Treatment of mild, moderate, and severe persisten asthma

Posology should be adjusted according to the the single patient and relating to severity and therapy phase.When transferring a patient to Budiair from other inhalaition devices, the treatment should be individualised. The previous active substance, dose regimen, and method of delivery should be considered.

Adultsand adolescents: in case of severe asthma, at the start of therapy with inhaled corticosteroids or when reducing or withdrawing oral corticosteroid therapy, the recommended dosage is 200 micrograms (1 puff) 2-4 times daily. During the period of severe asthma the daily dosage can be increased up to 1600 mcg maximum. The maintenance dose is individual, and should be the minimum one exerting therapeutic effect: one inhalation per day (200 mcg) is generally sufficient. Chidrenfrom 6 to 1 2 years of age: generally 200 micrograms (one puff) daily. If necessary, dosage can be increased up to 400 mcg daily. The limit age depends on the possibility of properly using the product. The dose should be reduced to the minimum needed to maintain good asthma controlPatients not treated with corticosteroids: the therapeutic effect of budesonide generally occurs within 10 days from the therapy start; however, for patients with abundant bronchial secretion, to such an extent as to prevent mucosal absorption of the active ingredient, a concomitant treatment (about two weeks) with oral corticosteroids is recommended. Start with full dosage, then gradually reduce it up to the maintenance dose with Budiair only. Asthma exacerbations due to bacterial infections should be treated with antibiotics and by increasing the posology of Budiair.Patients treated with corticosteroids: switch from oral corticosteroidal therapy to treatment with Budiair requires special attention, due to the slow reactivation of those hypothalamic function, impaired by the prolonged oral corticosteroidal therapy. The patient should be relatively stabilised before starting therapy with Budiair. Budiair should be administered for about 10 days while continuing the oral therapy; then, this should be gradually reduced, up to the minimum dose that, combined with Budiair, gives a stable outcome. In most cases it is possible to totally withdraw the oral therapy, whilst in some subjects it will be necessary to maintain the treatment with a minimal dose of oral corticosteroids. However, in some cases, when switching from oral therapy to treatment with Budiair, the systemic steroidal effect may decrease, with occurrence of rhinitis, eczema, headache, muscular and articular pain, and, seldom, nausea and vomiting. Should these events occur, the physician will evaluate the opportunity to maintain the inhalation therapy. It might take long to recover the physiological production of natural corticosteroids, and under some conditions, such as physical stress due to severe infections, injuries or surgery, it may be necessary to combine Budiair with oral corticosteroid therapy. Even in case of asthma growing acute again, especially if associated with increase of viscosity and formation of mucus plugs, it may be necessary to adopt a concomitant short-term treatment with oral steroids. It is of utmost importance for the patient to follow the prescribed instructions for use.

Method of AdministrationFor use, perform the following operations:STANDARD-ACTUATOR PACKAGEThe successful result of treatment depends on a correct use of the inhaler.Inhaler’s working test: before using the inhaler for the first time, or if it has not been used for three days or more, remove the mouthpiece protective cap by softly pressing it on its sides and press once in the air to release a blank actuation, in order to to verify the correct working of the inhaler.For use, carefully follow the following instructions:1. hold the actuator between thumb and index, with the mouthpiece downwards;2. remove the protecting cap;3. breathe out completely and place the mouthpiece firmly between the lips;4. make a long and deep inspiration with the mouth only and, at the same time press once only with the index.Once the inspiration is complete, hold breath as long as possible.When inhalations are completed, close the mouthpiece again with the protecting cap. The mouthpiece should always be kept clean. Cleaning should be made by rinsing it under lukewarm water, after removal of the pressurised canister.Administration in children should be supervised by an adult person. It is useful to close the child's nostrils during inhalation.JET ACTUATOR-SPACER PACKAGEFor use, carefully follow the following instructions:1. JET in closed position2. Remove the protecting cap from the JET and hold it as shown in the picture3. Breathe out completely, then place the mouthpiece firmly between the well closed lips4. Press the canister with the index finger and deeply inhale, even after a few seconds (it is possible to make several breaths through the Jet actuator)5. Once inhaled, hold breath as long as possible and close the Jet again with its protecting cap6. The Jet actuator has to be kept clean: rinse it under lukewarm water, after removal of the pressurised canister

Budiair is not indicated for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required. Patients should be properly instructed about the correct use of the inhaler.Budiair provides a prophylactic therapy of the asthmatic disease: it should therefore be administered regularly at the prescribed doses as long as directed by the physician and should not be stopped abruptly. In case of gastrointestinal ulcer, strict medical surveillance is advisable throughout therapy duration

The transfer of patients treated with oral corticosteroids to the inhaled corticosteroid and their subsequent management requires special care. The patients should be in a reasonably stable state before initiating a high dose of inhaled corticosteroid in addition to their usual maintenance dose of systemic corticosteroid. (see also Section 4.2 Posology and Method of Administration). After about 10 days, withdrawal of the systemic corticosteroid is started by reducing the daily dose gradually to the lowest possible level. It may be possible to completely replace the oral corticosteroid with inhaled corticosteroid. Transferred patients whose adrenocortical function is impaired may need supplementary systemic corticosteroid during periods of stress. During transfer from oral therapy to inhaled budesonide symptoms may appear that had previously been suppressed by systemic treatment with glucocorticosteroids, with occurrence of rhinitis, eczema, headache, muscular and articular pain, and, rarely, of nausea and vomiting. Specific treatment should be co-administered to treat these conditions.Some patients may feel unwell in a non-specific way during the withdrawal of systemic corticosteroids despite maintenance or even improvement in respiratory function. Such patients should be encouraged to continue treatment with inhaled budesonide and withdrawal of oral corticosteroid unless there are clinical signs to indicate the contrary, for example signs which might indicate adrenal insufficiency

Patients, who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery. As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If this occurs, treatment should be discontinued immediately, the patient assessed and an alternative therapy instituted if necessary.When despite a well monitored treatment, an acute episode of dyspnoea occurs, a rapid-acting inhaled bronchodilator should be used and medical reassessment should be considered. If despite maximum doses of inhaled corticosteroids asthma symptoms are not adequately controlled, patients may require short-term treatment with systemic corticosteroids.Systemic effects of inhaled corticosteroid may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur with inhaled than with oral corticosteroids. 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 and more rarely, a range of psycological or behavioural effects inlcuding psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).Therefore, it is important that the patient is reviewed regularly, and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.Vary rare cases of acute adrenal crisis occurred in young patients exposed to doses higher than those recommended (about 1000 mcg/day) for prolonged periods (several months or years). Adrenal insufficiency symptoms are initially aspecific and include: anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting; specific symptoms occurring with inhaled corticosteroid also include hypoglicemia with impaired consciousness and/or convulsions. Situations that might potentially determine an adrenal crisis are: traumas,

surgery, infections and rapid reduction of dosage. Patients receiving high doses should be strictly monitored and their dose gradually reduced. Monitoring of adrenal reserve may also be necessary.It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. In case of growth retardation, therapy should be reviewed in order to reduce the glucocorticoid dosage to the lowest possible dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.Patients who have previously been dependent on oral corticosteroids may, as a result of prolonged systemic corticosteroid therapy, experience effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral corticosteroid therapy and hence oral steroid-dependent patients transferred to budesonide may remain at risk from impaired adrenocortical function for some considerable time. In such circumstances hypothalamic pituitary adrenocortical (HPA) axis function should be monitored regularly Oral candidiasis may occur during the therapy with inhaled corticosteroids. This infection may require treatment with appropriate antifungal therapy and in some patients discontinuation of treatment may be necessary (see also section 4.2).To reduce the risk of oral candidiasis and hoarseness patients should be advised to rinse out the mouth properly or brush the teeth after each administration of inhaled corticosteroid.Exacerbation of clinical symptoms of asthma may be due to acute respiratory tract bacterial infections and treatment with appropriate antibiotics may be required. Such patients may need to increase the dose of inhaled budesonide and a short course of oral corticosteroids may be required. A rapid-acting inhaled bronchodilator should be used as “rescue” medication to relieve acute asthma symptoms.Special caution is necessary in patients with active and quiescent pulmonary tuberculosis and in patients with fungal, viral or other infections in the airways.. In patients with excessive mucous secretion in the respiratory tract, short-term therapy with oral corticosteroids may be necessary.Reduced liver function affects the elimination of corticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects. HPA axis function in these patients should be monitored at regular intervals.Concomitant treatment with ketoconazole and itraconazole or other potent CYP3A4 inhibitors should be avoided (see Section 4.5). The product contains small amounts of ethanol (less than 100 mg per dose) and glycerol. These quantities are negligible and do not represent any risk for the patient at usual therapeutic doses.

