acute adrenal crisis are trauma, surgery , infection or a rapid decrease in the dose. Symptoms are usually vague and may include anorexia , abdominal pain, weight loss, tiredness, headache , nausea, vomiting , hypotension, reduced clarity of consciousness , hypoglycemia and seizures. It is necessary to have regard to the further coating with systemic corticosteroids in patients during periods of stress or elective surgery .
Therapy with inhaled fluticasone propionate reduces the need for oral steroid administration . It should be borne in mind , however, that for a considerable period of time in patients switched from oral to inhaled corticosteroid therapy , there is a risk of impaired adrenal reserve . A similar risk exists for patients who in the past has imposed emergency corticosteroid therapy in high doses. The possibility of such a breach should always be considered in emergency planning and intervention, likely causing stress, and to discuss appropriate corticosteroid treatment . Extent of the adrenal impairment may require specialist advice before elective surgery .
Ritonavir can significantly increase levels of fluticasone propionate in plasma. For this reason, you should avoid concomitant use unless the potential effects to the patient outweighs the risk of side effects of systemic corticosteroids . The risk of systemic side effects is increased and when combining fluticasone propionate with other CYP3A inhibitors ( see section 4.5 Interactions ) .
 
 
 
4.5 . Interactions
Both non-selective and selective beta -blockers should be avoided unless there are compelling reasons for their use.
Concomitant treatment with other beta -adrenergic drugs may potentially have additive efekt.Pri normal after inhalation dose fluticasone propionate are achieved lower plasma concentrations due to primary liver metabolism greatly and significant systemic clearance mediated by cytochrome P450 enzymes in the gut and ZA4 liver. Therefore, it is unlikely that the realization of a clinically significant drug interactions involving fluticasone propionate.
In a study to determine the interaction when intranasally administered fluticasone propionate in healthy subjects, it has been found that ritonavir ( a highly potent inhibitor of cytochrome P450 ZA4 ) 100 mg twice daily, increased several hundred times the plasma concentrations of fluticasone propionate, which leads to a significant reduction in serum cortisol. No information on these effects inhaled fluticasone propionate, but expect a significant increase in plasma levels. Cases of Cushing's syndrome , and inhibit the function of the adrenal glands . Combining these two drugs should be avoided unless the benefit to the patient outweighs the increased risk of side effects of systemic corticosteroids .
In a small study in healthy volunteers, a little weaker inhibitor SURZA ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150% . This has resulted in a greater reduction in the levels of plasma cortisol as compared to single administration of fluticasone propionate. Combination therapy with other potent inhibitors of SURZA as itraconazole is also expected to increase the systemic exposure to fluticasone propionate and increase the risk of systemic side effects . Careful treatment of such a combination and if possible avoid prolonged application.
 
 
4.6 . Pregnancy and lactation
There is insufficient experience in the application of salmeterol xinafoate and fluticasone propionate during pregnancy and lactation in humans. In animal studies with use of B2 -adrenoceptor agonists and glucocorticoids , fetal malformations ( see section 5.3 . Preclinical safety data) .
The implementation of the drug during pregnancy should only be considered if the expected benefit to the mother superior to any possible risk to the fetus.
For the treatment of pregnant women should be used at the lowest effective dose of fluticasone propionate, needed to maintain optimal control of symptoms astmata.Ne data on the passage of salmeterol and fluticasone propionate in human milk. Salmeterol and fluticasone propionate are excreted in rat milk . During lactation Seretide should be used only if the expected benefit to the mother outweighs any possible risk to the child.
 
 
4.7 . Effects on ability to drive and use machines
No specific studies on the effect of Seretide on ability to drive and use machines.
 
