Proposed Preferred Drug List. Clinical Criteria

Transcription

1 Prpsed Preferred Drug List with Clinical Criteria Prpsal fr TennCare May 20, 2008 Page 1 f 56

2 Respnsibilities f the TennCare Pharmacy Advisry Cmmittee Surce: Tennessee Cde/Title 71 Welfare/Chapter 5 Prgrams and Services fr Pr Persns/Part 24 Tennessee TennCare Pharmacy Advisry Cmmittee/ thrugh Make recmmendatins regarding a preferred drug list (PDL) t gvern all state expenditures fr prescriptin drugs fr the TennCare prgram. The TennCare Pharmacy Advisry Cmmittee shall submit t the bureau f TennCare bth specific and general recmmendatins fr drugs t be included n any state PDL adpted by the bureau. In making its recmmendatins, the cmmittee shall cnsider factrs including, but nt limited t, efficacy, the use f generic drugs and therapeutic equivalent drugs, and cst infrmatin related t each drug. The cmmittee shall als submit recmmendatins t the bureau regarding cmputerized, vice, and written prir authrizatin, including prir authrizatin criteria and step therapy. The state TennCare pharmacy advisry cmmittee shall include evidence-based research in making its recmmendatins fr drugs t be included n the PDL. The TennCare bureau shall cnsider the recmmendatins f the state TennCare pharmacy advisry cmmittee in amending r revising any PDL adpted by the bureau t apply t pharmacy expenditures within the TennCare prgram. The recmmendatins f the cmmittee are advisry nly and the bureau may adpt r amend a PDL regardless f whether it has received any recmmendatins frm the cmmittee. It is the legislative intent that, insfar as practical, the TennCare bureau shall have the benefit f the cmmittee s recmmendatins prir t implementing a PDL r prtins theref. Keep minutes f all meetings including vtes n all recmmendatins regarding drugs t be included n the state preferred drug list The chair may request that ther physicians, pharmacists, faculty members f institutins f higher learning, r medical experts wh participate in varius subspecialties act as cnsultants t the cmmittee as needed. Page 2 f 56

3 PDL Decisin Prcess The primary clinical decisin that needs t be made is determining if the drugs within the therapeutic class f interest can be cnsidered therapeutic alternatives. A Therapeutic Alternative is defined by the AMA as: drug prducts with different chemical structures but which are f the same pharmaclgical and/r therapeutic class, and usually can be expected t have similar therapeutic effects and adverse reactin prfiles when administered t patients in therapeutically equivalent dses 1. The Cmmittee shuld nt feel bligated t decide if every drug within the therapeutic class is exactly equal t all ther drugs within the class, nr shuld they feel bligated t decide if every drug within the therapeutic class wrks equally well in every special patient ppulatin r in every disease. In special situatins (e.g., presence f cmrbid cnditins) and in special ppulatins (e.g., pediatrics) use f a nn-preferred drug might be the mst apprpriate therapy. These cases can be handled thrugh prir authrizatin (PA). PA serves as a safety valve in that it facilitates use f the mst apprpriate agent regardless f PDL status. LENGTH OF AUTHORIZATIONS: Dependent upn diagnsis and length f therapy needed t treat. (Mst medicatins are used chrnically, and thus wuld be apprved fr 1 year.) 1. Is there any reasn the patient cannt be changed t a medicatin nt requiring prir apprval within the same class? Acceptable reasns include: Allergy t medicatins nt requiring prir apprval Cntraindicatin t r drug-t-drug interactin with medicatins nt requiring prir apprval Histry f unacceptable/txic side effects t medicatins nt requiring prir apprval 2. The requested medicatin may be apprved if bth f the fllwing are true: If there has been a therapeutic failure f at least tw medicatins within the same class nt requiring prir apprval (unless therwise specified) The requested medicatin s crrespnding generic (if a generic is available and preferred by the State) has been attempted and failed r is cntraindicated 3. The requested medicatin may be apprved if the fllwing is true: An indicatin which is unique t a nn-preferred agent and is supprted by peer-reviewed literature r an FDA apprved indicatin exists The infrmatin prvided fr each drug class is rganized int the fllwing sectins, when applicable: BACKGROUND: General verview Pharmaclgy Therapeutic effect(s) Adverse reactins Outcmes data Place in therapy accrding t current Treatment Guidelines RECOMMENDATION: General recmmendatin regarding utility and therapeutic equivalence amng the agents in the class, as well as requirements fr prduct availability (PDL placement) 1 AMA Plicy H Drug Frmularies and Therapeutic Interchange Page 3 f 56