In patients undergoing treatment with oral corticosteroids, switching to the use of only Budiair by inhalation should occur gradually. After stabilising the patient, Budiair is combined to the therapy and oral corticosteroid dose is progressively reduced, while regularly assessing the patient’s general conditions. This is necessary due to the slow reactivation of adrenal function, compromised by the prolonged use of oral corticosteroids (see section 4.2). The metabolism of budesonide is primarily mediated by CYP3A4. Inhibitors of this enzyme, eg, ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide several times, see section 4.4. Since there is no data to support a dosage recommendation, the combination should be avoided. If this is not possible, the period between treatments should be as long as possible and a reduction of the budesonide dose could also be considered.Limited data about this interaction for high-dose inhaled budesonide indicate that marked increases in plasma levels (on average four- fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled budesonide (single dose of 1000 μg).Raised plasma concentrations and enhanced effects of corticosteroids have been observed in women also treated with oestrogens and contraceptive steroids, but no effect has been observed with budesonide and concomitant intake of low dose combination oral contraceptives. Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).The product contains a small amount of ethanol. There is the theoretical potential for interactions with disulfiram or metronidazole in particularly sensitive patients treated with these drugs 

PregnancyResults from a large prospective epidemiological study and from world-wide post marketing experience indicate that inhaled budesonide during pregnancy has no adverse effects on the health of the foetus / new born child. As with other drugs the administration of budesonide during pregnancy requires that the benefits for the mother are weighed against the risks for the foetus. In animal studies glucocorticosteroids have been shown to induce malformations. This is not likely to be relevant for humans given recommended dose. The lowest effective dose of budesonide needed to maintain adequate asthma control should be used

 BreastfeedingBudesonide is excreted in breast milk. However, at therapeutic doses of budesonide no effects on the suckling child are anticipated. Budesonide can be used during breast feeding.Maintenance treatment with inhaled budesonide (200 or 400 microg twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants. In a pharmacokinetic study, the estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification.Based on data from inhaled budesonide and the fact that budesonide exhibits linear PK properties within the therapeutic dosage intervals after nasal, inhaled, oral and rectal administrations, at therapeutic doses of budesonide, exposure to the suckling child is anticipated to be low

Budiair has no influence on the ability to drive and use machines

Tabulated list of adverse reactions:Adverse events are listed below by System Organ Class and frequency. The following definitions apply to the incidence of undesirable effects:

very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and < 1/1,000), very rare (<1/10,000), unknown (frequency cannot be estimated from the available data).

System Organ ClassAdverse ReactionFrequencyInfections and infestations Oropharyngeal candidiasisCommonImmune system disorderImmediate and delayed hypersensitivity reactions including rash, contactdermatitis, urticaria, angioedema and anaphylactic reactionRareEndocrine disordersSigns and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation*RarePsychiatric disordersPsychotic disorder, restlessness nervousness, depression and behavioural changes (predominantly in children)RareSleep disorders, anxiety, psychomotor hyperactivity, aggression.Unknown Nervous system disordersDysgeusiaVery rareEye disordersGlaucoma, cataract,UnknownRespiratory, Thoracic & Mediastinal DisordersCough, hoarseness, throat irritationCommonBronchospasmRareGastrointestinal disordersDysphagiaCommonNausea, glossodynia, stomatitis, dry mouthVery rareSkin and subcutaneous tissue disordersSkin atrophy, pruritus, erythema, bruising, RareMusculoskeletal and connective tissue disordersBack painVery rareGeneral disorders and administration site conditionsIrritabilityRareInvestigationsBone density decreasedVery rare

* refer to Paediatric population, belowThere is an increased risk of pneumonia in patients with newly diagnosed COPD starting treatment with inhaled corticosteroids. However a weighted assessment of 8 pooled clinical trials involving 4,643 COPD patients treated with budesonide and 3,643 patients randomized to non-ICS treatments does did not demonstrate an increased risk for pneumonia. The results from the first 7 of these 8 trials have been published as a metaanalysis.

Paediatric populationDue to the risk of growth retardation in the paediatric population, growth should be monitored as described in section 4.4.To report any side effect(s):The National Pharmacovigilance and Drug Safety Center (NPC)Fax +966-11-205-7662Call NPC at +966-11-2038222, Exts 2317-2356-2353-2354-2334-2340Tool Free Phone: 8002490000 E-mail: npc.drug@sfda.gov.saWebsite: www.sfda.gov.sa/npc

Acute overdosage with budesonide, even in excessive doses, is not expected to be a clinical problem. Symptoms of overdoseThe acute toxicity of budesonide is low. Chronic use in excessive doses can result in systemic glucocorticosteroid effects, such as increased susceptibility to infection, hypercorticism and adrenal suppression. Atrophy of the adrenal cortex can occur and the ability to adapt to stress can be impaired.Therapeutic management of overdose For acute overdosage, no special emergency action needs to be taken. The treatment with inhaled budesonide should be continued at the recommended dose to control asthma. HPA axis function recovers in a few days.

