Fluticasone propionate, formoterol fumarate.
Flutiform 125 microgram/5 microgram (fluticasone propionate 125 microgram and formoterol fumarate 5 microgram) per actuation pressurized inhalation.
Flutiform 250 microgram/10 microgram (fluticasone propionate 250 microgram and formoterol fumarate 10 microgram) per actuation pressurized inhalation.
Flutiform is available as a metered-dose inhaler containing a combination of fluticasone propionate (125 or 250 microgram) and formoterol fumarate (5 or 10 microgram) as an inhalation aerosol in the following strengths: 125/5 and 250/10. The aerosol cans are inserted into grey and white plastic dispensers with a light grey mouthpiece cover.
Each dosage strength contains 120 actuations per inhaler.
The canister contains white to off white liquid suspension. The canister is in a white actuator with a grey integrated dose indicator and a light grey mouthpiece cover.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic Effects: Flutiform inhaler contains both fluticasone propionate and formoterol fumarate. The mechanism of action described as follows for the individual components. These drugs represent two classes of medications (a synthetic corticosteroid and a long-acting selective beta2-adrenoceptor agonist).
Fluticasone propionate: Fluticasone propionate is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.
Formoterol fumarate: Formoterol fumarate is a long-acting selective beta2-adrenoceptor agonist with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. The onset of bronchodilating effect is rapid, within 1-3 minutes, and the duration of effect is at least 12 hours after a single dose.
Pharmacokinetics: Absorption: Fluticasone propionate: Following inhalation of a single 250 microgram dose of fluticasone propionate from 2 actuations of Flutiform 125 microgram/5 micrograms inhaler by healthy volunteers, fluticasone propionate was rapidly absorbed into the plasma, reaching a mean maximum plasma fluticasone concentration of 32.8 pg/mL within 45 minutes of inhalation. In asthma patients who received single doses of fluticasone propionate from Flutiform inhaler, mean maximum plasma concentrations of 15.4 pg/mL and 27.4 pg/mL were achieved within 20 minutes and 30 minutes for 100 microgram/ 10 microgram (2 actuations of Flutiform 50 microgram/5 microgram inhaler) and 250 microgram/10 microgram (2 actuations of Flutiform 125 microgram/5 microgram inhaler) doses respectively.
In multiple dose studies in healthy volunteers, Flutiform inhaler doses of 100 microgram/10 micrograms, 250 microgram/10 micrograms and 500 microgram/10 micrograms resulted in mean maximum plasma fluticasone concentrations of 21.4, 25.9 to 32.4 and 178 pg/mL respectively. The data for the 100 microgram/10 microgram and 250 microgram/ 10 microgram doses were generated by use of a device without a spacer and the data of the 500 microgram/20 microgram dose were generated by use of a device with a spacer. Use of an AeroChamber Plus spacer increases mean systemic (which equates to pulmonary absorption) bioavailability of fluticasone by 35% in healthy volunteers compared to administration of Flutiform inhaler via a pMDI alone.
Use of an AeroChamber Plus spacer decrease mean systemic bioavailability of formoterol by 25% in healthy volunteers compared to administration of Flutiform inhaler via a pMDI alone. This is likely to be due to a reduction in absorption from the gastrointestinal tract when the spacer is used, offsetting the expected corresponding increase in pulmonary absorption.
Formoterol fumarate: Following a single dose of Flutiform inhaler in healthy volunteers, a dose of 20 micrograms of formoterol fumarate from 2 actuations of Flutiform 250 microgram/10 microgram inhaler resulted in a mean maximum plasma formoterol concentration of 9.92 pg/mL within 6 minutes of inhalation. Following multiple doses, 20 micrograms of formoterol fumarate from 2 actuations of Flutiform 250 microgram/10 microgram inhaler resulted in a mean maximum of plasma formoterol concentration of 34.4 pg/mL.
Distribution: There is currently no plasma protein binding information specific to fluticasone propionate or formoterol fumarate from Flutiform inhaler.
Metabolism: There are currently no data relating to the metabolism of fluticasone propionate or formoterol fumarate specifically from the inhalation of Flutiform inhaler.
Elimination: Fluticasone propionate: Following inhalation of fluticasone propionate from 2 actuations of Flutiform 250 microgram/10 microgram inhaler, fluticasone propionate has a terminal elimination half-life of approximately 14.2 h.
Formoterol fumarate: Following inhalation of formoterol fumarate from 2 actuations of Flutiform 250 microgram/10 microgram inhaler, formoterol fumarate has a terminal elimination half-life of approximately 6.5 h. Less than 2% of a single dose of formoterol fumarate from Flutiform inhaler is excreted in the urine.
Flutiform inhaler is indicated in the regular treatment of asthma in patients 12 years of age and older, where the use of a combination product (an inhaled corticosteroid and a long-acting beta2 agonist) is appropriate.