4 RESPIRATORY AGENTS NEW: BETA 2 AGONISTS, ORAL BACKGROUND Beta 2 -agnists are the mst effective brnchdilatrs available fr the treatment f brnchspasms; hwever, inhaled shrt-acting beta 2 -agnists are preferred ver ral frmulatins because the ral agents are assciated with increased systemic effects. The ral beta 2 -agnists include albuterl, metaprterenl and terbutaline. Beta 2 -agnists stimulate beta-adrenergic receptrs f intracellular adenyl cyclase causing relaxatin f brnchial smth muscle and inhibitin f release f mediatrs f hypersensitivity frm mast cells. Albuterl is FDA-apprved fr the acute relief f brnchspasm in asthma as well as fr prphylaxis f exercise-induced asthma. Metaprterenl and terbutaline are indicated fr acute relief f brnchspasm in asthma as well as brnchspasms assciated with brnchitis and emphysema. Cmmn adverse reactins include: headache, tachyarrhythmias, tremr, and nervusness. Albuterl can als cause erythema multifrme / Stevens-Jhnsn syndrme, hypkalemia, mycardial infarctin, and pulmnary edema. Metaprterenl has been knwn t cause hypertensin and paradxical brnchspasms. Terbutaline can als cause paradxical brnchspasms r seizure. Metaprterenl is cntraindicated in patients with chrnic tachyarrhythmias, and the syrup is cntraindicated in patients with allergy t parabens. All beta 2 -agnists shuld be used with cautin in patients with cardivascular r cnvulsive disrders, diabetes mellitus, hyperthyridism, r hypkalemia. In additin, terbutaline shuld be used with cautin in patients with hypertensin. Albuterl and metaprterenl are pregnancy categry C; hwever, terbutaline is categry B. It is recmmended that albuterl be started at lwer dses initially and increased as tlerated in children and in the elderly. The dse f terbutaline shuld be reduced in patients with CrCl ml/min, and it is cntraindicated in patients with CrCl < 10 ml/min. Head t Head Trials: A duble-blind, 3-way crssver, single dse study examined the effects f ral albuterl 4 mg, metaprterenl sulfate 20 mg, and terbutaline sulfate 5 mg in 20 mderate-t-severe asthmatic patients. The study fund ral metaprterenl had a mre rapid nset f actin, prducing greater imprvements in FEV 1 at 30 minutes than albuterl r terbutaline. Albuterl and terbutaline, hwever, prduced significantly greater imprvements in FEV 1 than metaprterenl between 6 and 8 hurs after administratin. The incidence f side effects was 41% in the albuterl grup, 59% in the metaprterenl grup, and 73% in the terbutaline grup. Sixty-five children with asthma were given albuterl syrup 2 mg three times daily r metaprterenl syrup 10 mg three times daily. The albuterl treatment grup shwed a greater change in baseline FEV 1 (29% vs. 20%) n treatment days 1 and 28, a greater brnchdilatin frm hurs 2 t 8 pst administratin, and a smaller chrntrpic effect 1 and 1.5 hurs pst administratin n bth days 1 and 8. Similar safety prfiles were seen between the tw drugs. Place in Therapy: Metaprterenl and terbutaline have similar efficacy t albuterl; hwever, metaprterenl and terbutaline pssess mre beta 1 -activity and are therefre assciated with a greater incidence f tachycardia. While metaprterenl and terbutaline seem t have a quicker nset f actin (30 minutes and minutes, respectively, cmpared t minutes with albuterl), albuterl has a lnger duratin f actin (6-8 hurs cmpared t 4-8 with terbutaline and 4 hrs with metaprterenl). Terbutaline has als fund utility in the management f pre-term labr. Page 4 f 56

