Advair - Seretide Accuhaler Salmeterol / Fluticasone 50 mcg : 100mcg / dose

Description
Seretide accuhaler contains salmeterol xinafoate 50 mcg and fluticasone propionate 100 or 250 mcg.
The accuhaler is a moulded plastic device containing a foil strip with 60 regularly placed blisters.
Seretide evohaler contains salmeterol xinafoate 25 mcg and fluticasone propionate 50, 125 or 250 mcg.

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Pharmacology: Seretide contains salmeterol and fluticasone propionate which have different modes of action. Salmeterol protects against symptoms, fluticasone propionate improves lung function and prevents exacerbations of the condition. Seretide can offer a more convenient regimen for patients on concurrent ?-agonist and inhaled corticosteroid therapy. The respective mechanisms of action of both drugs are discussed as follows:
Salmeterol: Selective long-acting (12 hrs) ?2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.
These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilation, lasting for at least 12 hrs, than recommended doses of conventional short-acting ?2-agonists. In vitro tests have shown salmeterol as a potent and long-lasting inhibitor of the release, from human lung, of mast cell mediators, eg histamine, leukotrienes and prostaglandin D2.
In man, salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hrs after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. This mechanism is different from the anti-inflammatory effect of corticosteroids.
Fluticasone Propionate: Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Daily output of adrenocortical hormones usually remain within the normal range during chronic treatment with inhaled fluticasone propionate, even at the highest recommended doses in children and adults. After transfer from other inhaled steroids, the daily output gradually improves despite past and present intermittent use of oral steroids, thus demonstrating return of normal adrenal function on inhaled fluticasone propionate. The adrenal reserve also remains normal during chronic treatment as measured by a normal increment on a stimulation test. However, any residual impairment of adrenal reserve from previous treatment may persist for a considerable time and should be borne in mind (see Precautions).
Pharmacokinetics: There is no evidence in animal or human subjects that the administration of salmeterol and fluticasone propionate together by the inhaled route affects the pharmacokinetics of either component. For pharmacokinetic purposes, therefore, each component can be considered separately.
Even though plasma levels of Seretide are very low, potential interactions with other substrates and inhibitors of CYP3A4 cannot be excluded.
Salmeterol: Salmeterol acts locally in the lung, therefore, plasma levels are not an indication of therapeutic effects. In addition, there are only limited data on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately ? (smaller than or equal to) 200 pg/mL) achieved after inhaled dosing. After regular dosing with salmeterol xinafoate, hydroxynaphthoic acid can be detected in the systemic circulation, reaching steady-state concentrations of approximately 100 ng/mL. These concentrations are up to 1000-fold lower than steady-state levels observed in toxicity studies. No detrimental effects have been seen following long-term regular dosing (>12 months) in patients with airway obstruction.
Fluticasone Propionate: Following IV administration, the pharmacokinetics of fluticasone propionate are proportional to the dose, and can be described by 3 exponentials. Fluticasone propionate is extensively distributed within the body (Vss is approximately 300 L) and has a very high clearance (estimated to Cl 1.1 L/min) indicating extensive hepatic extraction. Peak plasma concentration are reduced by approximately 98% within 3-4 hrs, and only low plasma concentrations are associated with the terminal half-life, which is approximately 8 hrs. Following oral administration of fluticasone propionate, 87-100% of the dose is excreted in the faeces.
Following doses of either 1 or 16 mg, up to 20% and 75%, respectively, is excreted in the faeces as parent compound. Absolute oral bioavailability is negligible (<1%) due to a combination of incomplete absorption from the gastrointestinal tract and extensive first-pass metabolism.
Following inhaled dosing, systemic absolute bioavailability of fluticasone propionate is estimated as 12-26%, dependent on presentation.
Systemic absorption of fluticasone propionate occurs mainly through the lungs, and is initially rapid, then prolonged. Plasma protein-binding is 91%. Fluticasone propionate is extensively metabolised by CYP3A4 enzyme to an inactive carboxylic derivative.
The available data for paediatric pharmacokinetics show consistency with the adult findings.
Toxicology: Preclinical Safety Data: Salmeterol xinafoate and fluticasone propionate have been extensively evaluated in animal toxicity tests. Significant toxicities occurred only at doses in excess of those recommended for human use and were those expected for a potent ?2-adrenoreceptor agonist and glucocorticosteroid.
In long-term studies, salmeterol xinafoate induced benign tumours of smooth muscle in the mesovarium of rats and the uterus of mice. Rodents are sensitive to the formation of these pharmacologically-induced tumours. Salmeterol is not considered to represent a significant oncogenic hazard to man.
Co-administration of salmeterol and fluticasone propionate resulted in some cardiovascular interactions at high doses. In rats, mild atrial myocarditis and focal coronary arteritis were transient effects that resolved with regular dosing. In dogs, heart rate increases were greater after co-administration than after salmeterol alone. No clinically relevant serious adverse cardiac effects have been observed in studies in man. Co-administration did not modify other class-related toxicities in animals.

Indications
Regular treatment of reversible obstructive airway disease (ROAD), including asthma in children and adults, where use of a combination (bronchodilator and inhaled corticosteroid) is appropriate: Patients on effective maintenance doses of long-acting ?-agonists and inhaled corticosteroids; patients who are symptomatic on current inhaled corticosteroid therapy; patients on regular bronchodilator therapy who require inhaled corticosteroid.

