BUDESAL Respules (Budesonide + Levalbuterol)

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1 Published on: 10 Jul 2014 BUDESAL Respules (Budesonide + Levalbuterol) Composition BUDESAL 0.5 Respules Each 2 ml respule contains: Levalbuterol Sulphate, equivalent to levalbuterol.1.25 mg Budesonide BP mg BUDESAL 1 Respules Each 2 ml respule contains: Levalbuterol Sulphate, equivalent to levalbuterol.1.25 mg Budesonide BP mg Dosage Form Suspension for inhalation via a nebulizer Description BUDESAL Respules contain an aqueous suspension of levalbuterol and budesonide. Levosalbutamol is also known as levalbuterol. Levalbuterol is a single isomer beta 2 -agonist that differs from racemic salbutamol by the elimination of (S)- salbutamol. 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. Nebulized β 2 -agonist is the drug therapy of choice during acute exacerbations of asthma. In acute conditions, β 2 -agonist alone may not relieve acute airway obstruction since there is an exacerbation of the airway inflammatory response during acute severe asthma, leading to plasma exudation, cellular infiltration and mucosal oedema impairing the penetration of β 2 -agonist. This may be addressed by concomitant therapy with anti-inflammatory agent like corticosteroids. Both the drugs available in a single formulation for nebulization help to provide higher doses of the drugs, at the same time provides the convenience of dual therapy in a single formulation. Pharmacology Pharmacodynamics Levalbuterol Levalbuterol is an effective bronchodilator whose primary mechanism of action is unimpeded by (S)-salbutamol. Therefore, it can be used in doses that are half that of racemic salbutamol. Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an

2 increase in the intracellular concentration of cyclic-3', 5'-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Levalbuterol acts as a functional antagonist that relaxes the airway irrespective of the spasmogen involved, thereby protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Budesonide 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 Levalbuterol Pharmacokinetics (Adults and Adolescents) The inhalation pharmacokinetics of levalbuterol inhalation solution were investigated in a randomized crossover study in 30 healthy adults, following administration of a single dose of 1.25 mg and a cumulative dose of 5 mg of levalbuterol inhalation solution, and a single dose of 2.5 mg and a cumulative dose of 10 mg of Racemic Salbutamol inhalation solution by nebulization, using the nebulizer with a compressor. Following administration of a single 1.25 mg dose of levalbuterol inhalation solution, exposure to (R)-salbutamol was approximately 2-fold higher than following administration of a single 2.5 mg dose of racemic salbutamol inhalation solution (AUC of 1.7 ng hr/ml) (see table below). Following administration of a cumulative 5 mg dose of levalbuterol inhalation solution (1.25 mg given every 30 minutes for a total of four doses) or a cumulative 10 mg dose of racemic salbutamol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), C max and AUC of (R)-salbutamol were comparable. Table 1: Single and Cumulative Dose of Racemic Salbutamol and (R)- Salbutamol

3 Single Dose Cumulative Dose Levalbuterol 1.25 mg Racemic Salbutamol 2.5 mg Levalbuterol 5 mg Racemic Salbutamol 10 mg C max (ng/ml) (R)-salbutamol 1.1 (0.45) 0.8 (0.41) 4.5 (2.20) 4.2 (1.51) t max (h) (R)-salbutamol 0.2 (0.17, 0.37) 0.2 (0.17, 1.50) 0.2 (-0.18 *, 1.25) 0.2 (-0.28 *, 1.00) AUC (ng h/ml) (R)-salbutamol T ½ (h) (R)-salbutamol 3.3 (1.58) 1.7 (0.99) ** 17.4 (8.56) 16.0 (7.12) ** 3.3 (2.48) 1.5 (0.61) 4.0 (1.05) 4.1 (0.97) Table 2: (R)-Salbutamol Exposure in Adults and Adolescents Adults and Adolescents Treatment Levo salbutamol 0.63 mg Levo salbutamol 1.25 mg AUC0-(infinity) (ng hr/ml) 1.65 a 3.3 b Cmax (ng/ml) 0.56 a 1.1 b a The values are predicted by assuming linear pharmacokinetics. b The data obtained from Table 1. Metabolism and Elimination Information available in published literature suggests that the primary enzyme responsible for the metabolism of salbutamol enantiomers in humans is SULT1A3 (sulphotransferase). When racemic salbutamol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the AUCs between the (R)- and (S)-salbutamol enantiomers, with (S)-salbutamol concentrations being consistently higher. However, after either inhalation or oral administration without charcoal pre-treatment, the differences were 8- to 24-fold, suggesting that (R)-salbutamol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3. The primary route of elimination of salbutamol enantiomers is through renal excretion (80 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the faeces. Following intravenous administration of racemic salbutamol, between 25 46% of the (R)-salbutamol fraction of the dose was excreted as unchanged (R)-salbutamol in the urine. 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 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.