5 RESPIRATORY AGENTS Because beta 2- agnists relieve intermittent episdes f asthma as well as prevent exercise-induced asthma, current treatment guidelines published by the Natinal Asthma Educatin and Preventin Prgram (NAEPP), the Natinal Institutes f Health (NIH), Natinal, Heart, Lung, Bld Institute (NLBHI), as well as the Glbal Initiative fr Asthma (GINA), Glbal Strategy fr Asthma Management and Preventin advcate the use f an inhaled shrt-acting beta 2 agnist fr all patients with asthma Oral beta 2 agnists have a limited place in chrnic asthma management due t their greater incidence f side effects and lnger nset f actin. Current treatment guidelines frm the Medical Advisry Panel fr the Pharmacy Benefits Management Strategic Healthcare Grup state that shrt-acting beta 2 agnists shuld be used n an as needed basis fr the majrity f symptmatic patients with COPD. These agents may als be administered n a scheduled basis fr thse COPD patients wh are uncntrlled n ipratrpium alne. Oral beta 2 agnists can be useful fr patients wh are intlerant t all inhaled beta 2 agnists, althugh such cases are rare and the risk f systemic adverse reactins is increased significantly. These guidelines further state that all shrt-acting agents have similar efficacy and selectin culd be based n cst. RECOMMENDATION: The use f beta 2 -agnists t relieve intermittent episdes f asthma and COPD is the standard f practice. Hwever, the lwer incidence f systemic adverse events makes inhaled beta 2 -agnists preferred ver ral agents. While the use f ral beta 2 -agnists is rare in the treatment f brnchspasms, this rute f administratin prvides a useful alternative fr thse patients wh are unable t use the inhaled medicatins. All agents in this class have similar efficacy; hwever, due t the increased beta 1 activity, metaprterenl and terbutaline are nt as well-tlerated. While metaprterenl and terbutaline have a quicker nset f actin, albuterl has a lnger duratin f actin. In rder t ensure prvider chice amng agents and t allw fr the use f terbutaline in pre-term labr, it is recmmended that at least albuterl and terbutaline be available fr use. PREFERRED ALBUTEROL, syrup, tablets (cmpares t Prventil, VSpire ) ALBUTEROL ER, tablets (cmpares t VSpire ER) TERBUTALINE, tablets (cmpare t Brethine ) NEW: BETA 2 AGONIST, ORAL NON-PREFERRED METAPROTERENOL, syrup, tablets PROVENTIL (albuterl) VOSPIRE ER (albuterl ER) NEW: XANTHINE DERIVATIVES BACKGROUND The xanthine derivatives, aminphylline and thephylline, can be used t treat bth asthma and COPD. Aminphylline is a 2:1 cmplex f thephylline and ethylenediamine. Thugh the mechanism f actin f the xanthine derivatives is prly understd, it is thught bth thephylline and aminphylline exert their effect by inhibiting phsphdiesterase (PDE) III and IV, resulting in smth muscle relaxatin and brnchdilatin. Additinally, they appear t enhance calcium uptake thrugh adensinemediated channels causing an increase in the frce f cntractin f the diaphragm. Bth aminphylline and thephylline are indicated fr the symptmatic treatment r preventin f chrnic asthma and COPD. Page 5 f 56

