BUDECORT Respules (Budesonide)

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1 Published on: 10 Jul 2014 BUDECORT Respules (Budesonide) Composition BUDECORT 0.5 mg Respules Each 2 ml contains Budesonide IP mg BUDECORT 1 mg Respules Each 2 ml contains Budesonide IP... 1 mg Dosage Form Suspension for inhalation via a nebulizer Pharmacology Pharmacodynamics BUDECORT respules contain an aqueous suspension of budesonide. Budesonide is a non-halogenated glucocorticoid with an improved ratio of topical anti-inflammatory activity to systemic glucocorticoid effect. This is due to a high glucocorticoid receptor affinity combined with a high first-pass metabolism and a short half-life. Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1,000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear oedema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. The precise mechanism of corticosteroid actions on inflammation in asthma is not well known. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic- and non-allergic mediated inflammation. The anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Studies in asthmatic patients have shown a favourable ratio between topical anti-inflammatory activities and systemic corticosteroid effects over a wide dose range of inhaled budesonide in a variety of formulations and delivery systems, including the inhalation suspension for nebulization. This is explained by a combination of a relatively high local antiinflammatory effect, extensive first-pass hepatic degradation of orally absorbed drug (85 95%), and the low potency of the metabolites. Pharmacokinetics The activity of BUDECORT respules is also due to its component drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of

2 budesonide do not interconvert. Budesonide is primarily cleared by the liver. In asthmatic children, 4 6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight. After a single dose of 1 mg budesonide, a peak plasma concentration of 2.6 nmol/l was obtained approximately 20 minutes after nebulization in asthmatic children, 4 6 years of age. The exposure (AUC) of budesonide following administration of a single 1 mg dose of budesonide by nebulization to asthmatic children, 4 6 years of age, is comparable to healthy adults given a single 2 mg dose by nebulization. Absorption In asthmatic children, 4 6 years of age, the total absolute bioavailability (i.e., lungs + oral) following administration of budesonide respules via a jet nebulizer was approximately 6% of the labelled dose. The peak plasma concentration of budesonide occurred minutes after the start of nebulization. Distribution In asthmatic children, 4 6 years of age, the volume of distribution of budesonide at steady state was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85-90% bound to plasma proteins, the degree of binding being constant over the concentration range (1-100 nmol/l) achieved with, and exceeding, recommended doses. Budesonide showed little or no binding to corticosteroid-binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration-independent manner, with a blood/plasma ratio of about 0.8. Metabolism In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites, formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4)-catalysed biotransformation, have been isolated and identified as 16alpha-hydroxyprednisolone and 6betahydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the in vitro and in vivo metabolic patterns has been detected. Negligible metabolic inactivation was observed in the human lungs and in serum preparations. Excretion Budesonide is excreted in the urine and the faeces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabelled dose was recovered in the urine. No unchanged budesonide was detected in the urine. Special Populations No differences in pharmacokinetics due to race, gender, or age have been identified. Indications BUDECORT respules is indicated for the maintenance treatment and prophylactic of asthma. BUDECORT respules is not indicated for the relief of acute bronchospasm. BUDECORT respules are also recommended for use in infants and children with acute laryngotracheobronchitis - croup. Dosage And Administration The dosage of BUDECORT respules is individualized. The initial dose or during periods of severe asthma or while reducing oral corticosteroids: Initiating Dose Adults including elderly

3 1-2 mg twice daily Children 12 Years and Older Same as adults Children 3 Months to 12 Years mg twice daily Maintenance Dose The maintenance dose should be individualized. After the desired clinical effect has been obtained, the maintenance dose should be gradually reduced to the smallest amount necessary for control of symptoms. Adults (Including Elderly and Children 12 Years and Older) mg twice daily Children 3 Months to 12 Years mg twice daily Patients Maintained on Oral Steroids When transferring a patient from oral steroids to BUDECORT respules the patient should be in a relatively stable phase. A high dose of BUDECORT respules is given in combination with the previously used steroid for about 10 days. After that, the oral dose is gradually reduced (by for example 2.5 milligrams prednisolone or the equivalent each month to the lowest possible level. The dose of BUDECORT respules should not be altered while the patient remains on oral corticosteroids. In many cases, it is possible to completely substitute the oral steroid with BUDECORT respules. In other patients a low oral steroid maintenance dose may be necessary. During transfer from oral therapy to BUDECORT respules a lower systemic steroid action may be experienced. Earlier allergic symptoms may recur or patients may suffer from tiredness, headache, muscle and joint pain or occasionally nausea and vomiting. Patients Not Dependent on Oral Steroids Treatment with the recommended doses of BUDECORT respules usually gives a therapeutic effect within 10 days. In patients with excessive mucus secretion in the bronchi an initial short course (about 2 weeks) of an oral corticosteroid commencing with a high dose and gradually reducing, should be given in addition to BUDECORT respules. Treatment should be continued for at least one month before determining the maximal response to a given dose of BUDECORT respules. Croup In infants and children with croup, the usual dose is 2 mg as a single dose or two doses of 1 mg 30 minutes apart. Dosing can be repeated every 12 hour for a maximum of 36 hours or until clinical improvement. Data from various in vivo studies have estimated that the dose of nebulized budesonide delivered to the patient ranges between 11-22% of the nominal dose depending on the nebulizing equipment used. The use of a tight sealing facemask in infants and young children seems to maximize the delivered dose of budesonide. The nebulization time and the dose delivered is dependent on flow rate, volume of nebuliser chamber and volume fill. A suitable fill for most nebulizers is 2-4 ml. Some sedimentation may occur during storage of BUDECORT respules. If this does not readily resuspend on shaking, the respule should be discarded. To minimise the risk of oropharyngeal candida infection and facial skin irritation, the patient should rinse their mouth out with water after inhaling and wash the facial skin with water after using the face mask. BUDECORT respules can be admixed with Asthalin, Levolin or Ipravent Respules (to be used within 2 hours), with Foratec Respules (to be used within 30 minutes), with Mucinac Respules (to be used immediately) and with Inhalex Respules.

4 The ultrasonic nebulizers are not suitable for the administration of BUDECORT respules and therefore are not recommended. Contraindications The use of BUDECORT respules is contraindicated in the following conditions: Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. Hypersensitivity to any ingredient of the formulation Warnings And Precautions BUDECORT respules are to be used with a nebuliser, and only under the direction of a physician. The solution should not be injected or administered orally. Particular care is needed in patients who are being transferred from oral corticosteroids to BUDECORT respules. Special care is needed in patients with lung tuberculosis, and fungal and viral infections. Children who are on immunosuppressant drugs are more susceptible to infections than healthy children. Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex) can occur and hence is to be used with caution. Chicken pox and measles, for example, can take a more serious or even a fatal course in children on immunosuppressant corticosteroids. During long-term therapy, monitoring of hematological and adrenal function is advisable. Non Steroid-Dependent Patients: A therapeutic effect is usually reached within 10 days. In patients with excessive mucus secretion in the bronchi, a short (about 2 weeks) additional oral corticosteroid regimen can be given initially. After the course of the oral drug, BUDECORT respules alone should be sufficient therapy. Steroid-Dependent Patients: When transfer from oral corticosteroid to treatment with BUDECORT respules is initiated, the patient should be in a relatively stable phase. BUDECORT Respules is then given, in combination with the previously used oral steroid dose, for about 10 days. After that, the oral steroid dose should be gradually reduced (by, for example, 2.5 mg prednisolone or the equivalent each month), to the lowest possible level. In many cases, it is possible to completely substitute BUDECORT respules for the oral corticosteroid. During transfer from oral therapy to nebulised budesonide, a generally lower systemic corticosteroid action will be experienced, which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary. Patients should be advised that BUDECORT respules may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to BUDECORT respules. As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If a severe reaction occurs, treatment should be reassessed and an alternative therapy instituted if necessary. 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 cover should be considered during periods of stress or elective surgery. Systemic effects may occur with any inhaled corticosteroids, 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

5 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 psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids), should be monitored and treated with established standards of care. Close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained. Influence on Growth 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-evaluated with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. 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. BUDECORT respules is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required. If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy, e.g., higher doses of inhaled budesonide or the addition of a long-acting beta agonist, or for a course of oral glucocorticosteroid. Reduced liver function may affect the elimination of glucocorticosteroids. The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with nebulised budesonide is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected. In vivo studies have shown that oral administration of ketoconazole and itraconazole (known inhibitors of CYP3A4 activity in the liver and in the intestinal mucosa causes an increase in the systemic exposure to budesonide. Concomitant treatment with ketoconazole and itraconazole 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. A reduction in the dose of budesonide should also be considered. The nebuliser chamber should be cleaned after every administration. Wash the nebuliser chamber and mouthpiece or face-mask in hot water using a mild detergent. Rinse well and dry, by connecting the nebuliser chamber to the compressor or air inlet. In clinical trials with nebulised budesonide, localized infections with Candida albicans occurred in the mouth and pharynx in some patients. The incidences of localized infections of Candida albicans were similar between the placebo and nebulised budesonide treatment groups. If these infections develop, they may require treatment with appropriate local or systemic antifungal therapy and/or discontinuance of treatment with nebulised budesonide. Patients should rinse the mouth after inhalation of BUDECORT respules and should be monitored periodically for signs of adverse effects on the oral cavity. Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide respules. Discontinue BUDECORT respules if such reactions occur. In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these