4 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 6beta-hydroxybudesonide. 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 BUDESAL Respules are indicated in the treatment of acute exacerbations of asthma. Subsequent maintenance dosing may be more conveniently accomplished using a pressurized metered dose inhaler or powder formulation. Budesonide given by inhalation has a potent glucocorticoid anti-inflammatory action within the lungs. It reduces symptoms and exacerbations of asthma in patients previously treated with bronchodilators alone or with other prophylactic therapy. Relatively brief symptomatic episodes can generally be relieved by the use of fast-acting bronchodilators, but longer-lasting exacerbations require, in addition, the use of corticosteroid therapy as soon as possible to control the inflammation. Dosage And Administration BUDESAL Respules 0.5mg Adults 1-2 respules twice daily BUDESAL Respules 1mg Adults 1 respule twice daily

5 Add saline to increase the fill volume in the nebulizer to 2-5 ml. BUDESAL Respules are for inhalation use only. They should be administered as an aerosol produced by a jet nebulizer, as directed by a physician. As drug delivery from nebulizers is variable, the manufacturer's instructions for using the nebulizer must be followed. The ultrasonic nebulizers are not suitable for the administration of BUDESAL Respules and therefore are not recommended. BUDESAL Respules should not be injected or administered orally. It is advisable to administer BUDESAL Respules via a mouthpiece to avoid the possibility of atrophic changes to facial skin which may occur with prolonged use with a face-mask. When a face-mask is used, the exposed skin should be protected using a barrier cream, or the face should be thoroughly washed after treatment. Contraindications Hypersensitivity to any ingredient of the formulation. Reactions have included urticarial, angioedema, rash, bronchospasm, anaphylaxis and oropharyngeal edema. Warnings And Precautions BUDESAL 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. BUDESAL Respules should be used with care in patients who have received large doses of other sympathomimetic drugs. They should be administered cautiously to patients suffering from thyrotoxicosis. Special care is needed in patients with parasitic infection, orocular herpes simplex.. Special care and adequate specific therapeutic control of patients with active and quiescent pulmonary tuberculosis is necessary before commencing treatment with inhaled budesonide. Similarly, patients with fungal, viral or other infections of the airways require close observation and special care and should use budesonide only if they are also receiving adequate treatment for such infections. Children who are on immunosuppressant drugs are more susceptible to infections than healthy children. Chicken pox and measles, for example, can take a more serious or even a fatal course in children on immunosuppressant corticosteroids. Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than the recommended doses, may result in clinically significant adrenal suppression. Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide. 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 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. In clinical trials with nebulized budesonide, localized infections with Candida albicans occurred in the mouth and pharynx in some patients. Paradoxical bronchospasm may occur and should be treated immediately with alternative therapy. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial. If paradoxical bronchospasm occurs BUDESAL Respules should be discontinued

6 immediately and alternative therapy instituted. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. Need for more doses of levalbuterol than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. Cardiovascular effects may occur with beta-adrenergic agonists use. Consider discontinuation of levalbuterol if these effects occur. Use with caution in patients with underlying cardiovascular disorders. Immediate hypersensitivity reactions may occur. Discontinue levalbuterol if immediate hypersensitivity reactions occur as demonstrated by racemic salbutamol, such as rare cases of urticaria, angio-oedema, rash, bronchospasm, anaphylaxis, and oropharyngeal oedema. Levalbuterol should be used with caution in patients with coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator. As with other beta-adrenergic agonist medications, levalbuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation. In patients with excessive mucous secretion in the respiratory tract, short-term therapy with oral corticosteroids may be necessary. In patients with severe hepatic dysfunction, treatment with inhaled budesonide can result in a reduced elimination rate and hence enhanced systemic availability. Possible systemic effects may then result and therefore HPA axis function in these patients should be monitored at regular intervals. Concomitant treatment with ketoconazole, HIV protease inhibitors or other potent CYP3A4 inhibitors should be avoided. If this is not possible the time interval between administration of the two drugs should be as long as possible. Drug Interactions The metabolism of budesonide is primarily mediated by CYP3A4 and inhibitors of this enzyme, e.g. ketoconazole and itraconazole, can therefore increase systemic exposure to budesonide. Care should be exercised when budesonide is coadministered with long-term ketoconazole and other known CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, ketoconazole, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin). Cimetidine had a weak but clinically insignificant inhibiting effect on hepatic metabolism of budesonide. 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. The suppressive effect on adrenal function is additive if used concomitantly with systemic or intranasal steroids. Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values). Levalbuterol and non-selective beta-blocking drugs such as propranolol should not usually be prescribed together. In patients who are currently receiving digoxin and levalbuterol, serum digoxin levels should be evaluated. Caution is advised in the co-administration of beta-agonists with non-potassium-sparing diuretics (monitor potassium levels), patients treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents. Avoid concomitant use of other short acting sympathomimetic bronchodilators or epinephrine. Cardio selective use of beta blockers should be administered with caution. Hepatic Impairment Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide was affected

7 by compromised liver function, as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide was, however, similar in cirrhotic patients and in healthy adults. Pregnancy There are no adequate and well-controlled studies of levalbuterol in pregnant women. Because animal reproduction studies are not always predictive of human response, levalbuterol should be used during pregnancy and labor only if the potential benefit justifies the potential risk to the foetus. Most results from prospective epidemiological studies and world-wide post-marketing data have not been able to detect an increased risk for adverse effects for the foetus and newborn child from the use of inhaled budesonide during pregnancy. It is important for both foetus and mother to maintain an adequate asthma treatment during pregnancy. As with other drugs administered during pregnancy, the benefit of the administration of budesonide for the mother should be weighed against the risks to the foetus. Lactation Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of levalbuterol for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Plasma levels of levalbuterol after inhalation of therapeutic doses are very low in humans, but it is not known whether levalbuterol is excreted in human milk. Because of the potential for tumorigenicity shown for racemic salbutamol in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when BUDESAL Respules are administered to a nursing woman. Budesonide 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 micrograms twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants. 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. Mild irritation in the throat, coughing, hoarseness, and candida infection in the oropharynx have been reported. Skin reactions, urticaria, rash, contact dermatitis, immediate and delayed hypersensitivity reactions, angioedema, anaphylactic reaction, signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation, restlessness, nervousness, behavioral changes, bronchospasm, dysphonia, bruising, pruritus, erythema, decreased bone density, etc. may, in rare cases, occur in association with local corticosteroid therapy. In some cases, facial skin irritation has occurred when a nebulizer with a face mask has been used. To prevent such irritation, the face should be washed after using the face mask. If oropharyngeal candidiasis develops, it may be treated with appropriate anti-fungal therapy while continuing BUDESAL Respules. Other adverse reactions include respiratory infection, rhinitis, otitis media, viral infection, moniliasis, gastroenteritis, vomiting, diarrhoea, abdominal pain, ear infection, epistaxis, conjunctivitis, rash, 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