Dosage
Seretide is for oral inhalation only.
Adults and Adolescents ? (greater than or equal to) 12 years: 1 inhalation (salmeterol 50 mcg and fluticasone propionate 100 mcg) twice daily, or 1 inhalation (salmeterol 50 mcg and fluticasone propionate 250 mcg) twice daily.
Children ? (greater than or equal to) 4 years: 1 inhalation (salmeterol 50 mcg and fluticasone propionate 100 mcg) twice daily. There are no data available for use of Seretide in children <4 years.
Special Patient Groups: There is no need to adjust the dose in elderly patients or in those with renal or hepatic impairment.
Patients should be made aware that Seretide must be used regularly for optimum benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the strength of Seretide they are receiving remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained.
Patients should be given the strength of Seretide containing the appropriate fluticasone propionate dosage for the severity of their disease.
Instructions for Use/Handling: The device is opened and primed by sliding the lever. The mouthpiece is then placed in the mouth and the lips closed around it. The dose can then be inhaled and the device closed.
A dose indicator on the accuhaler indicates the number of doses left.

Overdosage
There are no data available from clinical trials on overdose with Seretide, however, data on overdose with both drugs are given as follows:
The signs and symptoms of salmeterol overdosage are tremor, headache and tachycardia. The preferred antidotes are cardioselective ?-blocking agents, which should be used with caution in patients with a history of bronchospasm. If Seretide therapy has to be withdrawn due to overdose of the ?-agonist component of the drug, provision of appropriate replacement steroid therapy should be considered.
Inhalation of fluticasone propionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a few days, as verified by plasma cortisol measurements. However, if higher than recommended dosage is continued over prolonged periods, some degree of adrenal suppression may result. Monitoring of adrenal reserve may be necessary. In cases of fluticasone propionate overdose, Seretide therapy may still be continued at a suitable dosage for symptom control. (See Precautions.)

Contraindication
Patients with a history of hypersensitivity to any of the ingredients of Seretide.

Precautions
The management of reversible obstructive airway disease should normally follow a stepwise programme, and patient response should be monitored clinically and by lung function tests.
Seretide is not for relief of acute symptoms for which a fast- and short-acting bronchodilator (eg, salbutamol) is required. Patients should be advised to have their relief medication available at all times.
Increasing use of short-acting bronchodilators to relieve asthma symptoms indicates deterioration of asthma control.
Sudden and progressive deterioration in control of asthma is potentially life threatening and the patient should be reviewed by a physician. Consideration should be given to increasing corticosteroid therapy. Also, where the current dosage of Seretide has failed to give adequate control of reversible obstructive airway disease, the patient should be reviewed by a physician. Consideration should be given to additional corticosteroid therapies, and to including administration of antibiotics if an infection is present.
Treatment with Seretide should not be stopped abruptly.
As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with active or quiescent pulmonary tuberculosis.
Seretide should be administered with caution in patients with thyrotoxicosis.
Rare instances of glaucoma and increased intraocular pressure have been reported following administration of inhaled corticosteroids.
Care should be taken when transferring patients to Seretide therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy.
In rare cases, inhaled therapy may unmask underlying eosinophilic conditions (eg, Churg Strauss syndrome). These cases have usually been associated with reduction or withdrawal of oral corticosteroid therapy. A direct causal relationship has not been established.
Fluticasone Propionate and Adrenocortical Function: Some depression of plasma cortisol may occur in a small number of adult patients on higher doses of inhaled fluticasone propionate (eg, >1 mg/day). However, adrenal function and adrenal reserve usually remain within normal range on inhaled fluticasone propionate therapy. In patients taking maintenance doses, systemic side effects [eg, through association with suppression of hypothalamic-pituitary-adrenal (HPA) axis] have not been observed in clinical trials. In particular, stunting of growth in younger patients is unlikely to occur.
The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high-dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.
Effects on the Ability to Drive or Operate Machinery: There have been no specific studies of the effect of Seretide on the previously mentioned activities, but the pharmacology of both drugs does not indicate any effect.
Use in pregnancy & lactation: Administration of drugs during pregnancy and lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus or child.
There is insufficient experience of the use of salmeterol xinafoate and fluticasone propionate in human pregnancy and lactation. Reproductive toxicity studies in animals, either with single drug or in combination, revealed the foetal effects expected at excessive systemic exposure levels of a potent ?2-adrenoreceptor agonist and glucocorticosteroid.
Extensive clinical experience with drugs in these classes has revealed no evidence that the effects are relevant at therapeutic doses. Neither salmeterol xinafoate nor fluticasone propionate have shown any potential for genetic toxicity.
Salmeterol and fluticasone propionate concentrations in plasma after inhaled therapeutic doses are very low and therefore, concentrations in human breast milk are likely to be correspondingly low. This is supported by studies in lactating animals, in which low drug concentrations were measured in milk. There are no data available for human breast milk.

Adverse Reactions
As Seretide contains salmeterol and fluticasone propionate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the 2 compounds.
Adverse events which have been associated with salmeterol or fluticasone propionate are given as follows:
Salmeterol: The pharmacological adverse effects of ?2-agonist treatment, eg tremor, subjective palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) may occur, usually in susceptible patients.
There have been reports of arthralgia and hypersensitivity reactions, including rash, oedema and angioedema. There have been rare reports of muscle cramps.
Fluticasone Propionate: Hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Cutaneous hypersensitivity reactions have been reported. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after use of salmeterol/fluticasone propionate accuhaler.
Symptomatic candidiasis can be treated with topical antifungal therapy while still continuing with salmeterol/fluticasone propionate accuhaler.
As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast- and short-acting inhaled bronchodilator. Salmeterol/fluticasone propionate accuhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Drug Interaction
Even though plasma levels of Seretide are very low, potential interactions with other substrates or inhibitors of CYP3A4 cannot be excluded. Both nonselective and selective ?-blockers should be avoided in patients with reversible obstructive airway disease, unless there are compelling reasons for their use.

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