Seretide

Salmeterol, fluticasone propionate.

Seretide Inhaler: Each single actuation of Seretide provides salmeterol as xinafoate equivalent to salmeterol 25 mcg, and fluticasone propionate 50 or 125 mcg.
Seretide inhaler comprises a suspension of salmeterol as xinafoate and fluticasone propionate in the non-CFC propellant HFA 134a. The suspension is contained in an aluminum alloy can sealed with a metering valve. The canisters are fitted into plastic actuators incorporating an atomizing orifice and fitted with dust caps.
Seretide Diskus: Each diskus contains salmeterol as salmeterol xinafoate 50 mcg and fluticasone propionate 100, 250 or 500 mcg. Seretide diskus also contains lactose (which contains milk protein) as excipient.

Pharmacology: Pharmacodynamics: Mechanism of Action: 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 β-agonist and inhaled corticosteroid therapy. The respective mechanisms of action of both drugs are discussed as follows:
Salmeterol: Salmeterol is a selective long-acting (12 hrs) β₂-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 β₂-agonists.
In vitro tests have shown salmeterol is a potent 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.
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).
Seretide Clinical Trials: Asthma: A large 12-month study (Gaining Optimal Asthma ControL, GOAL) in 3416 asthma patients compared the efficacy and safety of Seretide versus inhaled corticosteroid alone in achieving pre-defined levels of asthma control. Treatment was stepped-up every 12 weeks until **"Total control" was achieved or the highest dose of study drug was reached. Control needed to be sustained for at least 7 out of the last 8 weeks of treatment. The study showed that: 71% of patients treated with Seretide achieved *"Well-controlled" asthma compared with 59% of patients treated with inhaled corticosteroid alone; 41% of patients treated with Seretide achieved **"Total control" of asthma compared with 28% of patients treated with inhaled corticosteroid alone.
These effects were observed earlier with Seretide compared with inhaled corticosteroids alone and at a lower inhaled corticosteroid dose.
The GOAL study also showed that the rate of exacerbations was 29% lower with Seretide compared to inhaled corticosteroid treatment alone; attaining "Well-controlled" and "Totally controlled" asthma improved Quality of Life (QoL). Sixty-one percent (61%) of the patients reported minimal or no impairment on QoL as measured by an asthma specific QoL questionnaire after treatment with Seretide compared to 8% at baseline.
Note: *Well-controlled asthma; occasional symptoms or SABA use or <80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy.
**Total control of asthma; no symptoms, no SABA use ≥80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy.
Two further studies have shown improvements in lung function, percentage of symptom-free days and reduction in rescue medication use, at 60% lower inhaled corticosteroid dose with Seretide compared to treatment with inhaled corticosteroid alone, whilst the control of the underlying airway inflammation, measured by bronchial biopsy and bronchoalveolar lavage was maintained.
Additional studies have shown that treatment with Seretide significantly improves asthma symptoms, lung function and reduces the use of rescue medication compared to treatment with the individual components alone and placebo.
Results from GOAL show that the improvements seen with Seretide, in these endpoints, are maintained over at least 12 months.
COPD: Symptomatic COPD patients without restriction to 10% reversibility to a short-acting β₂-agonist in placebo-controlled clinical trials >6 months have shown that regular use of both Seretide 50/250 and 50/500 mcg rapidly and significantly improve lung function and significantly reduce breathlessness and the use of relief medication. There were also significant improvements in health status.
Symptomatic COPD patients who demonstrated <10% reversibility to a short-acting β₂-agonist in placebo-controlled clinical trials over 6 and 12 months, have shown that regular use of Seretide improves lung function, reduced breathlessness and the use of relief medication. Over a 12-month period, the risk of COPD exacerbations was reduced from 1.42 to 0.99 per year compared with placebo and the risk of exacerbations requiring oral corticosteroids was significantly reduced from 0.81 to 0.47 per year compared with placebo. There were also significant improvements in health status.
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. Therefore, for pharmacokinetic purposes, 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 available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to low plasma concentrations at therapeutic doses (approximately ≤200 pg/mL) achieved after inhaled dosing. After regular dosing with salmeterol xinafoate, hydroxynaphthoic acid can be detected in the systemic circulation.
Fluticasone Propionate: The absolute bioavailability of inhaled fluticasone propionate in healthy subjects varies between approximately 10-30% of the nominal dose depending on the inhalation device used. In patients with asthma or COPD, a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed. Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and presystemic metabolism, resulting in oral availability of <1%. There is a linear increase in systemic exposure with increasing inhaled dose. The disposition of fluticasone propionate is characterized by high plasma clearance (1150 mL/min), a large volume of distribution at steady state (approximately 300 L) and a terminal t_½ of approximately 8 hrs. Plasma protein-binding is moderately high (91%). Fluticasone propionate is cleared very rapidly from the systemic circulation, principally by metabolism to inactive carboxylic acid metabolite, by the cytochrome P-450 enzyme, CYP3A4.
The renal clearance of fluticasone propionate is negligible (<0.2%) and <5% as the metabolite. The main part of the dose is excreted in feces as metabolites and unchanged drug. Other unidentified metabolites are also found in feces. Care should be taken when co-administering with known CYP3A4 inhibitors as there is potential for increased systemic exposure to fluticasone propionate.
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 β₂-adrenoreceptor agonist and glucocorticosteroid.
In long-term studies, salmeterol xinafoate induced benign tumors of smooth muscles in the mesovarium of mice and the uterus of rats.
Rodents are sensitive to the formation of these pharmacologically induced tumors. 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, 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.
Seretide Inhaler: 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 has shown any potential for genetic toxicity.
The non-CFC propellant, HFA 134a, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients in a wide range of animal species exposed daily for periods of 2 years.