6 RESPIRATORY AGENTS The mst cmmn adverse reactins seen with xanthine derivatives are diuresis, dizziness, GI upset, insmnia, irritability, headache, and tremr r restlessness. These adverse events increase with increased levels. Rare, but severe, adverse effects include arrhythmias, hypersensitivity reactins, intracranial hemrrhage, seizure, and Stevens- Jhnsn syndrme. Xanthine derivatives are cntraindicated in patients with active peptic ulcer disease r underlying, untreated seizure disrder, as xanthines may exacerbate these c-mrbid cnditins. Risk fr thephylline txicity is increased in patients with CHF, fever 102 F fr 24 hurs, liver disease, hypthyridism, acute pulmnary edema, sepsis, and shck; patients with these cnditins shuld be mnitred clsely fr signs f thephylline txicity. In additin, cautin shuld be used in patients <1 and > 60 years ld, and in patients wh are discntinuing smking, because their clearance f thephylline is reduced. There is als a risk f exacerbatins f cardiac tachyarrhythmias r seizures in patients with these c-mrbid cnditins wh take a xanthine derivative. Cncmitant use with ephedrine r ther sympathmimetic brnchdilatrs may cause txic effects f xanthine derivatives. Aminphylline and thephylline are metablized by the cytchrme P450 enzyme system, specifically CYP1A2, CYP2E1 and CYP3A3 leading t several drug t drug interactins. There may be decreased serum levels f xanthine derivatives if cncmitantly administered with autinducers, such as carbamazepine, phenytin r rifampin. There may be increased serum xanthine levels, pssibly txic, if cadministered with enzyme inhibitrs, such as cimetidine, ciprflxacin, r macrlides. Xanthine derivatives will increase the renal clearance f lithium and decrease the clearance f alchl. The pharmackinetic prperties f xanthine derivatives are altered based n age and cmrbid cnditin; therefre, dsing shuld be recmmended using specific patient parameters. Aminphylline and thephylline dses shuld be increased in patients underging hemdialysis, as these agents are dialyzed. Dses shuld als be reduced in geriatric patients and thse with liver disease. Patients with mild persistent asthma (23-46 years ld) wh were stable n the equivalent f budesnide 200 mcg daily were randmized t receive either inhaled budesnide 400 mcg daily (n=25), mntelukast 10 mg daily (n=25) r sustained release thephylline 400 mg daily after a 3-week run-in perid. At the end f the 3-mnth study, there were n statistically significant differences between the grups with regard t change frm baseline in initial mrning peak expiratry flw (PEF) r frced expiratry vlume in 1 secnd (FEV 1 ), daytime and nighttime symptm scres, r supplemental beta-agnist use. Asthma exacerbatins ccurred in 16% f patients receiving mntelukast and 12.5% f patients receiving thephylline. N asthma exacerbatins were reprted in the patients receiving budesnide. Accrding t the 2007 NHLBI guidelines, sustained-release thephylline is a lng-term cntrller medicatin recmmended as an alternative r an adjunct t inhaled crticsterids (ICS) in patients wh are nt candidates fr higher dses f inhaled crticsterids r lng-acting beta agnists. Thephylline is a less desirable adjunctive therapy than the leuktriene receptr antagnists, crmlyn and nedcrmil, because f its safety prfile and the need t adjust dses based n diet, drug interactins and variable metablism with age. Aminphylline is generally nly recmmended in the IV frm fr the management f asthma exacerbatins. RECOMMENDATION: Bth aminphylline and thephylline are indicated fr the symptmatic treatment r preventin f chrnic asthma and COPD. Thephylline is recmmended as an alternative t lw-dse inhaled crticsterids (ICS) r as an adjunct t inhaled crticsterids (ICS) in patients wh are nt candidates fr higher dses f inhaled crticsterids r lng acting-beta agnists. While bth agents are clinically equivalent, aminphylline is generally nly used IV fr the management f asthma exacerbatins. Therefre, it is recmmended that at least thephylline be available fr use in asthma patients. Page 6 f 56

7 RESPIRATORY AGENTS PREFERRED AMINOPHYLLINE (Cmpares t Nrphyl, Phyllcntin, Truphylline ) ELIXOPHYLLIN (thephylline) THEO-24 (thephylline ER) THEOPHYLLINE ER/IR(cmpares t TheCap, Thechrn, The-Dur, The- Time, Quinrn-T, Uniphyl ) NEW: XANTHINE DERIVATIVES NON-PREFERRED THEOCAP (thephylline) THEOCHRON (thephylline) THEO-DUR (thephylline) UNIPHYL (thephylline) References: 1. Facts and Cmparisns n-line. Versin 4.0; Wlters Kluwer Health, Inc.; Accessed September, Thmpsn MICROMEDEX n-line Accessed September, Natinal Heart Lung and Bld Institute. Expert Panel Reprt 3: Guidelines fr The Diagnsis and Management f Asthma Yurdakul AS, Taci N, Eren A, et al: Cmparative efficacy f nce-daily therapy with inhaled crticsterid, leuktriene antagnist r sustained-release thephylline in patients with mild persistent asthma. Respir Med 2003; 97(12): NEW: MAST CELL STABILIZERS BACKGROUND Mast cell degranulatin is imprtant in the initiatin f immediate respnses fllwing expsure t allergens. Asthmatics with an allergic cmpnent usually have increased numbers f mast cells within the walls f their respiratry tact. Currently, there are tw mast cell stabilizers, crmlyn and nedcrmil, available fr use in these patients. After expsure t specific antigens, the mast cells release histamine, and the slwreacting substance f anaphylaxis (SRS-A), a leuktriene. Crmlyn inhibits the release f histamine and SRS-A frm the mast cells. Nedcrmil sdium inhibits the in vitr activatin f, and mediatr release frm, a variety f inflammatry cells, including esinphils, neutrphils, macrphages, mast cells, mncytes, and platelets. Crmlyn is FDA apprved fr prphylactic management f brnchial asthma and preventin f brnchspasms in patients 2 years and lder. Nedcrmil is FDA apprved fr prphylactic management f asthma in patients 6 years r lder. Althugh mast cell stabilizers are generally well-tlerated agents, bth agents can cause thrat irritatin, dry muth, bad taste, nausea/vmiting, and cugh. Crmlyn shuld be used with cautin in patients less than 2 years ld, and thse with crnary artery disease and cardiac arrhythmias. Mast cell stabilizers are nt fr use in acute asthma attacks. Head t Head Studies A multicenter, duble-blind, grup cmparative trial cmpared nedcrmil t crmlyn and placeb in patients already receiving shrt-acting inhaled beta 2 - agnists and inhaled crticsterids fr asthma. Bth mast cell stabilizers reduced symptms, but nedcrmil was fund t be mre effective than crmlyn in reducing asthma symptms in patients wh were maintained n regimens f lw t mderate dses f inhaled crticsterids. Page 7 f 56

8 RESPIRATORY AGENTS A duble-blind, crss-ver study invlving 12 children, ages 6.5 years t 13.5 years, with knwn exercise induced asthma (EIA), cmpared nedcrmil 4 mg, crmlyn 10 mg, and placeb. Participants exercised fr 6 minutes n a 10% grade treadmill adjusted t maintain a maximum heart rate f 180 beats/min. FEV 1 was measured befre administratin and pst-exercise. Bth drugs prvided equal prtectin frm EIA. Current treatment guidelines published by the Natinal Asthma Educatin and Preventin Prgram (NAEPP), the Natinal Institutes f Health (NIH), Natinal, Heart, Lung, Bld Institute (NLBHI), as well as the Glbal Initiative fr Asthma (GINA), Glbal Strategy fr Asthma Management and Preventin, emphasize the use f inhaled crticsterids (ICS) as first-line therapy fr managing persistent asthma symptms. Hwever, crmlyn and nedcrmil are recmmended as alternatives t ICS as lng-term cntrl medicatins particularly in thse yunger than 5 years f age, with mild persistent asthma. These agents may als be used t prevent exercise-induced brnchspasm. RECOMMENDATION: Crmlyn and nedcrmil prvide alternatives t inhaled crticsterids in the management f mild persistent asthma. While current guidelines make n differentiatin between the tw prducts, studies have shwn that nedcrmil may be mre effective than crmlyn in the treatment f asthma. Crmlyn is supplied in a nebulizer slutin as well as a MDI and is apprved in yunger patients than nedcrmil. Therefre, it is recmmended that bth nedcrmil and crmlyn prducts be available fr use in patients with asthma. NEW: MAST CELL STABILIZERS NON-PREFERRED PREFERRED CROMOLYN nebulizer slutin QL (cmpares t Intal ) INTAL MDI QL (crmlyn) TILADE MDI QL (nedcrmil) Quantity Limits Crmlyn 20 mg/2ml nebulizer slutin 120 vials/mnth Intal 20mg/mL nebulizer slutin 120 vials/mnth Intal 800 mcg/actuatin 8.1 g (112 sprays) MDI 2 inhalers/mnth Intal 800 mcg/actuatin 14.2 g (200 spays) MDI 2 inhalers/mnth Tilade 1.75 mg/actuatin 16.2 g (104 sprays) MDI 3 inhalers/mnth INTAL QL nebulizer slutin (crmlyn) Page 8 f 56