6 patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroids therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Healthcare providers should be alert to eosinophilia, vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established. Drug Interactions The metabolism of budesonide is primarily mediated by CYP3A4, one of the cytochrome p450 enzymes. Inhibitors of this enzyme, e.g. ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide. Care should be exercised when budesonide is co-administered with long-term ketoconazole and other known CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin). The limited data available on the interactions of high dose inhaled budesonide indicate marked increase 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 mcg). Raised plasma concentrations of 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). Hepatic Impairment Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function, as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy adults. Since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored. Pregnancy Pregnancy Category B Data on approximately 2000 exposed pregnancies indicate no increased teratogenic risk associated with the use of inhaled budesonide. In animal studies, glucocorticosteroids have been shown to induce malformations. This is not likely to be relevant for humans given recommended doses, but therapy with inhaled budesonide should be regularly reviewed and maintained at the lowest effective dose. The administration of budesonide during pregnancy requires that the benefits for the mother be weighed against the risk for the foetus. Inhaled glucocorticosteroids should be considered in preference to oral glucocorticosteroids because of the lower systemic effects at the doses required to achieve similar pulmonary responses. Lactation Budesonide is excreted in breast milk. However, at therapeutic doses of budesonide respules no effects on the suckling child are anticipated. Budesonide respules can be used during breast feeding. Maintenance treatment with inhaled budesonide (200 or 400 micrograms 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

7 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 pharmacokinetic properties within the therapeutic dosage intervals after nasal, inhaled, oral and rectal administrations, at therapeutic doses of budesonide, exposure to the breast-fed child is anticipated to be low. Undesirable Effects Budesonide is generally well tolerated. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions occurring at an incidence of 3% in clinical trials with budesonide respules and where the incidence was higher with budesonide respules than placebo were: Respiratory infection, rhinitis, coughing, otitis media, viral infection, moniliasis, gastroenteritis, vomiting, diarrhoea, abdominal pain, ear infection, epistaxis, conjunctivitis, rash. Adverse reactions occurring at an incidence of 1 to < 3% in clinical trials with budesonide respules and where the incidence was higher with budesonide respules than placebo were: cervical lymphadenopathy, earache, fatigue, flu-like disorder, allergic reaction, eye infection, herpes simplex, external ear infection, infection, fracture, anorexia, myalgia, hyperkinesias, emotional lability, chest pain, dysphonia, stridor, contact dermatitis, eczema, pustular rash, pruritus, purpura. The following adverse reactions have been reported during post-approval use of budesonide respules: Endocrine disorders: signs and symptoms of systemic corticosteroid effects, including adrenal suppression hypocorticism and hypercorticism. Eye disorders: cataracts, glaucoma, increased intraocular pressure. General disorders and administration site conditions: fever, pain. Immune system disorders: immediate and delayed hypersensitivity reactions including, anaphylaxis, angioedema, bronchospasm, rash, contact dermatitis, and urticaria Infection and Infestation: sinusitis, pharyngitis, bronchitis, oropharyngeal candidiasis Musculoskeletal and connective tissue disorders: avascular necrosis of the femoral head, osteoporosis, growth suppression Nervous system disorders: headache Psychiatric disorders: psychiatric symptoms including psychosis, psychomotor hyperactivity, depression, aggressive reactions, irritability, sleep disorders, nervousness, restlessness, anxiety and behavioural changes (predominantly in children). Respiratory, thoracic, and mediastinal disorders: cough, dysphonia, hoarseness and throat irritation. Skin and subcutaneous tissue disorders: skin bruising, facial skin irritation. Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for budesonide respules. Some of these adverse reactions may also have been observed in clinical studies with budesonide respules. The candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dosing will minimise the risk. As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases. Facial skin irritation has occurred in some cases when a nebuliser with a face mask has been used. To prevent irritation, the facial skin should be washed with water after use of the face mask. There is an increased risk of pneumonia in patients with newly diagnosed COPD starting treatment with inhaled

8 corticosteroids. However a weighed assessment of 8 pooled clinical trials involving 4643 COPD patients treated with budesonide and 3643 patients randomized to non-ics treatments did not demonstrate an increased risk of pneumonia. The results from the first 7 pooled clinical trials have been published as a meta-analysis. Due to the risk of growth retardation, growth should be monitored in the paediatric population. Overdosage Overdosage due to budesonide should not be a clinical problem. The potential for acute toxic effects following overdose of budesonide respules is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur. Withdrawal of budesonide respules or a decrease in dose will get rid of these effects, although the normalization of the hypothalamic-pituitary-adrenal (HPA) axis function may be a slow process. Treatment of acute overdosage: The treatment with budesonide should be continued with the lowest possible effective maintenance dose, and the adrenocortical function will repair itself automatically within 1-2 days. Treatment of chronic overdosage: The patient should be treated as a steroid dependent and be transferred to a suitable maintenance dose with a systemic steroid, for example prednisolone. When the condition is stabilized, the patient should continue the treatment with the inhalation of budesonide at the recommended doses. Packaging Information BUDECORT 0.5 mg Respules... available as respule of 2 ml BUDECORT 1 mg Respules.....available as respule of 2 ml Last Updated: July 2015 Last Reviewed: July 2015 BUDECORT Respules Source URL: