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تاريخ التسجيل : 23/02/2008

مُساهمةموضوع: hاقرأ المزيد حول الزفير لوكاست و المنتولوكاست   الثلاثاء فبراير 26, 2008 3:55 am

[left]Leukotriene Inhibitor Criteria for Use in Veteran Patients
VHA Pharmacy Benefits Management Strategic Healthcare Group
and the Medical Advisory Group
The following recommendations are based on current medical evidence and expert opinion from clinicians. The content of the
document is dynamic and will be revised as new clinical data becomes available. The purpose of this document is to assist
practitioners in clinical decision-making, to standardize and improve the quality of patient care, and to promote cost-effective drug
prescribing. The clinician should utilize this guidance and interpret it in the clinical context of the individual patient situation.
The two leukotriene inhibitors that are available are montelukast (Singulair) and zafirlukast (Accolate). Montelukast is listed on the VA National Formulary.
1. Asthma
Mild Persistent Asthma
• Orally inhaled corticosteroids (ICS), at low-moderate doses, remain the drug of choice.
• Leukotriene inhibitors are an option for patients unable to use a metered dose inhaler (MDI) with spacer or a dry powder inhaler (DPI) or are poorly compliant with inhalers.
ICS and leukotriene inhibitors are both effective as monotherapy; however, current evidence shows that low dose ICS have a greater effect than leukotriene inhibitors.1, 2
Moderate Persistent Asthma
For patients uncontrolled on low-moderate doses of ICS there are several options
• Increase dose of ICS
• Add a regularly scheduled beta-agonist to the current ICS dose
• Add a leukotriene inhibitor to the current ICS dose
• Add a mast cell stabilizer to the current ICS dose
Either increasing the dose of ICS or adding a long-acting beta-agonist (LABA) to the existing ICS dose improves asthma control. However, there is a large body of literature suggesting that adding a LABA to low dose ICS is superior to doubling or increasing the dose of ICS.3-13
There are insufficient data to show that either increasing the ICS dose or adding montelukast provides better asthma control (the only published study used zafirlukast at 4 times the recommended dose14)
There are 3 studies comparing the addition of a LABA versus a leukotriene inhibitor to ICS. Adding either drug to ICS improved peak flow or FEV1, symptom scores, as needed albuterol use. Improvement in pulmonary function was statistically, although probably not clinically, better with LABA. There was no difference is exacerbation rates over a 12 week period.15-17
Severe Persistent Asthma
There are insufficient data to recommend the addition of a leukotriene inhibitor to high dose ICS in this group of patients.
One crossover study found no additional benefit in pulmonary function or symptoms when montelukast 10mg daily for 2 weeks was added to high dose ICS + LABAs, theophylline, or oral steroids.18
In a 12-week study of patients requiring moderate-high dose ICS, addition of montelukast 10mg daily allowed a 47% reduction in the dose of ICS versus by 30% in those given placebo (p=0.046). 19
August 2002 (use in allergic rhinitis updated March 2003)
Updated versions may be found at http://www.vapbm.org or http://vaww.pbm.med.va.gov
Criteria for Use of Leukotriene Inhibitors in VA Patients
Exercise-induced asthma
• For patients with exercise-induced symptoms, a short-acting beta-agonist (SABA) should be used before exercise.
• For those patients who participate in prolonged exercise/activity where a SABA is not providing the needed control, a LABA can be used prior to exercise. Administer 15 and 30 minutes prior to exercise for formoterol and salmeterol respectively.
• Montelukast can be used for those patients who participate in prolonged exercise/activity where a SABA is not providing the needed control; however, it should be used in conjunction with asthma maintenance medications and not used as monotherapy.
When given as single-doses prior to exercise, a crossover study in 10 patients found salmeterol 100mcg and montelukast 10mg to have similar protective effects.20 Two 8-week and one 12-week trials comparing salmeterol and montelukast 10mg daily found a greater bronchoprotective effect with montelukast.21-23
2. Chronic Obstructive Lung Disease (COPD)
The leukotriene believed to mediate inflammation in COPD is LTB4 and in asthma is LTD4. Montelukast and zafirlukast do not inhibit the LTB4 receptor and are therefore not expected to improve pulmonary function and symptoms of COPD. 24 One single dose study of 16 patients (majority who had >12% increased in FEV1 with albuterol 400mcg) with COPD found the following rank order improvement in FEV1: salmeterol 50mcg + zafirlukast 40mg = salmeterol 50mcg > zafirlukast 40mg > placebo. However, there was a subgroup of 7 patients who had a better response with the combination than with salmeterol alone.25, 26 Larger and longer term studies are needed before these agents can be routinely recommended
3. Seasonal Allergic Rhinitis27-35
Montelukast does not offer a clinical advantage over the other currently available drugs used to treat seasonal allergic rhinitis. Because nasally inhaled steroids and antihistamines are more cost-effective, they remain the drugs of choice both as first-line and second-line agents. The benefit of adding montelukast to a combination of nasal steroids and antihistamines has not been evaluated and thus cannot be recommended. Montelukast has not been evaluated in perennial rhinitis.
4. Other uses
There are preliminary data on the use of leukotriene inhibitors in atopic dermatitis 37,38 and chronic urticaria39. Until more is known, these conditions should be managed with established therapies.
5. Safety
Overall, the incidence of adverse events is low for both agents. Two issues that merit further discussion are the potentials for hepatotoxicity and Churg-Strauss syndrome.
Rarely, zafirlukast and montelukast can cause elevated hepatic enzymes. Seven cases of liver impairment have been reported in the literature with zafirlukast. If liver dysfunction is suspected based upon clinical signs or symptoms, the leukotriene inhibitor should be discontinued.40-44
Churg-Strauss syndrome
Churg-Strauss syndrome (allergic angiitis and granulomatosis) is an uncommon syndrome that generally occurs in patients with asthma and allergic rhinitis. The hallmark features are eosinophilia > 10% of WBC, mono- or polyneuropathy, pulmonary infiltrates, and eosinophilic vasculitis. Several cases of Churg-Strauss have been reported with zafirlukast and montelukast use.45-62 In most of these cases, the leukotriene inhibitor was started while steroids were being withdrawn or within a few months of stopping steroids. It is thought that the syndrome is the result of unmasking a previously existing condition due to systemic steroid withdrawal and not necessarily a direct effect of the leukotriene inhibitor. Nonetheless, clinicians need to monitor the patient for eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy.
August 2002 (use in allergic rhinitis updated March 2003)
Updated versions may be found at http://www.vapbm.org or http://vaww.pbm.med.va.gov
Criteria for Use of Leukotriene Inhibitors in VA Patients
6. Drug interactions 63-67
Zafirlukast is an inhibitor of CYP450 isoenzymes 2C9 and 3A4; therefore, the metabolism of co-administered drugs that utilize 2C9 or 3A4 pathway may be inhibited. Montelukast does not inhibit or induce the CYP450 isoenzymes. Both zafirlukast and montelukast are metabolized via 2C9; co-administered drugs that either induce or inhibit this enzyme may potentially affect the disposition of the leukotriene inhibitor.
7. Dosage
Adult dose
10mg q evening
20mg BID at least 1 hour ac or 2 hours pc
Adjustment in elderly
Cmax and AUC are nearly doubled; dosing suggestions for the elderly not provided
Adjustment for hepatic insufficiency
No adjustment for mild-moderate hepatic insufficiency; pts. with severe impairment or hepatitis have not been studied
Cmax and AUC are doubled in patients with stable EtOH cirrhosis; dosing recommendations not provided
Adjustment for renal insufficiency
Dosage form
10mg film-coated tablet
4 mg and 5mg chew tablet
10mg and 20mg coated tablet
8. Patient Follow-up
Responses vary in different subsets of asthmatics, making it important to individualize therapy. Leukotriene inhibitor therapy should be continued only if pulmonary function, symptoms, or exercise tolerance improves.
1. Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. Ann Intern Med 1999; 130:487-95.
2. Busse W, Raphael GD, Galant S et al. Low-dose fluticasone propionate compared with montelukast for first-line treatment of persistent asthma: a randomized clinical trial. J Allergy Clin Immunol 2001; 107:461-68.
3. O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma. Am J Respir Crit Care Med 2001; 164:1392-1397.
4. Kips JC, O’Connor BJ, Inman MD, et al. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Am J Respir Crit Care Med 2000; 161:996-1001.
5. van Noord JA, Schreurs AJM, Mol SJM, et al. Addition of salmeterol versus doubling the dose of fluticasone propioate in patients with mild to moderate asthma. Thorax 1999; 54(3): 207-212.
6. Matz J, Emmett A, Rickard K, et al. Addition of salmeterol to low-dose fluticasone versus higher-dose fluticasone: an analysis of asthma exacerbations. J Allergy Clin Immunol 2001; 107:783-789.
7. Condemi JJ, Goldstein S, Kalberg C, et al. The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Ann Allergy, Asthma Immunol 1999; 82:383-389.
8. Vermetten FA, et al. Comparison of salmeterol with beclomethasone in adult patients with mild persistent asthma who are already on low-dose inhaled steroids. Asthma 1999; 36(1): 97-106
9. Murray JJ, et al. Concurrent use of salmeterol with inhaled corticosteroids is more effective than inhaled corticosteroid dose increases. Allergy Asthma Proc 1999; 20(3): 173-80.
10. Kelsen SG, et al. Salmeterol added to inhaled corticosteroid therapy is superior to doubling the dose of inhaled corticosteroids: a randomized clinical trial. J Asthma 1999; 36(Cool: 703-15.
11. Bouros D, et al. Formoterol and beclomethasone versus higher dose beclomethasone as maintenance therapy in adult asthma. Eur Respir J 1999; 14(3): 627-32.
12. Woolcock A, Lundback B, Ringdal N, et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153:1481-8.
13. Greening AP, Ind PW, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroids. Allen & Hanburys Limited UK Study Group. Lancet 1994; 23: 344:219-24.
August 2002 (use in allergic rhinitis updated March 2003)
Updated versions may be found at http://www.vapbm.org or http://vaww.pbm.med.va.gov
Criteria for Use of Leukotriene Inhibitors in VA Patients
14. Vichow JC, Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving high-dose inhaled steroids. Am Rev Respir Crit Care Med 2000; 162:578-85.
15. Nelson HS, Busse WW, Kerwin E, et al. Fluticasone propionate/salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroids plus montelukast. J Allergy Clin Immunol 2000; 106:1088-95.
16. Fish JE, Israel E, Murray JJ, et al. Salmeterol powder provides significantly better benefit than montelukast in asthmatic patients receiving concomitant inhaled corticosteroid therapy. Chest 2001; 120:423-430.
17. Laviolette M, Malmstrom K, Lu S, et al. Montelukast added to inhaled beclomethasone in treatment of asthma. Am J Respir Crit Care Med 1999; 160:1862-1868.
18. Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial. Lancet 2001 Jun 23; 357(9273): 2007-11.
19. Lofdahl CG, Reiss TF, Leff JA, et al. Randomized, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 1999; 319:87-90
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