For patients not adequately controlled with inhaled corticosteroids and 'as required' inhaled short-acting beta2 agonist, or for patients already adequately controlled on both and inhaled corticosteroid and a long-acting beta2 agonist.
Flutiform inhaler is for oral inhalation only.
Flutiform 50 microgram /5 microgram inhaler (for patients ≥12 years)-two inhalations (puffs) twice daily normally taken in the morning and in the evening. If the patient's asthma remains poorly controlled the total daily dose of the inhaled corticosteroid can be increased by administering a higher strength of this combination product-i.e. Flutiform 125 microgram/5 microgram inhaler-two inhalations (puffs) twice daily.
For adults only: The total daily dose can be further increased if asthma remains poorly controlled by administering the highest strength of this combination product - i.e. Flutiform 250 microgram/10 microgram inhaler – two inhalations (puffs) twice daily. This highest strength is for use in adults only; it should not be used in adolescents aged 12 years and above.
Children under 12 years: Flutiform should not be used in this young age group. No data are available for this strength of Flutiform inhaler in children. Experience in children under the age of 12 year is limited. Flutiform inhaler in any strength is not recommended for use in children less than 12 years of age.
Mode of Administration: To ensure proper administration of the drug, the patient should be shown how to use the inhaler correctly by a physician or other health professionals. The correct use of the pressurized metered dose inhaler (pMDI) is essential for successful treatment. The patient should follow the instructions for use.
The actuator has an integrated dose indicator (counter) which counts down the number of actuations (puffs) remaining. When this is getting near to zero the patient should be advised to contact their prescriber for a replacement inhaler. The inhaler must not be used after the counter read "0".
Priming the inhaler: Before using the inhaler for the first time, or if the inhaler has not been used for 3 days or more, or after exposure of the freezing or refrigerated conditions the inhaler must be primed before use: Remove the mouthpiece cover and shake the inhaler well.
Actuate (puff) the inhaler whilst pointing it away from the face. This step must be performed 4 times.
The inhaler should always be shaken immediately before use.
Whenever possible patients should stand or sit in an upright position when inhaling from the inhaler.
Steps to follow when using the inhaler: Remove the mouthpiece cover and check that the mouthpiece is clean, and free from dust and dirt. The inhaler should be shaken immediately before releasing each actuation (puff).
Breathe out as far as is comfortable and as slowly and deeply as possible.
Hold the canister vertically with its body upwards and put the lips around the mouthpiece. Hold the inhaler upright with a thumb(s) on the base of the mouthpiece and a forefinger/index finger(s) on the top of the inhaler. Do not bite the mouthpiece.
At the same time, breathe in slowly and deeply through the mouth. After starting to breathe in press down on the top of the inhaler to release one actuation (puff) and continue to breathe in steadily and deeply.
Patients should continue to hold their breath for as long as is comfortable (optimally about 10 seconds), then breathe out slowly. Do not breathe out into the inhaler.
Keep the inhaler in a vertical position for about half a minute, shake the inhaler, and repeat steps 2 to 5. After use, replace the mouthpiece cover.
IMPORTANT: Do not perform steps 2 to 5 too quickly.
Patients may be advised to practice their technique in front of a mirror. If a mist appears following inhalation, either from the inhaler or from the sides of the mouth, the procedure should be repeated from the 2nd step mentioned previously.
For patients with weak hands, it may be easier to hold the inhaler with both hands. Therefore the index fingers should be placed on the top of the inhaler canister and both thumbs on the base of the inhaler.
Patients should rinse their mouth, gargle with water or brush the teeth after inhaling and spit out the residue to minimize the risk of oral candidiasis or dysphonia.
Cleaning: The inhaler should be cleaned once a week.
Remove the mouth piece 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 or tissue.
Replace the mouthpiece cover in the correct orientation.
Do not put the metal canister into water.
Flutiform contains both fluticasone propionate and formoterol fumarate; therefore, the risks associated with overdosage for the individual components are given as follows.
Formoterol fumarate: An overdose of formoterol would likely lead to an exaggeration of effects that are typical for beta2-agonists: angina, hypertension or hypotension, palpitations, tachycardia, arrhythmia, prolonged QT-interval, headache, tremor, nervousness, muscle cramps, dry mouth, insomnia, fatigue, malaise, seizures, metabolic acidosis, hypokalemia, hyperglycaemia, nausea and vomiting.
Treatment of formoterol overdose consists of discontinuation of the medication together with institution of appropriate symptomatic and/ or supportive therapy. The judicious use of cardio selective beta receptor blockers may be considered, bearing in mind that such medication can induce bronchospasm. There is insufficient evidence to determine if dialysis beneficial in cases of formoterol overdose. Cardiac monitoring is recommended in cases of overdosage.
Fluticasone propionate: The potential for acute toxic effect following overdose of fluticasone is low. The only harmful effect after inhalation of a large amount of the drug over a short period is suppression of hypothalamic pituitary adrenocortical (HPA) axis function. HPA axis function usually recovers in a few days.
In the management of chronic overdose oral or systemic corticosteroids may be required in situations of stress. All patients deemed to be chronically overdosed should be treated as if steroid dependent with a suitable maintenance dose of a systemic corticosteroid.
Hypersensitivity to any of the active substances or to any of the excipients.
The management of asthma should normally follow a stepwise programme and patients' responses should be monitored clinically and by lung function tests. Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Flutiform inhaler. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Flutiform inhaler should be used.
Patients should be reminded to take their Flutiform inhaler maintenance dose as prescribed, even when worsening or acutely deteriorating asthma. Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should undergo urgent medical assessment. The patient should also be medically reviewed when the current dosage of Flutiform inhaler has failed to give adequate control of asthma. Consideration should be given to additional corticosteroid therapies.
Serious asthma-related adverse events and exacerbations may occur during treatment with Flutiform inhaler. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Flutiform inhaler.
The prophylactic use of Flutiform inhaler in exercise-induced asthma has not been studied. For such use, a separate rapid-acting bronchodilator should be considered. Flutiform inhaler should be used with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, uncorrected hypokalemia or patients predisposed to low levels of serum potassium, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, cardiac arrhythmias or severe heart failure.
Potentially serious hypokalaemia may result from high doses of beta2-agonist. Concomitant treatment of beta2-agonist with drugs which can introduce hypokalaemia or potentiate a hypokalaemic effect, e.g. xanthine derivatives, steroids and diuretics, may add to a possible hypokalaemic effect to the beta2-agonist. Particular caution is recommended in unstable asthma with variable use of rescue bronchodilators, in acute severe asthma as the associated risk may be augmented by hypoxia and in other conditions when the likelihood for hypokalaemia adverse effects is increased. It is recommended that serum potassium levels are monitored during these circumstances.
Caution must be observed when treating patients with existing prolongation of the QTc interval. Formoterol itself may induce prolongation of the QTc interval.
As for all beta2-agonist, additional blood sugar controls should be considered in diabetic patients.
Administration of Flutiform inhaler is not recommended during pregnancy, and should only be considered if expected benefit to the mother is greater than any possible risk to the fetus. If this is the case, then the lowest effective dose needed to maintain adequate asthma control should be used. Because of the potential for beta agonist interference with uterine contractility, use of Flutiform inhaler for management of asthma during labour should be restricted to those patients in whom the benefit outweighs the risks. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Flutiform inhaler therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Uncommon side effects (probably affecting less than 1 in 100 people using the inhaler) include the followings: hyperglycaemia, worsening of asthma, headache, tremor, dizziness, palpitation, changes in taste or alteration in voice, dry mouth, sore throat, and peripheral edema.
Rare side effects (probably affecting less than 1 in 1,000 people using this inhaler) include the followings: oral candidiasis, acute sinusitis, abnormal dreams or insomnia, tachycardia, angina pectoris, muscle spasms, coughing or shortness of breath, diarrhoea, dyspepsia, vertigo, rash, hypertension, and asthenia.
There is an increased risk of systemic side effects when combining fluticasone propionate with potent CYP3A4 inhibitors (e.g. ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nelfinavir, saquinavir, ketoconazole, telithromycin). The caution needs to be taken in long-term treatment and co-administration with such drugs should be avoided if possible. Particularly co-medication of ritonavir should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side-effects. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing's syndrome and adrenal suppression have been reported.
The ECG changes and/or hypokalaemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta agonist, especially when the recommended dose of beta agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of a beta agonist with non-potassium sparing diuretics. Xanthine derivatives and glucocorticosteroids may add to a possible hypokalaemic effect of the beta agonists.
In addition L-Dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2 sympathomimetics.
Concomitant treatment with monoamine oxidase inhibitors, including agents with similar properties such as furazolidone and procarbazine, may precipitate hypertensive reactions.
There is an elevated risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.
Concomitant use of other beta adrenergic drugs can have a potentially additive effect.
Hypokalaemia may increase the risk of arrhythmias in patients who are treated with digitalis glycosides.
Formoterol fumarate, as with other beta2-agonist, should be administered with extreme caution to patients being treated with tricyclic antidepressants or monoamine oxidase inhibitors, and during the immediate two week period following their discontinuation, or other drugs known to prolong the QTc interval such as antipsychotics (including phenothiazines), quinidine, disopyramide, procainamide, and antihistamines. Drugs that are known to prolong the QTc interval can increase the risk of ventricular arrhythmias.
Store below 30°C. Do not refrigerate or freeze. Do not use the inhaler if it has been removed from the foil pouch for more than 3 months.
R03AK11 - formoterol 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.
125 mcg/5 mcg MDI (pressurized inhalation, white to off-white liquid suspension) 120 doses. 250 mcg/10 mcg MDI (pressurized inhalation, white to off-white liquid suspension) 120 doses.