Reversible Obstructive Airways Disease (ROAD): Regular treatment of reversible obstructive airways disease (ROAD), including asthma in children and adults, where use of a combination (bronchodilator and inhaled corticosteroid) is appropriate. This may include patients on effective maintenance doses of long-acting β-agonists and inhaled corticosteroids; patients who are symptomatic on current inhaled corticosteroid therapy; and patients on regular bronchodilator therapy who require inhaled corticosteroids.
Chronic Obstructive Pulmonary Disease (COPD): Regular treatment of COPD including chronic bronchitis and emphysema.

Seretide is for inhalation only.
Patients should be made aware that Seretide must be used regularly for optimum benefit even when asymptomatic.
Patients should be regularly re-assessed by a doctor so that the strength of Seretide received remains optimal and is only changed on medical advice.
Reversible Obstructive Airway Disease (ROAD): The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Where the control of symptoms is maintained with Seretide twice daily, titration to lowest effective dose could include Seretide given once daily.
Patients should be given the strength of Seretide containing the appropriate fluticasone propionate dosage for the severity of the disease.
If a patient is inadequately controlled on inhaled corticosteroid therapy alone, substitution with Seretide at a therapeutically equivalent corticosteroid dose may result in an improvement in asthma control. For patients whose asthma control is acceptable on inhaled corticosteroid therapy alone, substitution with Seretide may permit a reduction in corticosteroid dose while maintaining asthma control. For further information see Pharmacology: Pharmacodynamics under Actions.
Seretide Inhaler: Adults and Adolescents ≥12 years: Recommended Dose: 2 inhalations of 25 mcg salmeterol and 50 mcg fluticasone propionate, or 25 mcg salmeterol and 125 mcg fluticasone propionate, or 25 mcg salmeterol and 250 mcg fluticasone propionate. All doses are to be taken twice daily.
Children ≥4 years: 2 inhalations of 25 mcg salmeterol and 50 mcg fluticasone propionate twice daily.
There are no data available for the use of Seretide in children <4 years.
Seretide Diskus: Adults ≥18 years: Recommended dose: Doubling the dose of all strengths of Seretide in adults for up to 14 days has comparable safety and tolerability to regular twice-daily dosing and may be considered when patients require additional short-term (up to 14 days) inhaled corticosteroid therapy as outlined in asthma treatment guidelines.
Adults and Adolescents ≥12 years: 1 inhalation of 50/100, 50/250 or 50/500 mcg diskus twice daily.
Children ≥4 years: 1 inhalation of 50/100 diskus twice daily. There are no data available in children <4 years.
Chronic Obstructive Pulmonary Disease (COPD): Seretide Inhaler: Adults: Recommended Dose: 2 inhalations of 25/125 to 25/250 mcg salmeterol/fluticasone propionate twice daily.
Seretide Diskus: Adults: 1 inhalation of 50/250 to 50/500 mcg salmeterol/fluticasone propionate twice daily.
Special Patient Groups: There is no need to adjust the dose in elderly patients or in those with renal or hepatic impairment.