Pharmacodynamic propertiesPharmacotherapeutic group: Antiasthmatic glucocorticoid inhalant. ATC code: R03BA02Budesonide, active ingredient of Budiair, is a synthetic, non-halogenated corticosteroid for topic inhalation use only, endowed with potent anti-inflammatory activity and, at the recommended dose, devoid of systemic effects or of activity inihibiting the adrenocortical function. Improvement in asthma control following inhalation of budesonide can occur within 24 hours of commencing the treatment although maximum benefit is achieved after a few weeks of continuous treatment.The precise mechanism of corticosteroid actions on inflammation in asthma is not known. Budesonide has been shown to have a wide range of inhibitory effects against several cell types (e.g., eosinophils, macrophages, mast cells, lymphocytes, and neutrophils) and mediators (e.g., cytokines, leukotrienes, eicosanoids, and histamine) involved in allergic and non-allergic respiratory inflammation. These actions of budesonide may contribute to its efficacy in asthma resulting in a reduction of hypersecretion, hyperreactivity and inhibiting the occurrence of bronchospasm. In patients with hyperreactivity the administration of budesonide reduces airway reactivity after stimulation with histamine or methacholine

Budesonide is provided as a mixture of two epimers (22R and 22S). In glucocorticoid receptor affinity studies, the 22R form is twice as active as the 22S epimer. These two forms of budesonide do not interconvert.

AbsorptionBudesonide is a moderately lipophilic drug with high affinity to the glucocorticoid receptors, rapidly by the airway mucosa. After inhalation, in about 20 minutes after administration by inhalation budesonide forms esters with intracellular fatty acids, via a reversible conjugation process that is able to prolong the local antiinflammatory activity at pulmonary level. The quantity absorbed in circulation, partly through the lungs and partly swallowed by oral route, varies between 10 and 30%, and is rapidly and widely metabolised at the hepatic level, to yield poorly active metabolites. Bonding to plasma proteins is 88% and the distribution volume is high. Biotransformation:Budesonide is mainly eliminated by metabolism. Budesonide is rapidly and extensively metabolised in liver via cytochrome P4503A4 to two major metabolites. The in vitro glucocorticoid activity of these metabolites is less than 1% of that of the parent compound. Negligible metabolic inactivation has been observed in human lung and serum preparations.Elimination:Budesonide is excreted in urine and faeces as conjugated and non-conjugated metabolites.The elimination half life is about 3 hours, after inhalation. Special patient populations: The exposure to budesonide may be increased in patients with liver disease. In children the elimination half-life from plasma is markedly lower than in adults

The toxicity observed in animal studies with budesonide was associated with exaggerated pharmacological activity.No genotoxic effects of budesonide have been observed in conventional genotoxicity tests.In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). Similar effects are considered unlikely to occur in humans at therapeutic doses.Specific tolerability studies by inhalation proved the good local tolerability of the formulation with HFA 134a propellant.The HFA 134a propellant did not show any toxic effects, even at concentrations far higher than those recommended for human use, when administered by nebulisation to different animal species daily exposed up to a two-years period.Studies on the effects of the propellant HFA 134a on reproductive function and embryofoetal development in animals failed to detect any clinically important adverse events. It is therefore unlikely that adverse events can occur in humans.

List of excipients1,1,1,2 Tetrafluoroethane (HFA 134a), ethanol, anhydrous glycerol.

Not applicable

Pressurised container. Do not pierce, expose to heat, even if empty, freeze and exposed to direct sunlight. Store below 25°C

Primary conteiner: mono-bloc aluminium canister, pressurised with metering valve, equipped either with a standard actuator with mouthpiece cover or with a polypropyleneJet-spacer actuator with mouthpiece cover. Characteristics of the Jet actuator-spacerThe Jet device was studied in order to improve the efficiency of a metered dose inhaler and to ease the compliance to therapy of patients (particularly elderly and children) poorly familiar with the inhalation technique, as it avoids the need to synchronise actuation with inspiration. The Jet device reduces the amount of active ingredient deposited in the oropharynx, favouring a good local tolerability.The particular shape of the Jet expansion chamber causes the formation of a whirling flow in which the delivered particles remain suspended for as long as sufficient to discharge their kinetic energy and to allow the propellant to partially evaporate. Therefore, impaction of particles mostly occurs within the device rather than in the oropharyngeal cavity, while the size reduction of droplets, before they enter the respiratory tree, favours better penetration into the lower airways.Outer package: printed thin-cardboard box.Presentation: pressurised canister providing 200 inhalationsPackages: •pressurised canister with standard actuator, providing 200 actuations•pressurised canister with Jet actuator-spacer, providing 200 actuations

The package contains a pressurised container equipped with a standard actuator or with a Jet actuator-spacerAny unused product or waste material should be disposed of in accordance with local requirements.