Seretide舒悅泰

Seretide

salmeterol + fluticasone

Manufacturer:

GlaxoSmithKline

Distributor:

Zuellig
/
Agencia Lei Va Hong
Full Prescribing Info
Contents
Salmeterol, fluticasone propionate.
Description
Accuhaler: SERETIDE ACCUHALER is a range of three multiple dose powder inhalers consisting of the following three formulations: Moulded plastic device containing a foil strip with regularly placed blisters each containing 50 mcg of salmeterol (as xinafoate) and 100 mcg of fluticasone propionate.
Moulded plastic device containing a foil strip with regularly placed blisters each containing 50 mcg of salmeterol (as xinafoate) and 250 mcg of fluticasone propionate.
Moulded plastic device containing a foil strip with regularly placed blisters each containing 50 mcg of salmeterol (as xinafoate) and 500 mcg of fluticasone propionate.
Inhaler: SERETIDE Inhaler comprises a suspension of fluticasone propionate and salmeterol in the non-CFC propellant HFA-134a. The suspension is contained in an aluminium alloy can sealed with a metering valve. SERETIDE Inhaler delivers 50, 125 or 250mcg of fluticasone propionate and 25 mcg of salmeterol per actuation.
Available in 120 dose formats.
Excipient/Inactive Ingredient: Accuhaler: SERETIDE Accuhaler also contains the excipient lactose (which contains milk protein).
Action
Pharmacology: Clinical Studies: Asthma: SERETIDE clinical trials: A large twelve-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 corticosteroid 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). 61% of patients reported minimal or no impairment on QoL, as measured by an asthma specific quality of life questionnaire, after treatment with SERETIDE compared to 8% at baseline.
#Well controlled asthma; occasional symptoms or SABA use or less than 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 greater than or equal to 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.
Accuhaler: SEREVENT clinical trials: The Salmeterol Multi-center Asthma Research Trial (SMART) was a large US study that compared the safety of SEREVENT or placebo added to usual therapy. There were no significant differences in the primary endpoint of the combined number of respiratory-related deaths and respiratory-related life-threatening experiences. The study showed a significant increase in asthma-related deaths in patients receiving SEREVENT (13 deaths out of 13,176 patients treated for 28 weeks on SEREVENT versus 3 deaths out of 13,179 patients on placebo). The study was not designed to assess the impact of concurrent inhaled corticosteroid use. However, post-hoc analyses showed there was no significant difference between treatment groups for asthma-related deaths for those patients using inhaled steroids at baseline (4/6127 on SEREVENT versus 3/6138 on placebo). The numbers of asthma-related deaths in the groups not using inhaled steroids were 9/7049 on SEREVENT versus 0/7041 on placebo. Further, a meta-analysis of 42 clinical studies involving 8,030 patients on SERETIDE and 7,925 patients on FLIXOTIDE did not show a statistical difference between SERETIDE and FLIXOTIDE for serious respiratory-related events or asthma-related hospitalisations.
Inhaler: Safety and efficacy of salmeterol-FP versus FP alone in asthma: Two multi-centre 26-week studies were conducted to compare the safety and efficacy of salmeterol-FP versus FP alone, one in adult and adolescent subjects (AUSTRI trial), and the other in paediatric subjects 4-11 years of age (VESTRI trial). For both studies, enrolled subjects had moderate to severe persistent asthma with history of asthma-related hospitalisation or asthma exacerbation in the previous year. The primary objective of each study was to determine whether the addition of LABA to ICS therapy (salmeterol-FP) was non-inferior to ICS (FP) alone in terms of the risk of serious asthma related events (asthma-related hospitalisation, endotracheal intubation, and death). A secondary efficacy objective of these studies was to evaluate whether ICS/LABA (salmeterol-FP) was superior to ICS therapy alone (FP) in terms of severe asthma exacerbation (defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids).
A total of 11,679 and 6,208 subjects were randomized and received treatment in the AUSTRI and VESTRI trials, respectively. For the primary safety endpoint, non-inferiority was achieved for both trials (see Table 1 as follows).