4.8 . Undesirable effects
As Seretide contains salmeterol and fluticasone propionate, the type and degree of adverse reactions associated with each of these substances can provide . No case of occurrence of additional adverse events resulting from co-administration of both drugs veshtestva.Nezhelanite effects associated with salmeterol and fluticasone propionate, are listed below by organ systems affected and incidence . Frequencies are defined as: very common (> 1/10 ), common (> 1/100 and <1 /10) , uncommon (> 1/1000 and <1 /100) and very rare (< 1/10 , 000 ) including isolated reports. Very common, common and uncommon events were identified from clinical trial data . The incidence of adverse events in placebo not reported . Very rare side effects are derived from post-marketing data
Reported pharmacological side effects when treated with B2 - agonists, such as tremor, palpitations and headache , they tend to be transient and disappear in the course of lechenieto.Nezhelana reaction of fluticasone propionate is hoarseness and thrush in the mouth and throat, which can occur in some patients. Hoarseness and candidiasis may be relieved by gargling with water after taking Seretide Diskus. Symptomatic candidiasis can be treated with topical antifungal products with the use of Seretide Diskus.Vazmozhnite systemic effects include Cushing's syndrome and kashingoidni features, adrenal suppression , growth retardation in children and adolescents , decrease in bone mineral density , cataract and glaucoma (see 4.4 special warnings and precautions for use). been very rarely reported cases of hyperglycemia (see 4.4 special warnings and precautions for use).
As with other products for inhalation may occur paradoxical bronchospasm (see 4.4 Special warnings and precautions for use).
 
 
4.9 . overdose
No data from clinical trials on overdose with Seretide, but the following are reactions that occur after an overdose of one of two drugs :
Symptoms of overdose with salmeterol are tremor, headache and tachycardia. The preferred antidotes are cardioselective beta -blockers, which should be used with caution in patients with a history of bronchospasm . If treatment with Seretide, should be terminated due to an overdose of beta- agonist in the product should be considered to have an appropriate replacement therapy with a corticosteroid. Further possible hypokalemia . In this case, you must determine the compensation of potassium.
Acute overdose : Inhalation of fluticasone propionate doses than recommended may lead to temporary suppression of adrenal function. This state does not require immediate action, as adrenal function is recovered in the course of several days , as determined by measurement of plasma cortisol .
Chronic overdose of inhaled fluticasone propionate: In this case it is appropriate monitoring of renal reserve. Overdose of fluticasone propionate treatment with Seretide may still continue with appropriate dosage control symptoms (see 4.4 . Special warnings and special precautions for use).
 
 
5 . pharmacological
 
5.1. Pharmacodynamic properties
 
ATC code : R03AK06
Seretide for asthma - clinical trials
Twelve month study (Gaining Optimal Asthma ControL, GOAL) in 3416 adult and adolescent patients with persistent asthma compared the safety and efficacy of treatment with Seretide and treatment with inhaled corticosteroids (Fliticasone propionate), to determine whether control of asthma is an achievable goal . In the treatment concentration was increased every 12 weeks until a ** full control or begin to apply the highest dose of study medication . Data from GOAL show that more patients treated with Seretide achieved control of asthma compared to those treated with inhaled corticosteroids (ICS). In general, this effect has been observed earlier in Seretide compared with inhaled corticosteroids alone , also at a low dose of inhaled corticosteroid as a component of Seretide.
* Well-controlled asthma : rare symptoms or use of short-acting B2 - agonists, or less than 80% of predicted values of pulmonary function will wake during the night , no exacerbations and no observed adverse drug reactions requiring change of therapy
** Full asthma control : no symptoms , no use of short-acting B2 -agonists more than or equal to 80% of the predicted values of pulmonary function will wake during the night , no exacerbations and no observed adverse drug reactions requiring change therapy
Two further studies in adults and adolescent patients with mild to moderately severe asthma have shown that the control of asthma symptoms can be achieved with a lower dose of inhaled corticosteroid by treatment with Seretide compared to treatment with inhaled corticosteroids .
 
Seretide Diskus in COPD - clinical trials
Results from a placebo - controlled clinical trials conducted over a period of 6 to 12 months have shown that regular use of Seretude Diskus 50/500 ug improves lung function , reduces shortness of breath and need to use short-acting medication to relieve breathing. For a period of 12 months the risk of exacerbations of COPD decreased from 1.42 to 0.99 for the year compared with the placebo group. Risk of exacerbations leading to the need for oral corticosteroids decreased significantly - from 0.81 to 0.47 per year in the placebo group .
 
Mechanism of action:
Seretide Diskus contains salmeterol and fluticasone propionate, which act differently. The mechanism of action of the two active ingredients is described below :
 
Salmeterol:
Salmeterol is a selective long -acting (12 hours ) 2-adrenoreceptor agonist with a long side chain , which is associated with the outer portion of the receptor.
Salmeterol provides longer lasting bronchodilation lasting at least 12 hours, in comparison with short-acting ß2- agonists conventional .
 
Fluticasone propionate:
Administered by inhalation at recommended doses of fluticasone propionate has anti-inflammatory glucocorticoid action in the lung , resulting in a reduction of symptoms and exacerbations of asthma without the side effects seen with systemic corticosteroids .
 
 
5.2 . pharmacokinetics
When simultaneous administration of salmeterol and fluticasone propionate by inhalation the pharmacokinetics of each component is similar to that observed in the inhalation administration of either substance alone .
Therefore , for the purposes of pharmacokinetic each of the two components can be considered separately
 
Salmeterol:
Salmeterol acts locally in the lung and therefore plasma levels are not indicative of the therapeutic effect . Also , there is only limited information on the pharmacokinetics of salmeterol because of technical difficulties for the evaluation of the drug in the plasma due to the low plasma concentrations at therapeutic doses ( approximately 200 pg / ml or less ), obtainable by inhalation .
 
Fluticasone propionate:
The absolute bioavailability of inhaled fluticasone propionate in healthy subjects varies between approximately 10 and 30 % of the normal dose depending on the device used for inhalation. In patients with asthma or COPD, was observed in a low degree of systemic absorption ekspozitsiya.Sistemnata is predominantly in the lung , initially rapid, then - continuing . The remainder of the inhaled dose may be swallowed , but this contributes to a minimal extent of systemic exposure due to the low solubility in water and presystemic metabolism and results in a bioavailability of less than 1% . With the increase of the inhaled dose is a linear increase in systemic exposure.
The disposition of fluticasone propionate is characterized by high plasma clearance (1150 ml / min), a large volume of distribution at steady state ( approximately 3001 ) and the terminal half-life of approximately 8 hours.
Plasma protein binding is 91%.
Fluticasone propionate is cleared very rapidly from the systemic circulation primarily by metabolism to an inactive carboxylic acid metabolite by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites were found in the faeces.
Renal clearance of fluticasone propionate is negligible . Less than 5% of the dose is excreted in the urine primarily as metabolites . The main part of the dose is excreted in the feces as metabolite or unchanged drug .
 
 
 5.3 . Preclinical safety data
In animal studies of salmeterol xinafoate and fluticasone propionate, applied separately , the only effects that may affect the safety of medicines in humans are those related to the extraordinary efforts of their pharmacological actions.
In animal reproductive studies it was observed that glucocorticoids induce malformations ( cleft palate, skeletal malformations ) . These are not supposed to be relevant for people using recommended doses. Animal studies of salmeterol xinafoate have shown developmental toxicity only at high levels of ekspozitsiya.Pri concomitant administration of both drugs in rats at doses associated with known glucocorticoid -induced malformations is nablyudavanapovishena incidence of transposed umbilical artery and incomplete ossification of occipital bone .
 
 
6 . pharmaceutical particulars
6.1. List of excipients and their amounts
 
Lactose monohydrate ( contains milk proteins ) - up to 12.5 mg
 
 
6.2 . Incompatibilities
Not reported .
 
 
6.3. Expiration date
18 months
 
 
6.4 . Special precautions for storage
Do not store above 30 ° C. Store in a dry place .
 
 
6.5. Packaging Data
Primary packaging :
inhaler device molded from plastic material , comprising a strip of film 28 , or 60 evenly spaced blisters .
 
 
6.6. Recommendations for use
Powder inhaler device Diskus releases a powder which is inhaled into lung drobove.Diskus has a dose counter , which indicates the remaining doses.
In the leaflet Patient Information contained detailed instructions for use .