Agencia Lei Va Hong
Full Prescribing Info
Fluticasone propionate.
FLIXOTIDE Inhaler is a range of pressurised metered-dose inhalers in three strengths.
FLIXOTIDE inhaler 50 mcg / actuation delivers 50 mcg of fluticasone propionate per inhalation.
FLIXOTIDE inhaler 125 mcg / actuation delivers 125 mcg of fluticasone propionate per inhalation.
FLIXOTIDE inhaler 250 mcg / actuation delivers 250 mcg of fluticasone propionate per inhalation.
FLIXOTIDE inhaler contains the CFC-free propellant HFA 134a.
Pharmacology: Pharmacodynamics: FLIXOTIDE given by inhalation at recommended doses has potent glucocorticoid activity in the airway. The potent anti-inflammatory action improves the symptomatic control of asthma, allows reduction of other drugs, such as rescue bronchodilators, and may limit the risk of decline in lung function over time. The low systemic bioavailability of FLIXOTIDE provides a better risk: benefit outcome without the adverse effects that accompany systemically administered corticosteroids.
Pharmacokinetics: Following inhaled doses of 2000mcg per day (1000mcg twice daily) for 14 days in healthy volunteers, peak plasma concentrations of about 0.3ng/mL were observed at 30-60 minutes post-dosing.
Absorption: The absolute bioavailability of fluticasone propionate for each of the available inhaler devices has been estimated from within and between study comparisons of inhaled and intravenous pharmacokinetic data based on AUC(0-infinity) data. In healthy adult subjects the absolute bioavailability has been estimated for FLIXOTIDE Inhaler (10.9%). Since the bioavailability of the swallowed portion of an inhaled dose which reaches the gastrointestinal tract is virtually zero, the systemic absorption would be a reflection of the amount of drug reaching the lungs.
FLIXOTIDE has many pharmacokinetic and pharmacodynamic features similar to those of other inhaled glucocorticoids used for the treatment of asthma. However, in contrast to these other steroids, a combination of incomplete gastrointestinal absorption and high first pass metabolic extraction ensures that virtually no FLIXOTIDE swallowed after oral inhalation reaches the systemic circulation.
Metabolism: In animals and humans, propellant HFA-134a was eliminated rapidly in the breath, with no evidence of metabolism or accumulation in the body. Time to maximum plasma concentration (tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.
Distribution: Following intravenous administration, the pharmacokinetics of FLIXOTIDE are proportional to the dose. FLIXOTIDE is extensively distributed within the body. The volume of distribution at steady state is approximately 300 litres and has a very high clearance which is estimated to be 1.1 litre/minute indicating extensive hepatic extraction. Peak plasma fluticasone propionate concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations are associated with the terminal half-life, which is approximately 8 hours.
Excretion: Studies with radiolabelled and unlabelled FLIXOTIDE administered orally to human volunteers indicate that the majority of the dose (87%-100%) is excreted in the faeces, with up to 75% as unchanged drug, depending on the dose administered. Between 1% and 5% of the dose is excreted as metabolites in urine.
Single oral doses of 16mg in healthy volunteers produced plasma levels of less than 0.5ng/mL.
Single intravenous doses of 2mg in healthy volunteers revealed that the clearance of FLIXOTIDE approximates liver blood flow (900ml/min), with renal clearance (0.11mL/min) accounting for less than 1%. These results indicate that hepatic extraction is almost complete and that oral bioavailability is close to zero.
FLIXOTIDE has a marked anti-inflammatory effect in the lungs. It reduces symptoms and exacerbations of asthma in patients previously treated with bronchodilator alone or with other prophylactic therapy.
Adults and adolescents 16 years of age and older: Prophylactic management in: Mild asthma: Patients requiring intermittent symptomatic bronchodilator asthma medication on more than an occasional basis.
Moderate asthma: Patients requiring regular asthma medication and patients with unstable or worsening asthma on currently available prophylactic therapy or bronchodilator alone.
Severe asthma: Patients with severe chronic asthma. On introduction of inhaled fluticasone propionate many patients who are dependent on systemic corticosteroids for adequate control of symptoms may be able to reduce significantly or to eliminate their requirement for oral corticosteroids.
Children 12 months of age and older: Any child who requires preventive asthma medication, including patients not controlled on currently available prophylactic medication.
Dosage/Direction for Use
FLIXOTIDE is for administration by oral inhalation only. It is intended that each prescribed dose is given by a minimum of 2 inhalations.
In patients who find coordination of a pressurised metered-dose inhaler difficult, a spacer may be used with FLIXOTIDE Inhaler.
Patients should be made aware of the prophylactic nature of therapy with inhaled FLIXOTIDE and that it should be taken regularly even when they are asymptomatic. The onset of therapeutic effect is within 4 to 7 days.
If patients find that relief with short-acting bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought.
The dosage of fluticasone propionate should be adjusted according to the individual response.
Adults and adolescents 16 years of age and older: 100 to 1000 micrograms twice daily.
Patients should be given a starting dose of inhaled FLIXOTIDE which is appropriate for the severity of their disease: Mild asthma: 100 to 250 micrograms twice daily.
Moderate asthma: 250 to 500 micrograms twice daily.
Severe asthma: 500 to 1000 micrograms twice daily.
The dose may then be adjusted until control is achieved or reduced to the minimum effective dose, according to the individual response.
Children 4 to <16 years of age: 50 to 200 micrograms twice daily.
It should be noted that only the 50 microgram device is suitable for the administration of this dose.
Many children's asthma will be well controlled using the 50 to 100 micrograms twice daily dosing regime. For those patients whose asthma is not sufficiently controlled, additional benefit may be obtained by increasing the dose up to 200 micrograms twice daily.
Children should be given a starting dose of inhaled FLIXOTIDE which is appropriate for the severity of their disease. The dose may then be adjusted until control is achieved or reduced to the minimum effective dose according to the individual response.
This presentation of FLIXOTIDE may not offer the required paediatric dose, in which case an alternative presentation of FLIXOTIDE should be considered (e.g dry powder inhalers).
Children 12 months to 4 years of age: 100 micrograms twice daily administered via a paediatric spacer device with a face mask.
Inhaled FLIXOTIDE is of benefit to younger children in the control of frequent and persistent asthma symptoms.
Clinical trials in 1 to 4 year old children have shown that the optimal control of asthma symptoms is achieved with 100 micrograms twice daily. Higher doses of inhaled drug are required in younger children compared to older children because of reduced efficiency of drug delivery due to smaller airways, use of a spacer device and increased nasal breathing.
The diagnosis and treatment of asthma should be kept under regular review.
Special patient groups: There is no need to adjust the dose in elderly patients or in those with hepatic or renal impairment.
Acute inhalation of FLIXOTIDE 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 are continued over prolonged periods, significant adrenocortical suppression is possible. There have been very rare reports of acute adrenal crisis occurring in children exposed to higher than approved doses (typically 1000 micrograms daily and above), over prolonged periods (several months or years); Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased level of consciousness, hypoglycaemia, and seizures. Situations which could potentially trigger acute adrenal crisis include exposure to trauma, surgery, infection or any rapid reduction in dosage. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.
It is not recommended that patients receive higher than approved doses. It is important to review therapy regularly and titrate down to the lowest dose at which effective control of disease is maintained (see Dosage & Administration).
FLIXOTIDE is contra-indicated in patients with a history of hypersensitivity to any ingredient of the preparation (see Description).
Special Precautions
The management of asthma should follow a stepwise programme, and patient response should be monitored clinically and by lung function tests. Increasing use of short-acting inhaled beta-2 agonists to control symptoms indicates deterioration of asthma control. Under these conditions, the patient's therapy plan should be reassessed. Sudden and progressive deterioration in asthma control is potentially life-threatening and consideration should be given to increasing corticosteroid dosage. In patients considered at risk, daily peak flow monitoring may be instituted.
Lack of response or severe exacerbations of asthma may be an indication for review of the patient. Treatment options may include increasing the dose of inhaled FLIXOTIDE and, if necessary, by giving a systemic steroid and/or an antibiotic if there is an infection.
FLIXOTIDE is not for use in acute asthma attacks, but for routine long-term management. Patients will require a fast- and short-acting inhaled bronchodilator to relieve acute asthmatic symptoms.
Treatment with FLIXOTIDE should not be stopped abruptly.
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.
As with all inhaled corticosteroids, special care is necessary in patients with active or quiescent pulmonary tuberculosis.
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 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 (see Interactions).
As with other inhalation therapy, paradoxical bronchospasm may occur rarely, with an immediate increase in wheezing after dosing. This should be treated immediately with a fast and short-acting inhaled bronchodilator. FLIXOTIDE should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted if necessary.
Patients' inhaler technique should be checked to make sure that inhaler actuation is synchronised with inspiration to ensure optimum delivery of the drug to the lungs.
Spacer Devices: Most patients will benefit from the consistent use of a spacer device with their metered dose inhaler (MDI), particularly those with poor inhaler technique. Use of a spacer will also decrease the amount of drug deposited in the mouth and back of the throat, and therefore reduce the incidence of local side effects such as 'thrush' and a hoarse voice.
A change in the make of spacer may be associated with alterations in the amount of drug delivered to the lungs. The clinical significance of these alterations is uncertain. However, in these situations, the person should be monitored for any loss of asthma control.
If using a spacer, the patient should be instructed to actuate the inhaler into the spacer and then slowly breathe in as far as possible. Hold the breath for as long as comfortable, before breathing out slowly. This should be repeated for each actuation of the drug into the spacer. Any delays between actuation and inhalation should be kept to a minimum.
Static on the walls of the spacer may cause variability in drug delivery. Patients should be instructed to wash the spacer in warm water and detergent and allow it to air dry without rinsing or drying with a cloth. This should be performed before initial use of the spacer and at least monthly thereafter.
Possible systemic effects, including Adrenocortical function, Bone density and Growth: Inhaled steroids are designed to direct glucocorticoid delivery to the lungs in order to reduce overall systemic glucocorticoid exposure and side effects. With sufficient doses however, all inhaled steroids can have adverse effects; possible systemic effects include Cushing's syndrome, Cushingoid features, depression of the hypothalamic-pituitary adrenal (HPA) axis, reduction of bone density, retardation of growth rate, cataract and glaucoma (see Overdosage).
The lowest doses of inhaled corticosteroids that cause suppression of the HPA axis (as indicated by the 24 hour urinary cortisol concentrations), effects on bone mineral density or growth retardation in children has not yet been established. Some depression of plasma cortisol may occur in a small number of adult patients receiving inhaled FLIXOTIDE at recommended and higher doses but it is not possible to predict which patients are at risk based solely on dose, previous history or length of exposure to inhaled or oral steroids. Adrenal function and adrenal reserve usually remain within normal range on inhaled FLIXOTIDE therapy. To minimise the systemic effects of orally inhaled corticosteroids, including FLIXOTIDE, each patient should be titrated down to the lowest dose that effectively controls his/her asthma (see Dosage & Administration).
Medical Emergency: Patients in a medical or surgical emergency, who in the past have required high doses of other inhaled steroids and/or intermittent treatment with oral steroids, remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled FLIXOTIDE. The extent of the adrenal impairment may require specialist advice before elective procedures. The possibility of residual impaired adrenal response should always be borne in mind in emergency and elective situations likely to produce stress and appropriate corticosteroid treatment must be considered (see Overdosage).
Transfer of patients being treated with oral corticosteroids: Because of the possibility of impaired adrenal response, patients transferring from oral steroid therapy to inhaled FLIXOTIDE therapy should be treated with special care and adrenocortical function regularly monitored.
Following introduction of inhaled FLIXOTIDE, withdrawal of systemic therapy should be gradual and patients whose adrenocortical function is still impaired should carry a steroid warning card indicating that they may need supplementary systemic steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.
In rare cases inhaled therapy may unmask underlying eosinophilic conditions (e.g. 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.
Similarly, replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.
Effects on ability to drive and use machines: FLIXOTIDE is unlikely to produce an effect.
Use in Children: The growth of paediatric patients receiving corticosteroids, including FLIXOTIDE, should be monitored. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained.
In children taking recommended doses of inhaled FLIXOTIDE, adrenal function and adrenal reserve usually remain within the normal range. However, the possible effects of previous or intermittent treatment with oral steroids should not be discounted. Nevertheless, the benefits of inhaled FLIXOTIDE should minimise the need for oral steroids.
Use In Pregnancy & Lactation
Effects on Fertility: There are no data on human fertility. No effects of FLIXOTIDE on male or female fertility were observed in rats at subcutaneous doses up to 50 μg/kg/day.
Use in Pregnancy: There are limited data in pregnant women. Administration of FLIXOTIDE during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
An observational retrospective epidemiological cohort study utilising electronic health records from the United Kingdom was conducted to evaluate the risk of major congenital malformations (MCMs) following first trimester exposure to inhaled fluticasone propionate alone and salmeterol-fluticasone propionate combination relative to non-fluticasone propionate containing inhaled corticosteroids. No placebo comparator was included in this study.
Within the asthma cohort of 5,362 first trimester inhaled corticosteroid-exposed pregnancies, 131 diagnosed MCMs were identified: 1,612 (30%) were exposed to fluticasone propionate or salmeterol-fluticasone propionate of which 42 diagnosed MCMs were identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5 - 2.3) for fluticasone propionate exposed vs non-fluticasone propionate inhaled corticosteroid exposed women with moderate asthma and 1.2 (95%: 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 fluticasone propionate alone versus salmeterol-fluticasone propionate combination. Absolute risks of MCM across the asthma severity strata ranged from 2.0 to 2.9 per 100 fluticasone propionate-exposed pregnancies which is comparable to results from a study of 15,840 pregnancies unexposed to asthma therapies in the General Practice Research Database (2.8 MCM events per 100 pregnancies).
Results from the retrospective epidemiological study did not find an increased risk of MCMs following exposure to fluticasone propionate when compared to other inhaled corticosteroids, during the first trimester of pregnancy.
There was no evidence of mutagenic or clastogenic activity for fluticasone propionate in the standard battery of genotoxicity assays.
Use in Lactation: The excretion of fluticasone propionate into human breast milk has not been investigated. When measurable plasma levels were obtained in lactating laboratory rats following subcutaneous administration there was evidence of fluticasone propionate in the milk. However plasma levels in patients following inhaled application of fluticasone propionate at recommended doses are likely to be low.
However, the amount of fluticasone propionate ingested by the newborn is estimated to be very small as a consequence of very low maternal plasma concentration of fluticasone propionate.
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
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) including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data.
Infections and infestations: Very common: Candidiasis (thrush) of mouth and throat.
Candidiasis of the mouth and throat (thrush) occurs in some 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 FLIXOTIDE.
Rare: Oesophageal candidiasis.
Immune system disorders: Hypersensitivity reactions with the following manifestations have been reported: Uncommon: Cutaneous hypersensitivity reactions.
Rare: Angioedema (mainly facial and oropharyngeal oedema), respiratory symptoms (dyspnoea and/or bronchospasm).
Very rare: Anaphylactic reactions.
Skin and subcutaneous tissue disorders: Common: Contusions.
Endocrine disorders: Possible systemic effects include (see Precautions): Rare: Adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma.
There have also been reports of Cushing's syndrome and Cushingoid features.
Psychiatric disorders: Very rare: Anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability (predominantly in children).
Metabolism and nutrition disorders: Very rare: Hyperglycaemia.
Respiratory, thoracic and mediastinal disorders: Common: Hoarseness.
In some patients FLIXOTIDE may cause hoarseness. It may be helpful to rinse out the mouth with water immediately after inhalation.
Rare: Paradoxical bronchospasm (see Precautions).
In two studies in children from ages 1- 4, fluticasone propionate 50 mcg b.d., 100 mcg b.d. and 250 mcg b.d. was as well tolerated as placebo. In these studies, skin rash, allergic skin reactions, throat irritation, nasal irritation, epistaxis, hoarseness/dysphonia, and candidiasis of the mouth/throat were reported at frequencies between 0% and 5%. There were no significant differences in incidence of these occurrences between groups.
Drug Interactions
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 FLIXOTIDE 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 cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving FLIXOTIDE and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, concomitant use of FLIXOTIDE 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.
Caution For Usage
Instructions for Use/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: 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 down on the top of the inhaler to release FLIXOTIDE 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 further puffs, keep the inhaler upright and wait about half a minute before repeating steps 3 to 7.
9. Replace the mouthpiece cover by firmly pushing and snapping the cap into position.
Important: Do not rush steps 5, 6 and 7. It is important to start to breathe in as slowly as possible just before operating the inhaler. Practise in front of a mirror for the first few times. If "mist" is seen coming from the top of the inhaler or the sides of the mouth, the procedure should be started again from step 2.
If the doctor has given different instructions for using the inhaler, please follow them carefully. Tell the doctor if the patient has any difficulties.
After using the inhaler, rinse the mouth with water and spit it out.
Children: Young users of FLIXOTIDE inhaler may need assistance. Parents of toddlers must practice using the inhaler, encouraging the child to breathe out and then releasing FLIXOTIDE at the exact moment of inhalation.
Patients with weak hands should use the inhaler with both hands - the two forefingers on the top and both thumbs beneath the mouthpiece.
Caution: The metal canister is pressurized. Do not attempt to puncture it or burn even when empty.
It is dangerous to exceed the recommended dose.
If the inhaler becomes very cold, remove the metal canister and 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. Pull the metal canister out of the plastic casing of the inhaler and remove the mouthpiece cover.
2. Wipe the plastic casing and mouthpiece with a damp cloth.
3. Leave to dry in a warm place. Avoid excessive heat.
4. Replace the canister and mouthpiece cover.
Do not put the metal canister into water.
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
R03BA05 - fluticasone ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, glucocorticoids.
Inhaler (CFC-free) 50 mcg/actuation x 120 actuations. 125 mcg/actuation x 60 actuations. 250 mcg/actuation x 120 actuations.
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