Click on icon to see table/diagram/image

For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for salmeterol-FP relative to FP was seen in both studies, however only AUSTRI met statistical significance: See Table 2.

Click on icon to see table/diagram/image

Salmeterol Multi-center Asthma Research Trial (SMART): The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week US study that evaluated the safety of salmeterol compared to placebo added to usual therapy in adult and adolescent subjects. Although there were no significant differences in the primary endpoint of the combined number of respiratory-related deaths and respiratory-related life-threatening experiences, the study showed a significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated with salmeterol versus 3 deaths out of 13,179 patients on placebo). The study was not designed to assess the impact of concurrent inhaled corticosteroid use.
COPD: Symptomatic COPD patients without restriction to 10% reversibility to a short acting beta-2-agonist: Placebo-controlled clinical trials, over 6 months, have shown that regular use of both SERETIDE 50/250 and 50/500 micrograms rapidly and significantly improves lung function, significantly reduced breathlessness and the use of relief medication. There were also significant improvements in health status. Symptomatic COPD patients who demonstrated less than 10% reversibility to a short acting beta-2-agonist: Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of SERETIDE 50/500 micrograms rapidly and significantly improves lung function, significantly reduced breathlessness and the use of relief medication. Over a 12-month period the risk of COPD exacerbations and the need for additional courses of oral corticosteroids was significantly reduced. There were also significant improvements in health status.
SERETIDE 50/500 micrograms was effective in improving lung function, health status and reducing the risk of COPD exacerbations, in both current and ex-smokers.
TORCH study (TOwards a Revolution in COPD Health): TORCH was a 3-year study to assess the effect of treatment with SERETIDE ACCUHALER 50/500 micrograms twice daily, salmeterol ACCUHALER 50 micrograms twice daily, FP Accuhaler 500 micrograms twice daily or placebo on all-cause mortality in patients with COPD. Patients with moderate to severe COPD with a baseline (pre-bronchodilator) FEV1 <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators, and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all-cause mortality at 3 years for SERETIDE vs placebo. (See Table 3.)

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SERETIDE reduced the risk of dying at any time during the 3 years by 17.5% compared to placebo (Hazard Ratio 0.825 (95% CI 0.68, 1.00, p=0.052; all adjusted for interim analyses). There was a 12% reduction in the risk of dying at any time within 3 years from any cause for salmeterol compared with placebo (p=0.180) and a 6% increase for FP compared with placebo (p=0.525).
A supporting analysis using Cox's Proportional Hazards model gave a hazard ratio of 0.811 (95% CI 0.670, 0.982, p=0.031) for SERETIDE vs placebo which represented a 19% reduction in the risk of dying at any time within 3 years. The model adjusted for important factors (smoking status, age, sex, region, baseline FEV1 and Body Mass Index). There was no evidence that treatment effects varied for these factors.
The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for FP and 4.7% for SERETIDE.
SERETIDE reduced the rate of moderate to severe exacerbations by 25% (95% CI: 19% to 31%; p<0.001) compared with placebo. SERETIDE reduced the exacerbation rate by 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively.
Health Related Quality of Life, as measured by the St George's Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for SERETIDE compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with FP was -1.2 units (p=0.017).
Over the 3 year treatment period, FEV1 values were higher in subjects treated with SERETIDE than for those treated with placebo (average difference over 3 years 92mL, 95% CI: 75 to 108 mL; p<0.001). SERETIDE was also more effective than salmeterol or FP in improving FEV1 (average difference 50 mL, p<0.001 for salmeterol and 44mL, p<0.001 for FP).
The estimated 3 year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for FP and 19.6% for SERETIDE (Hazard ratio for SERETIDE vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for FP and 8 for SERETIDE. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% SERETIDE; Hazard ratio for SERETIDE vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248). The incidence of adverse events of eye disorders, bone disorders, and HPA axis disorders was low and there was no difference observed between treatments. There was no evidence of an increase in cardiac adverse events in the treatment groups receiving salmeterol.
Inhaler: Fluticasone propionate containing medications in asthma during pregnancy: An observational retrospective epidemiological cohort study utilising electronic health records from the United Kingdom was conducted to evaluate the risk of MCMs following first trimester exposure to inhaled FP alone and salmeterol-FP combination relative to non-FP containing ICS. No placebo comparator was included in this study. As an epidemiologic study, biases may not have been controlled to the same extent as in a clinical trial.
Within the asthma cohort of 5362 first trimester ICS-exposed pregnancies in which MCMs were diagnosed by one year of age, 131 major MCMs were identified; in the 1612 (30%) pregnancies which were exposed to FP or salmeterol-FP, 42 diagnosed MCMs were identified. In 3750 (70%) pregnancies which were exposed to non-FP inhaled corticosteroid (ICS), 89 diagnosed MCMs were identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5 - 2.3) for FP exposed vs non-FP ICS exposed women with moderate asthma and 1.2 (95%CI: 0.7 - 2.0) for women with considerable to severe asthma. No difference in the risk of MCMs was identified following first trimester exposure to FP alone versus salmeterol-FP combination. Absolute risks of MCMs across the asthma severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies.
Indications/Uses
Asthma: SERETIDE is indicated in the regular treatment of 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 beta-agonists and inhaled corticosteroids.
Patients who are symptomatic on current inhaled corticosteroid therapy.
Patients on regular bronchodilator therapy who require inhaled corticosteroids.
Chronic Obstructive Pulmonary Disease (COPD): Accuhaler: SERETIDE ACCUHALER 50mcg/250mcg and SERETIDE ACCUHALER 50mcg/500mcg are indicated for the maintenance treatment of COPD, including emphysema and chronic bronchitis in patients where the use of a combination product is considered appropriate.
Inhaler: SERETIDE Inhaler 25/125 and SERETIDE Inhaler 25/250 are indicated for the symptomatic treatment of patients with severe COPD (FEV1<50% predicted normal) and a history of repeated exacerbations who have significant symptoms despite regular beta-2 agonist bronchodilator therapy. SERETIDE is not indicated for the initiation of bronchodilator therapy in COPD.
Dosage/Direction for Use
SERETIDE is for oral inhalation only.
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.
Asthma: The dose should be titrated to the lowest dose at which effective control of symptoms is maintained.
If asthma is insufficiently controlled by monotherapy with inhaled corticosteroids, transfer to SERETIDE at therapeutically equivalent doses of the corticosteroid can lead to improved asthma control. For patients whose asthma is well controlled by inhaled corticosteroids, transfer to SERETIDE makes it possible to reduce the dose of corticosteroid while retaining the same asthma control.
Patients should be given the strength of SERETIDE containing the appropriate fluticasone propionate dosage for the severity of their disease.
Accuhaler: Where the control of symptoms is maintained with the lowest strength of the combination then the next step could include a test of inhaled corticosteroid alone. As an alternative, patients requiring a long acting beta-2-agonist could be titrated to SERETIDE given once daily if, in the opinion of the prescriber, it would be adequate to maintain disease control. In the event of once daily dosing, when the patient has a history of nocturnal symptoms the dose should be given at night and when the patient has a history of mainly day-time symptoms the dose should be given in the morning.
If an individual patient should require dosages outside the recommended regimen, appropriate doses of beta-agonist and/or corticosteroid should be prescribed.
Adults and adolescents 12 years and older: One inhalation (50 mcg salmeterol and 100 mcg fluticasone propionate) twice daily; or One inhalation (50 mcg salmeterol and 250 mcg fluticasone propionate) twice daily; or One inhalation (50 mcg salmeterol and 500 mcg fluticasone propionate) twice daily.
Children 4 to 11 years of age: One inhalation (50 mcg salmeterol and 100 mcg fluticasone propionate) twice daily.
There are no data available for use of SERETIDE in children aged under 4 years.
Inhaler: Adults and adolescents 12 years and older: Two inhalations of 25 mcg salmeterol and 50 mcg fluticasone propionate twice daily; or Two inhalations of 25 mcg salmeterol and 125 mcg fluticasone propionate twice daily; or Two inhalations of 25 mcg salmeterol and 250 mcg fluticasone propionate twice daily.
Children 4 years and older: Two inhalations of 25 mcg salmeterol and 50 mcg fluticasone propionate twice daily.
There are no data available for use of SERETIDE in children aged under 4 years.
Special patient groups: There is no need to adjust the dose in elderly patients or in those with renal or hepatic impairment.
Chronic Obstructive Pulmonary Disease (COPD): Accuhaler: Adults (18 years and older): One inhalation (50mcg salmeterol and 250mcg fluticasone propionate) twice daily; or One inhalation (50mcg salmeterol and 500mcg fluticasone propionate) twice daily.
Elderly and patients with impaired renal or hepatic function: There is no need to adjust the dose in the otherwise healthy elderly or in patients with impaired renal function. Since salmeterol is predominantly cleared by hepatic metabolism, patients with hepatic disease should be closely monitored.
Inhaler: Adults: Two inhalations of 25 mcg salmeterol and 250 mcg fluticasone propionate twice daily; or Two inhalations of 25 mcg salmeterol and 125 mcg fluticasone propionate twice daily may be a consideration in patients who are at greater risk of inhaled corticosteroid adverse effects.
Overdosage
The available information on overdose with SERETIDE, salmeterol and/or fluticasone propionate is given as follows: The expected symptoms and signs of salmeterol overdosage are those typical of excessive beta-2-adrenergic stimulation, including tremor, headache, tachycardia, increases in systolic blood pressure and hypokalaemia.
Acute inhalation of fluticasone propionate doses in excess of those approved may lead to temporary suppression of the hypothalamic-pituitary-adrenal axis. This does not usually require emergency action as normal adrenal function typically recovers within a few days.
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 hypoglycaemia 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).
Accuhaler: The preferred antidotes are cardioselective beta-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 beta agonist component of the drug, provision of appropriate replacement corticosteroid therapy should be considered.
Inhaler: There is no specific treatment for an overdose of salmeterol and fluticasone propionate. If overdose occurs, the patients should be treated supportively with appropriate monitoring as necessary.
Contraindications
SERETIDE is contraindicated in patients with a history of hypersensitivity to any of the ingredients.
Special Precautions
The management of asthma/reversible obstructive airways 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 (e.g. salbutamol (Ventolin)) is required. Patients should be advised to have their relief medication available at all times.
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 asthma, 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.
There was an increased reporting of pneumonia in studies of patients with COPD receiving SERETIDE (see Adverse Reactions). Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.
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.
Cardiovascular effects, such as 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 with pre-existing cardiovascular disease.
A transient decrease in serum potassium may occur with all sympathomimetic drugs at higher therapeutic doses. Therefore, 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 asthma 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 corticosteroids 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 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.
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 (see Interactions).
It was observed in a drug interaction study that concomitant use of systemic ketoconazole increases exposure to SEREVENT. This may lead to prolongation in the QTc interval. Caution should be exercised when strong CYP3A4 inhibitors (e.g. ketoconazole) are co-administered with SEREVENT (see Interactions and Pharmacology: Pharmacokinetics under Actions).
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. Seretide/Salmeterol-FP Accuhaler or Inhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary (see Adverse Reactions).
The pharmacological side-effects of beta-2 agonist treatment, such as tremor, subjective palpitations and headache have been reported, but tend to be transient and may/to reduce with regular therapy (see Adverse Reactions).
This medicine should be used for the shortest duration of time required to achieve control of asthma symptoms and discontinue, if possible, once asthma control is achieved. This medicine should only be used long-term in patients whose asthma cannot be adequately controlled on asthma controller medications.
Effects on Ability to Drive and 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.
Accuhaler: SERETIDE contains lactose (which contains milk protein) up to 12.5mg/dose. This amount does not normally cause problems in lactose intolerant people.
Data from a large US study (SMART) comparing the safety of SEREVENT (a component of SERETIDE) or placebo added to usual therapy showed a significant increase in asthma-related deaths in patients receiving SEREVENT. Data from this study suggested that African-American patients may be at greater risk of serious respiratory-related events or deaths when using SEREVENT compared to placebo. It is not known if this was due to pharmacogenetic or other factors. The SMART study was not designed to determine whether concurrent use of inhaled corticosteroids modifies the risk of asthma-related death (see Pharmacology: Clinical Studies under Actions).
Use In Pregnancy & Lactation
Fertility: There are no data on human fertility. Animal studies indicate no effects of fluticasone propionate or salmeterol xinafoate on male or female fertility.
Pregnancy: 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. Results from a retrospective epidemiological study based on the UK General Practice Research Database (GPRD), did not find an increased risk of major congenital malformations (MCMs) following exposure to fluticasone propionate when compared to other inhaled corticosteroids, during the first trimester of pregnancy (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). 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 beta-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 or fluticasone propionate have shown any potential for genetic toxicity.
Lactation: 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. Administration during lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the child.
Adverse Reactions
Accuhaler: 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 two compounds.
Adverse events are listed as follows 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), rare (≥1/10,000 and <1/1000) and very rare (<1/10,000).
Clinical Trial Data: Infections and infestations: Common: Candidiasis of mouth and throat, pneumonia (in COPD patients).
Such patients may find it helpful to rinse out their mouth with water after inhalation. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the fluticasone propionate.
Rare: Oesophageal candidiasis.
Immune system disorders: Hypersensitivity Reactions: Uncommon: Cutaneous hypersensitivity reactions, dyspnoea.
Rare: Anaphylactic reactions.
Endocrine disorders: Possible systemic effects include (see Precautions): Uncommon: Cataract.
Rare: Glaucoma.
Metabolism and nutrition disorders: Uncommon: Hyperglycaemia.
Psychiatric disorders: Uncommon: Anxiety, sleep disorders.
Rare: Behavioural changes, including hyperactivity and irritability (predominantly in children).
Nervous system disorders: Very common: Headache (see Precautions).
Uncommon: Tremor (see Precautions).
Cardiac disorders: Common: Palpitations (see Precautions).
Uncommon: Tachycardia, atrial fibrillation.
Rare: Cardiac arrhythmias including supraventricular tachycardia and extrasystoles.
Peripheral vasodilation and a compensatory small increase in heart rate may occur in some patients.
Respiratory, thoracic and mediastinal disorders: Common: Hoarseness/dysphonia, throat irritation.
Skin and subcutaneous tissue disorders: Uncommon: Contusions.
Musculoskeletal and connective tissue disorders: Common: Muscle cramps, arthralgia.
Postmarketing Data: Immune system disorders: Hypersensitivity reactions manifesting as: Uncommon: Cutaneous hypersensitivity reactions.
Rare: Angioedema (mainly facial and oropharyngeal oedema) and respiratory symptoms (dyspnoea and/or bronchospasm), anaphylactic reactions.
Endocrine disorders: Possible systemic effects include (see Precautions): Rare: Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density.
Metabolism and nutrition disorders: Uncommon: Hyperglycaemia.
Psychiatric disorders: Uncommon: Anxiety, sleep disorders.
Rare: Behavioural changes, including hyperactivity and irritability (predominantly in children).
Respiratory, thoracic and mediastinal disorders: Rare: Paradoxical bronchospasm (see Precautions).
Inhaler: All of the adverse reactions associated with the individual components, salmeterol xinafoate and fluticasone propionate, are listed as follows. There are no additional adverse reactions attributed to the combination product when compared to the adverse event profiles of the individual components.
Adverse events are listed as follows by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and very rare (<1/10,000). The majority of frequencies were determined from pooled clinical trial data from 23 asthma and 7 COPD studies. Not all events were reported in clinical trials. For these events, the frequency was calculated based on spontaneous data.
Clinical Trial Data: Infections and infestations: Common: Candidiasis of mouth and throat, pneumonia (in COPD patients).
Rare: Oesophageal candidiasis.
Immune system disorders: Hypersensitivity Reactions: Uncommon: Cutaneous hypersensitivity reactions, dyspnoea.
Rare: Anaphylactic reactions.
Endocrine disorders: Possible systemic effects include (see Precautions): Uncommon: Cataract.
Rare: Glaucoma.
Metabolism and nutrition disorders: Uncommon: Hyperglycaemia.
Psychiatric disorders: Uncommon: Anxiety, sleep disorders.
Rare: Behavioural changes, including hyperactivity and irritability (predominantly in children).
Nervous system disorders: Very common: Headache (see Precautions).
Uncommon: Tremor (see Precautions).
Cardiac disorders: Uncommon: Palpitations (see Precautions), tachycardia, atrial fibrillation.
Rare: Cardiac arrhythmias including supraventricular tachycardia and extrasystoles.
Respiratory, thoracic and mediastinal disorders: Common: Hoarseness/dysphonia.
Uncommon: Throat irritation.
Skin and subcutaneous tissue disorders: Uncommon: Contusions.
Musculoskeletal and connective tissue disorders: Common: Muscle cramps, arthralgia.
Postmarketing Data: Immune system disorders: Hypersensitivity reactions manifesting as: Rare: Angioedema (mainly facial and oropharyngeal oedema) and bronchospasm.
Endocrine disorders: Possible systemic effects include (see Precautions): Rare: Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density.
Respiratory, thoracic and mediastinal disorders: Rare: Paradoxical bronchospasm (see Precautions).
Drug Interactions
Both non-selective and selective beta-blockers should be avoided in patients with asthma, 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 P450 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 P450 3A4 inhibitor) can greatly increase fluticasone propionate plasma concentrations, resulting in markedly reduced serum concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled 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 P450 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 P450 3A4 inhibitors (e.g. ketoconazole) as there is potential for increased systemic exposure to fluticasone propionate.
Co-administration of ketoconazole and SEREVENT resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC) and this may cause a prolongation of the QTc interval (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Caution For Usage
Instructions for Use/Handling: Accuhaler: About the ACCUHALER: The ACCUHALER contains 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 ACCUHALER tells how many doses are left. Numbers 5 to 0 will appear in RED, to warn the patient when there are only a few doses left.
When taking the ACCUHALER out of its box, it will be in the closed position.
How the ACCUHALER works: Sliding the lever of the ACCUHALER opens a small hole in the mouthpiece and unwraps a dose, ready for the patient to inhale it. When closing the ACCUHALER, the lever automatically moves back to its original position, ready for the next dose when the patient needs it. The outer case protects the ACCUHALER when it is not in use.
The ACCUHALER is easy to use. When the patient needs a dose, just follow the four simple steps: 1. Open. 2. Slide. 3. Inhale. 4. Close.
How to use the ACCUHALER: 1. Open: To open the ACCUHALER, hold the outer case in one hand and put the thumb of the other hand on the thumbgrip. Push the thumb away from the patient as far as it will go.
2. Slide: Hold the ACCUHALER with the mouthpiece towards the patient.
Slide the lever away from the patient, as far as it will go - until it clicks.
The ACCUHALER is now ready to use.
Every time the lever is pushed back, a dose is made available for inhaling.
This is shown by the dose counter.
Do not play with the lever as this releases doses which will be wasted.
3. Inhale: Before starting to inhale the dose, read through this section carefully.
Hold the ACCUHALER away from the mouth. Breathe out as far as is comfortable. Remember - never breathe into the ACCUHALER.
Put the mouthpiece to the lips. Breathe in steadily and deeply - through the ACCUHALER, not through the nose.
Remove the ACCUHALER from the mouth.
Hold breath for about 10 seconds, or for as long as is comfortable.
Breathe out slowly.
4. Close: To close the ACCUHALER, put the thumb in the thumbgrip, and slide the thumbgrip back towards the patient, as far as it will go.
When closing the ACCUHALER, it clicks shut.
The lever automatically returns to the original position and is reset.
The ACCUHALER is now ready for the patient to use again.
If the patient has been instructed to take two inhalations the patient must close the ACCUHALER and repeat stages 1 to 4.
REMEMBER: Keep the ACCUHALER dry.
Keep it closed when not in use.
Never breathe into the ACCUHALER.
Only slide the lever when ready to take a dose.
SERETIDE ACCUHALER must only be breathed in through the mouth.
Do not exceed the stated dose.
Inhaler: Testing the inhaler: Before using for the first time, remove the mouthpiece cover by gently squeezing the sides of the cover, shake the inhaler well, hold the inhaler between fingers and thumb with the thumb at the base below the mouthpiece and release puffs into the air until the counter reads 120 to make sure that it works. The inhaler should be shaken immediately before releasing each puff. If the inhaler has not been used for a week or more remove the mouthpiece cover, shake the inhaler well and release two puffs into the air. Each time the inhaler is activated the number on the counter will count down by one.
In certain circumstances dropping the inhaler may cause the counter to count on.
Using the inhaler: 1. Remove the mouthpiece cover by gently squeezing the sides of the cover.
2. Check inside and outside of the inhaler including the mouthpiece for the presence of loose objects.
3. Shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed.
4. Hold the inhaler upright between fingers and thumb with the thumb on the base, below the mouthpiece.
5. Breathe out as far as is comfortable and then place the mouthpiece in the mouth between the teeth and close the lips around it, but do not bite it.
6. Just after starting to breathe in through the mouth press firmly down on the top of the inhaler to release SERETIDE while still breathing in steadily and deeply.
7. While holding the breath, take the inhaler from the mouth and take the finger from the top of the inhaler. Continue holding the breath for as long as is comfortable.
8. To take a second inhalation keep the inhaler upright and wait about half a minute before repeating steps 3 to 7.
9. Immediately replace the mouthpiece cover in the correct position. The cap when correctly fitted will click into position. If it does not click into place, turn the cap the other way round and try again. Do not use excessive force.
IMPORTANT: Do not rush steps 5, 6 and 7. It is important that the patient starts to breathe in as slowly as possible just before operating the inhaler. Practise in front of a mirror for the first few times. If the patient sees "mist" coming from the top of the inhaler or the sides of the mouth the patient should start again from step 2.
The patient should consider getting a replacement when the counter shows the number 020. When the counter reads 000 the patient must replace it. Any puffs left in the device may not be enough to give the patient a full dose.
Never try to alter the numbers on the counter or detach the counter from the metal canister. The counter cannot be reset and is permanently attached to the canister.
If the doctor has given the patient different instructions for using the inhaler, please follow carefully. Tell the doctor if the patient has any difficulties.
Children: Young children may need help 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 two forefingers on the top of the inhaler and both thumbs on the base below the mouthpiece.
Caution: The metal canister is pressurised. Do not attempt to puncture it or burn even when empty.
If the inhaler becomes very cold, warm in the hand a few minutes before use. Never use other forms of heat.
Cleaning: The inhaler should be cleaned at least once a week.
1. Remove the mouthpiece cover.
2. Do not remove the canister from the plastic casing.
3. Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth, tissue or cottonbud.
4. Replace the mouthpiece cover.
DO NOT PUT THE METAL CANISTER INTO WATER.
Storage
Accuhaler: Store in a dry place.
Inhaler: Replace the mouthpiece cover firmly and snap it into position.
Protect from frost and direct sunlight.
As with most inhaled medications in pressurised canisters, the therapeutic effect of this medication may decrease when the canister is cold.
The canister should not be punctured, broken or burnt even when apparently empty.
ATC Classification
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.
Presentation/Packing
50/100 mcg Accuhaler 60 doses. 50/250 mcg Accuhaler 60 doses. 50/500 mcg Accuhaler 60 doses. 25/50 mcg Inhaler 120 doses. 25/125 mcg Inhaler 120 doses. 25/250 mcg Inhaler 120 doses.
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