8 rash, pruritus, purpura, symptoms of hypocorticism and hypercorticism, cataract, oral mucosal irritation, difficulty in swallowing, muscle spasm, blurred vision, glaucoma, increased intraocular pressure, fever, pain, sinusitis, pharyngitis, bronchitis, avascular necrosis of the femoral head, osteoporosis, growth suppression, headache, psychiatric symptoms including psychosis, psychomotor hyperactivity, depression, aggressive reactions, irritability, sleep disorders, nervousness, restlessness, anxiety and behavioural changes (predominantly in children), cough, risk of pneumonia (in COPD patients), dysphonia, skin bruising, facial skin irritation. Common side effects by levalbuterol reported by greater than 2% in adults and adolescents were pain, flu syndrome, accidental injury, tachycardia, migraine, dyspepsia, leg cramps, dizziness, nervousness, tremor, anxiety, as well as certain respiratory effects such as increased cough, viral infection, rhinitis, sinusitis and turbinate edema. Other undesirable effects observed in less than 2% of the subjects were chills, pain, chest pain, changes in ECG, ECG abnormal, leg cramps, dyspepsia, anxiety, hyperesthesia of the hand, insomnia, paresthesia, tremor, hypertension, hypotension, syncope, diarrhoea, dry mouth, dry throat, gastroenteritis, nausea, lymphadenopathy, myalgia, hypesthesia of the hand, insomnia, paresthesia and eye itch. Common side effects observed in more than 2% of children were abdominal pain, accidental injury, asthenia, fever, headache, pain, viral infections, diarrhoea, lymphadenopathy, myalgia, asthma, pharyngitis, rhinitis, rash, urticaria; whereas in; less than 2% were cyst, flu syndrome, viral infection, constipation, gastroenteritis, myalgia, hypertension, epistaxis, lung disorder, acne, herpes simplex, conjunctivitis, ear pain, dysmenorrhea, hematuria, and vaginal moniliasis. In children, frequently occurring adverse events were accidental injury, vomiting, bronchitis, pharyngitis. The following events, considered potentially related to levalbuterol, occurred in less than 2% of the treated subjects but at a frequency less than in patients who received placebo: asthma ation, cough increased, wheezing, sweating, and vomiting. The incidence of systemic beta-adrenergic adverse effects (e.g., tremor, nervousness) was low. Changes in heart rate and plasma glucose and potassium levels were slightly low. Potentially serious hypokalaemia may result from beta 2 -agonist therapy. This effect may be potentiated by hypoxia. Particular caution is advised in severe asthma in such cases, monitoring of serum potassium levels is recommended. In addition to the adverse events reported in clinical trials, the following adverse events have been observed in post approval use of levalbuterol. These events have been chosen for inclusion due to their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles), asthma, chest pain, cough increased, dysphonia dyspnea, gastrooesophagial reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, and urticaria. Because these events have been reported spontaneously from a population of unknown size, estimates of frequency cannot be made. In addition, levalbuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, headache, and drying or irritation of the oropharynx. Overdosage The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation, e.g., seizures, angina, hypertension or hypotension, tachycardia (rates upto 200 beats/min.), arrhythmias, nervousness, headache, tremor, dry mouth, palpitations, nausea, dizziness, fatigue, malaise, cardiac arrest and sleeplessness. Hypokalaemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of levalbuterol. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of levalbuterol.

9 The preferred antidote to overdosage with BUDESAL Respules, due to the effects of levalbuterol, is a cardioselective beta-blocking agent, but beta-blocking drugs should be used with caution in patients with a history of bronchospasm. Overdosage due to budesonide should not be a clinical problem. Packaging Information BUDESAL 0.5 Respules available as respule of 2 ml BUDESAL 1 Respules available as respule of 2 ml Last Updated: September 2017 Last Reviewed: September 2017 BUDESAL Respules Source URL: