Drug Class Description
Selective B2-agonist

Generic Name
Eformoterol fumarate

Drug Description
Each delivered dose (the dose that leaves the mouthpiece) contains: budesonide 80 micrograms/inhalation and formoterol fumarate dihydrate 4.5 micrograms/inhalation.Symbicort Turbohaler® 100 micrograms/6 micrograms/inhalation delivers the same amount of budesonide and formoterol as the corresponding Turbohaler monoproducts, i.e. budesonide 100 micrograms/inhalation (metered dose) and formoterol 6 micrograms/inhalation (metered dose) alternatively labelled as 4.5 micrograms/inhalation (delivered dose).Excipient: lactose monohydrate 810 micrograms per dose.

Presentation
Inhalation powder.White powder.

Indications
Symbicort Turbohaler is indicated in the regular treatment of asthma where use of a combination (inhaled corticosteroid and long-acting beta2-agonist) is appropriate: - patients not adequately controlled with inhaled corticosteroids and “as needed” inhaled short-acting beta2-agonists. or - patients already adequately controlled on both inhaled corticosteroids and long-acting beta2-agonists.Note: Symbicort Turbohaler (100 micrograms/6 micrograms/inhalation) is not appropriate in patients with severe asthma.

Adult Dosage
Symbicort Turbohaler is not intended for the initial management of asthma. The dosage of the components of Symbicort is individual and should be adjusted to the severity of the disease. This should be considered not only when treatment with combination products is initiated but also when the maintenance dose is adjusted. If an individual patient should require a combination of doses other than those available in the combination inhaler, appropriate doses of beta2-agonists and/or corticosteroids by individual inhalers should be prescribed.The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Patients should be regularly reassessed by their prescriber/health care provider so that the dosage of Symbicort remains optimal. When long-term control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone.For Symbicort there are two treatment approaches:A. Symbicort maintenance therapy: Symbicort is taken as regular maintenance treatment with a separate rapid-acting bronchodilator as rescue.B. Symbicort maintenance and reliever therapy: Symbicort is taken as regular maintenance treatment and as needed in response to symptoms.A. Symbicort maintenance therapyPatients should be advised to have their separate rapid-acting bronchodilator available for rescue use at all times.Recommended doses:Adults (18 years and older): 1-2 inhalations twice daily. Some patients may require up to a maximum of 4 inhalations twice daily.Adolescents (12 – 17 years): 1-2 inhalations twice daily.Children (6 years and older): 2 inhalations twice daily.In usual practice when control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include Symbicort given once daily, when in the opinion of the prescriber, a long-acting bronchodilator would be required to maintain control.Increasing use of a separate rapid acting bronchodilator indicates a worsening of the underlying condition and warrants a reassessment of the asthma therapy.Children under 6 years: Symbicort is not recommended for children under 6 years of age.B. Symbicort maintenance and reliever therapyPatients take a daily maintenance dose of Symbicort and in addition take Symbicort as needed in response to symptoms. Patients should be advised to always have Symbicort available for rescue use.Symbicort maintenance and reliever therapy should especially be considered for patients with :• inadequate asthma control and in frequent need of reliever medication• asthma exacerbations in the past requiring medical interventionClose monitoring for dose-related adverse effects is needed in patients who frequently take high numbers of Symbicort as-needed inhalations.Recommended doses:Adults (18 years and older): The recommended maintenance dose is 2 inhalations per day, given either as one inhalation in the morning and evening or as 2 inhalations in either the morning or evening. Patients should take 1 additional inhalation as needed in response to symptoms. If symptoms persist after a few minutes, an additional inhalation should be taken. Not more than 6 inhalations should be taken on any single occasion.A total daily dose of more than 8 inhalations is not normally needed; however, a total daily dose of up to 12 inhalations could be used for a limited period. Patients using more than 8 inhalations daily should be strongly recommended to seek medical advice. They should be reassessed and their maintenance therapy should be reconsidered.Children and adolescents under 18 years: Symbicort maintenance and reliever therapy is not recommended for children and adolescents.General informationSpecial patient groups:There are no special dosing requirements for elderly patients. There are no data available for use of Symbicort in patients with hepatic or renal impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.Instructions for correct use of Turbohaler:Turbohaler is inspiratory flow-driven, which means that when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways.Note: It is important to instruct the patient• to carefully read the instructions for use in the patient information leaflet which is packed together with each inhaler• to breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs• never to breathe out through the mouthpiece• to replace the cover of the Symbicort Turbohaler after use• to rinse their mouth out with water after inhaling the maintenance dose to minimise the risk of oropharyngeal thrush. If oropharyngeal thrush occurs, patients should also rinse their mouth with water after the as-needed inhalations.The patient may not taste or feel any medication when using Symbicort Turbohaler due to the small amount of drug dispensed.

Child Dosage
Adolescents (12 – 17 years):1-2 inhalations twice daily. Children (6 years and older): 2 inhalations twice daily. Patients should be regularly reassessed by a doctor, so that the dosage of Symbicort Turbohaler remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone. In usual practice when control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include Symbicort Turbohaler given once daily, when in the opinion of the prescriber, a long acting bronchodilator would be required to maintain control. Children under 6 years: Symbicort is not recommended for children under 6 years of age. Children (6 years and older): 2 inhalations twice daily. Patients should be regularly reassessed by a doctor, so that the dosage of Symbicort Turbohaler remains optimal. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. When control of symptoms is maintained with the lowest recommended dosage, then the next step could include a test of inhaled corticosteroid alone. In usual practice when control of symptoms is achieved with the twice daily regimen, titration to the lowest effective dose could include Symbicort Turbohaler given once daily, when in the opinion of the prescriber, a long acting bronchodilator would be required to maintain control.Children under 6 years: Symbicort is not recommended for children under 6 years of age.

Elderly Dosage
:There is no need to adjust the dose in elderly patients. There are no data available for use of Symbicort Turbohaler in patients with hepatic or renal impairment. As budesonide and formoterol are primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver cirrhosis.

Contra Indications
Hypersensitivity (allergy) to budesonide, formoterol or lactose (which contains small amounts of milk proteins).

Special Precautions
It is recommended that the dose is tapered when the treatment is discontinued and should not be stopped abruptly.If patients find the treatment ineffective, or exceed the highest recommended dose of Symbicort, medical attention must be sought. Sudden and progressive deterioration in control of asthma is potentially life threatening and the patient should undergo urgent medical assessment. In this situation consideration should be given to the need for increased therapy with corticosteroids e.g. a course of oral corticosteroids, or antibiotic treatment if an infection is present.Patients should be advised to have their rescue inhaler available at all times, either Symbicort (for patients using Symbicort as maintenance and reliever therapy) or a separate rapid-acting bronchodilator (for patients using Symbicort as maintenance therapy only).Patients should be reminded to take their Symbicort maintenance dose as prescribed, even when asymptomatic. The prophylactic use of Symbicort, e.g. before exercise, has not been studied. The reliever inhalations of Symbicort should be taken in response to asthma symptoms but are not intended for regular prophylactic use, e.g. before exercise. For such use, a separate rapid-acting bronchodilator should be considered.Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Symbicort. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Symbicort should be used.Patients should not be initiated on Symbicort during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.Serious asthma-related adverse events and exacerabations may occur during treatment with Symbicort. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation with Symbicort.As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. Symbicort should then be discontinued; treatment should be re-assessed and alternative therapy instituted if necessary.Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-eva luated with the aim of reducing the dose of inhaled corticosteroid. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition consideration should be given to referring the patient to a paediatric respiratory specialist.Limited data from long-term studies suggest that most children and adolescents treated with inhaled budesonide will ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment.Long-term studies with inhaled budesonide in children at mean daily doses of 400 micrograms (metered dose) or in adults at daily doses of 800 micrograms (metered dose) have not shown any significant effects on bone mineral density. No information regarding the effect of Symbicort at higher doses is available.If there is any reason to suppose that adrenal function is impaired from previous systemic steroid therapy, care should be taken when transferring patients to Symbicort therapy.The benefits of inhaled budesonide therapy would normally minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of impaired adrenal reserve for a considerable time. Patients who have required high dose emergency corticosteroid therapy in the past or prolonged treatment with high doses of inhaled corticosteroids,, may also be at risk. Additional systemic corticosteriod cover should be considered during periods of stress or elective surgery.To minimise the risk of oropharyngeal candida infection, the patient should be instructed to rinse their mouth out with water after inhaling the maintenance dose. If oropharyngeal thrush occurs, patients should also rinse their mouth with water after the as-needed inhalations.Concomitant treatment with itraconazole, ritonavir or other potent CYP3A4 inhibitors should be avoided. If this is not possible the time interval between administration of the interacting drugs should be as long as possible. In patients using potent CYP3A4 inhibitors, Symbicort maintenance and reliever therapy is not recommended.Symbicort should be administered with caution in patients with thyrotoxicosis, phaeochromocytoma, diabetes mellitus, untreated hypokalaemia, hypertrophic obstructive cardiomyopathy, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm or other severe cardiovascular disorders, such as ischaemic heart disease, tachyarrhythmias or severe heart failure.Caution should be observed when treating patients with prolongation of the QTc-interval. Formoterol itself may induce prolongation of the QTc-interval.The need for, and dose of inhaled corticosteroids should be re-eva luated in patients with active or quiescent pulmonary tuberculosis, fungal and viral infections in the airways.Potentially serious hypokalaemia may result from high doses of beta2-agonists. Concomitant treatment of beta2-agonists with drugs which can induce hypokalaemia or potentiate a hypokalaemic effect, e.g. xanthine-derivatives, steroids and diuretics, may add to a possible hypokalaemic effect of 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.As for all beta2-agonists, additional blood glucose controls should be considered in diabetic patients.Symbicort Turbohaler contains lactose (<1 mg/inhalation). This amount does not normally cause problems in lactose intolerant people. The excipient lactose contains small amounts of milk proteins, which may cause allergic reactions

Interactions
Pharmacokinetic interactionsThe metabolic conversion of budesonide is impeded by substances metabolized by CYP P450 3A4 (e.g. itraconazole, ritonavir). The concomitant administration of these potent inhibitors of CYP P450 3A4 may increase plasma levels of budesonide. The concomitant use of these drugs should be avoided unless the benefit outweighs the increased risk of systemic side-effects. In patients using potent CYP3A4 inhibitors, Symbicort maintenance and reliever therapy is not recommended.Pharmacodynamic interactionsBeta-adrenergic blockers can weaken or inhibit the effect of formoterol. Symbicort should therefore not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons.Concomitant treatment with quinidine, disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), monoamine oxidase inhibitors and tricyclic antidepressants can prolong the QTc-interval and increase the risk of ventricular arrhythmias.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 disposition towards arrhythmias in patients who are treated with digitalis glycosides.Budesonide and formoterol have not been observed to interact with any other drugs used in the treatment of asthma

Adverse Reactions
Since Symbicort Turbohaler contains both budesonide and formoterol, the same pattern of undesirable effects as reported for these substances may occur. No increased incidence of adverse reactions has been seen following concurrent administration of the two compounds. The most common drug related adverse reactions are pharmacologically predictable side-effects of beta2-agonist therapy, such as tremor and palpitations. These tend to be mild and usually disappear within a few days of treatment.Adverse reactions, which have been associated with budesonide or formoterol, are given below, listed by system organ class and frequency. Frequency 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).Cardiac disordersCommonPalpitationsUncommonTachycardiaRareCardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia, extrasystolesVery rareAngina pectorisEndocrine disordersVery rareSigns or symptoms of systemic glucocorticosteroid effects e.g. adrenal suppression, growth retardation, decrease in bone mineral density, cataract and glaucomaGastrointestinal disordersUncommonNauseaImmune system disordersRareImmediate and delayed hypersensitivity reactions, e.g. exanthema, urticaria, pruritus, dermatitis, angioedema and anaphylactic reactionInfections and infestationsCommonCandida infections in the oropharynxMetabolic and nutrition disordersRareHypokalemiaVery rareHyperglycemiaMusculoskeletal, connective tissue and bone disordersUncommonMuscle crampsNervous system disordersCommonHeadache, tremorUncommonDizzinessVery rareTaste disturbancesPsychiatric disordersUncommonAgitation, restlessness, nervousness, sleep disturbancesVery rareDepression, behavioural disturbances (mainly in children)Respiratory, thoracic and mediastinal disordersCommonMild irritation in the throat, coughing, hoarsenessRareBronchospasmSkin and subcutaneous tissue disordersUncommonBruisesVascular disordersVery rareVariations in blood pressureAs with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases.Treatment with beta2-agonists may result in an increase in blood levels of insulin, free fatty acids, glycerol and ketone bodies.

Manufacturer
Astra Zeneca

Drug Availability
(POM)

Updated
12 August 2009