The available information on overdose with Seretide, salmeterol and/or fluticasone propionate is given as follows: The signs and symptoms of salmeterol overdosage are tremor, headache and tachycardia. The preferred antidotes are cardioselective β-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 β-agonist component of the drug, provision of appropriate replacement corticosteroid therapy should be considered.
Acute inhalation of fluticasone propionate doses in excess of those approved may lead to temporary suppression of hypothalamic-pituitary-adrenal axis. This does not usually require emergency action as normal adrenal function typically recovers within a few days, as verified by plasma cortisol measurements.
If higher than approved doses of Seretide are continued over prolonged periods, significant adrenocortical suppression is possible.
There have been very rare reports of acute adrenal crisis, mainly occurring in children exposed to higher than approved doses over prolonged periods (several months or years); observed features have included hypoglycemia associated with decreased consciousness and/or convulsions. Situations which could potentially trigger acute adrenal crisis include exposure to trauma, surgery, infection or any rapid reduction in the dosage of the inhaled fluticasone propionate component.
It is not recommended that patients receive higher than approved doses of Seretide. It is important to review therapy regularly and titrate down to the lowest approved dose at which effective control of disease is maintained (see Dosage & Administration).
Additionally, hypokalaemia can occur and potassium replacement should be considered.
Although the bioavailability of the active principles contained in Seretide is low, accidental consumption <1 hr before which could lead to severe intoxication, gastric lavage and then (if necessary repeated) administration of charcoal should be carried out. In the case of severe intoxication, monitoring and correction of the electrolyte and acid-base balance is required.

Patients with a history of hypersensitivity to salmeterol xinafoate, fluticasone propionate or to any of the excipients of Seretide.

The management of ROAD 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. Seretide is not intended for the initial management of asthma until the need for an approximate dosage of corticosteroids has been established.
Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a physician.
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 ROAD, the patient should be reviewed by a physician.
For patients with asthma or COPD, consideration should be given to additional corticosteroid therapies and administration of antibiotics if an exacerbation is associated with infection.
Treatment with Seretide should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be titrated down under physician supervision. For patients with COPD, cessation of therapy may be associated with symptomatic decompensation and should be supervised by a physician.
As with all inhaled medications 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 severe cardiovascular disorders, including heart rhythm abnormalities, diabetes mellitus, untreated hypokalemia or thyrotoxicosis.
Cardiovascular effects eg, increases in systolic blood pressure and heart rate may occasionally be seen with all sympathomimetic drugs, especially at higher than therapeutic doses. For this reason, Seretide should be used with caution in patients predisposed to low levels of serum potassium.
Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much less likely to occur than with oral corticosteroids (see Overdosage).
Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore for ROAD patients, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained.
The possibility of impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment considered (see Overdosage).
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.
Certain individuals can show greater susceptibility to the effects of inhaled corticosteroid than do most patients.
Because of the possibility of impaired adrenal response, patients transferring from oral steroid therapy to inhaled fluticasone propionate therapy should be treated with special care and adrenocortical function regularly monitored.
Following introduction of inhaled fluticasone propionate, withdrawal of systemic therapy should be gradual and patients are encouraged to carry a steroid warning card indicating the possible need for additional therapy in times of stress.
There have been very rare reports of increases in blood glucose levels (see Adverse Reactions) and this should be considered when prescribing to patients with a history of diabetes mellitus.
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P-450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations.
During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Effects on the Ability to Drive or Operate Machinery: There have been no specific studies of the effect of Seretide on the ability to drive or operate machinery, but the pharmacology of both salmeterol xinafoate and fluticasone propionate 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 fetus or child. There is insufficient experience on 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 fetal effects expected at excessive systemic exposure levels of a potent β₂-adrenoceptor 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 or fluticasone propionate have shown any potential for genetic toxicity.
The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.
Both salmeterol and fluticasone propionate are excreted into breast milk in rats. 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. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
Seretide Inhaler: Salmeterol and fluticasone propionate concentration in plasma after inhaled therapeutic doses are very low and therefore, concentrations in human breast milk are likely to be correspondingly low.
Use in children: There are no data available in children <4 years.

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 fetus or child. There is insufficient experience on 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 fetal effects expected at excessive systemic exposure levels of a potent β₂-adrenoceptor 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 or fluticasone propionate have shown any potential for genetic toxicity.
The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.
Both salmeterol and fluticasone propionate are excreted into breast milk in rats. 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. Administration of Seretide to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
Seretide Inhaler: Salmeterol and fluticasone propionate concentration in plasma after inhaled therapeutic doses are very low and therefore, concentrations in human breast milk are likely to be correspondingly low.

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.
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 inhaler/diskus should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. Adverse events which have been associated with salmeterol or fluticasone propionate are given as follows: Salmeterol: The pharmacological side effects of β₂-agonist treatment eg, tremor, subjective palpitations and headache have been reported but tend to be transient and reduced with regular therapy.
Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) may usually occur in susceptible patients.
There have been reports of arthralgia and hypersensitivity reactions, including rash, edema and angioedema, and oropharyngeal irritation, and rare reports of muscle cramps. There have been very rare reports of hyperglycaemia.
Fluticasone Propionate: Hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients.
There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal edema), respiratory symptoms (dyspnea and/or bronchospasm) and very rarely, anaphylactic reactions.
Both hoarseness and incidence of candidiasis may be relieved by gargling with water after use of salmeterol/fluticasone propionate inhaler/diskus. Symptomatic candidiasis can be treated with topical antifungal therapy whilst still continuing with salmeterol/fluticasone propionate inhaler/diskus.
Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see Precautions). There have been very rare reports of hyperglycaemia, anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children).
Salmeterol/Fluticasone Propionate Clinical Trials: The following undesirable effects were commonly reported in salmeterol/fluticasone propionate clinical trials: Hoarseness/dysphonia, throat irritation, headache, candidiasis of mouth and throat and palpitations.
Salmeterol/Fluticasone Propionate Post-Marketing: There have been uncommon reports of cutaneous hypersensitivity reactions. There have also been rare reports of hypersensitivity reactions manifesting as angioedema (mainly facial and oropharyngeal edema), respiratory symptoms (dyspnea and/or bronchospasm) and very rarely, anaphylactic reactions.
There have also been rare reports of hyperglycaemia.
Adverse events which have been associated with salmeterol/fluticasone propionate are given as follows, listed by system organ class and frequency. 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 derived from clinical trial data. The incidence in placebo was not taken into account. Very rare events were derived from post-marketing spontaneous data.
Infections and Infestations: Common: Candidiasis of the mouth and throat.
Immune System Disorders: Uncommon: Hypersensitivity reactions with the following manifestation: Cutaneous hypersensitivity reactions. Very Rare: Angioedema (mainly facial and oropharyngeal edema), respiratory symptoms (dyspnea and/or bronchospasm), anaphylactic reactions.
Endocrine Disorders: Very Rare: Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma.
Metabolism and Nutrition Disorders: Very Rare: Hyperglycaemia.
Psychiatric Disorders: Very Rare: Anxiety, sleep disorders and behavioural changes including hyperactivity and irritability (predominantly in children).
Nervous System Disorders: *Very Common: Headache. Common: Tremor.
Cardiac Disorders: Common: Palpitations. Uncommon: Tachycardia. Very Rare: Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles).
Respiratory, Thoracic and Mediastinal Disorders: Common: Throat irritation, hoarseness/dysphonia. Very Rare: Paradoxical bronchospasm.
Musculoskeletal and Connective Tissue Disorders: Common: Muscle cramps. Very Rare: Arthralgia, myalgia.
Note: *Reported commonly in placebo.

Both nonselective and selective β-blockers should be avoided unless there are compelling reasons for their use.
Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing due to extensive first-pass metabolism and high systemic clearance mediated by cytochrome P-450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.
A drug interaction study in healthy subjects has shown that ritonavir (a highly potent cytochrome P-450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum cortisol concentrations.
During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Studies have shown that other inhibitors of cytochrome P-450 3A4 produce negligible (erythromycin) and minor (ketoconazole) increases in systemic exposure to fluticasone propionate without notable reductions in serum cortisol concentrations. Nevertheless, care is advised when co-administering potent cytochrome P-450 3A4 inhibitors (eg, ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.
Concomitant use of other β-adrenergic containing drugs can have a potentially addictive effect.
Monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, L-dopa, L-thyroxine, oxytocin and in some cases also antiarrhythmics can increase the cardiovascular side effects of β-sympathomimetics and thus also of Seretide. With xanthines, there is a risk of hypokalaemia. Short-acting β₂-agonist are effective when administered together with Seretide and should be kept available as rescue medications.

Seretide Inhaler: As with most inhaled medications in pressurized canisters, the therapeutic effect of Seretide may decrease when the canister is cold.
The canister should not be punctured, broken or burnt even when apparently empty.
Instructions for Use and Handling: Testing the Inhaler: Before using for the first time or if the inhaler has not been used for a week or more, remove the mouthpiece cover by gently squeezing the sides of the cover, shake the inhaler well and release one puff into the air to make sure that it works.
Using the Inhaler: Remove the mouthpiece cover by gently squeezing the sides of the cover and check the mouthpiece inside and outside to see that it is clean.
Shake the inhaler well.
Hold the inhaler upright between fingers and thumb with thumb on the base, below the mouthpiece.
Breathe out as far as is comfortable and then place the mouthpiece in the mouth between the teeth and close lips around it but do not bite it.
Just after starting to breathe in through the mouth, press down on the top of the inhaler to release salmeterol and fluticasone propionate, while still breathing in steadily and deeply.
While holding the breath, take the inhaler from the mouth and take finger off the top of the inhaler. Continue holding the breath for as long as is comfortable.
To take the 2nd puff, keep the inhaler upright and wait about half a minute before repeating the previous steps.
The mouthpiece cover is replaced by firmly pushing and snapping the cap into position.
Do not rush stages 4, 5 and 6. It is important to start to breathe in as slowly as possible just before operating the inhaler. Practice in front of a mirror for the first few times. If a mist coming from the top of the inhaler is seen or on the sides of the mouth, start again from stage 2.
If the physician has given different instructions for using the inhaler, follow carefully. Tell the physician of any difficulty.
Children: Young children may need help and it is recommended to use a spacer, and an adult may need to operate the inhaler for them. Encourage the child to breathe out and operate the inhaler just after the child starts to breathe in. Practice the technique together. Older children or people with weak hands should hold the inhaler with both hands. Put the 2 forefingers on top of the inhaler and both thumbs on the base below the mouthpiece.
Cleaning: The inhaler should be cleaned at least once a week. Remove the mouthpiece cover. Do not remove the canister from the plastic casing. Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth, tissue or cotton bud. Replace the mouthpiece cover.
Do not put the metal canister into water.
Incompatibilities: None reported.
Seretide Diskus: Instructions for Use/Handling: The diskus releases a powder which is inhaled into the lungs.
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 diskus indicates the number of doses left.
Closed: When the diskus is taken out of the box, it will be in the closed position.
Open: A new diskus contains 28 or 60 individually protected doses of the medicine in powder form. The dose indicator tells how many doses are left.
Each dose is accurately measured and hygienically protected. It requires no maintenance and no refilling.
The dose indicator on top of the diskus indicates how many doses are left. Numbers 5 to 0 will appear in red to warn when there are only a few doses left.
How the Diskus Works: Sliding the lever of the diskus opens a small hole in the mouthpiece and unwraps a dose, ready for inhalation. When the diskus is closed, the lever automatically moves back to its original position, ready for the next dose when needed.
When a dose is needed, 4 simple steps are to be followed.
1. Open: To open the diskus, hold the outer case in 1 hand and put the thumb of the other hand on the thumbgrip. Push thumb away as far as it will go.
2. Slide: Hold the diskus with the mouthpiece towards the holder. Slide the lever away as far as it will go, until it clicks. The diskus is now ready for use. Every time the lever is pushed back, a dose is made available for inhaling. This is shown by the dose counter. The lever should not be played, as it releases doses which will be wasted.
3. Inhale: Before starting to inhale the dose, hold the diskus away from the mouth. Breathe out as far as it is comfortable. Never breathe into the diskus.
Put the mouthpiece to the lips. Breathe in steadily and deeply, through the diskus, not through the nose. Remove the diskus from the mouth. Hold breath for about 10 sec or for as long as it is comfortable. Breathe out slowly.
4. Close: To close diskus, put thumb in the thumbgrip and slide the thumbgrip backwards as far as it will go. When the diskus is closed, it clicks shut. The lever automatically returns to its original position and is reset. The diskus is now ready for use again.
If instructed to take 2 inhalations, close the diskus and repeat steps 1-4.
Keep the diskus dry. Keep it closed when not in use. Never breathe into the diskus. Only slide the lever when ready to take a dose. Do not exceed the stated dose.

Seretide Inhaler: Do not store above 30°C. Store in a dry place. Protect from light and frost.
Seretide Diskus: Do not store above 30°C. Store in a dry place.
Shelf-Life: 18 months.

Antiasthmatic & COPD Preparations

R03AK06 - salmeterol and fluticasone ; Belongs to the class of adrenergics in combination with corticosteroids or other drugs, excluding anticholinergics. Used in the treatment of obstructive airway diseases.

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