9 RESPIRATORY AGENTS References 1. Facts and Cmparisns n-line. Versin 4.0; Wlters Kluwer Health, Inc.; Accessed September, Thmpsn MICROMEDEX n-line Accessed September, Natinal Heart Lung and Bld Institute. Expert Panel Reprt 3: Guidelines fr The Diagnsis and Management f Asthma Natinal Asthma Educatin and Preventin Prgram Expert Panel Reprt: Guidelines fr the Diagnsis and Management f Asthma. Expert Panel Reprt 3. Available at Accessed Octber 3, Cmis A, Valletta EA, Sette L, et al: Cmparisn f nedcrmil sdium and sdium crmglycate administered by pressurized aersl, with and withut a spacer device in exercise-induced asthma in children. Eur Respir J 1993; 6: Lal S, Drw PD, Venh KK, et al: Nedcrmil sdium is mre effective than crmlyn sdium fr the treatment f chrnic reversible bstructive airway disease. Chest 1993; 104: REREVIEW: LONG-ACTING BETA 2 AGONIST/INHALED CORTICOSTEROID COMBINATIONS BACKGROUND Fr the treatment f asthma at any age, it is recmmended t add a lng acting beta 2 agnist (LABA) t an inhaled crticsterid (ICS) if the asthma cannt be cntrlled n an ICS alne. Therefre, tw prducts are nw available which cmbine an ICS and a LABA: fluticasne with salmeterl (Advair ) and budesnide with frmterl (Symbicrt ). Salmeterl and frmterl selectively bind t the beta 2 receptrs in brnchial smth muscle resulting in brnchial relaxatin and inhibitin f the release f hypersensitivity mediatrs frm mast cells. Crticsterids, budesnide and fluticasne, decrease the metablism f arachidnic acid and reduce the synthesis f prinflammatry prstaglandins and leuktrienes. Crticsterids als increase the number and respnsiveness f beta-adrenergic receptrs, blck the late-phase reactin t allergens, reduce airway hyperrespnsiveness and inhibit inflammatry cell migratin and activatin. The cmbinatin LABA / ICS prducts are apprved fr the chrnic treatment f persistent asthma. These agents shuld nt be used fr acute asthma exacerbatins. The dry pwder frmulatin (DPI) f fluticasne (250 mcg) and salmeterl (50 mcg) are als apprved fr the treatment f chrnic bstructive pulmnary disease (COPD) assciated with chrnic brnchitis. The mst cmmn adverse events assciated with these cmbinatin prducts include cugh, headache, nausea, ral candidiasis, pharyngitis and upper respiratry infectin. Bth f these prducts carry a black bx warning abut a small, but significant, increased risk f life-threatening asthma episdes r asthma related deaths bserved in patients taking salmeterl in the Salmeterl Multi-center Asthma Research Trial (SMART). Cautin shuld be used in patients with hepatic impairment wh take fluticasne/salmeterl due t pssible accumulatin f bth active ingredients. This prduct shuld als be used cautiusly in patients with milk allergy because the salmeterl cmpnent cntains milk prteins. Frmterl has been assciated with exacerbatins f cnvulsive disrders, hypkalemia and thyrtxicsis, and shuld be used cautiusly in these patient ppulatins. The sterid cmpnents may cause an inadequate adrenal respnse, bne mineral density lss r a small grwth velcity reductin in children and adlescents. The beta agnist cmpnent may cause cardivascular disrders such as palpitatins r tachycardia due t stimulatin f beta receptrs in the heart. Page 9 f 56

10 RESPIRATORY AGENTS A randmized, duble-blind, duble-dummy study cmpared the efficacy f fluticasne/salmeterl (250/50 mcg BID) t budesnide/frmterl (200/6 mcg BID) in 688 adults with persistent asthma and a FEV 1 f 81% (CONCEPT trial). After 4 weeks n stable dsing bth grups cntinued fr an additinal 48 weeks n either a stable dse f fluticasne/salmeterl r an adjustable dsing regimen f budesnide/frmterl that required either halving the dse and stepping up r dwn as indicated by the percentage f symptm free days (primary endpint), presence r absence f ncturnal awakenings due t asthma, frequency f rescue medicatin use r changes in mrning peak expiratry flw (PEF). Patients receiving stable dses f fluticasne/salmeterl had a greater percentage f symptm-free days cmpared t thse receiving adjustable budesnide/frmterl (p=0.034) and fewer emergency rm visits r hspitalizatins (p=0.008). Patients in the adjustable budesnide/frmterl grup used an average f 1.8 inhalatins daily with nearly 83% stepping dwn t ne inhalatin daily. A fllw up t the CONCEPT trial lked at lng-term efficacy as well as impact n health-related quality f life f the stable-dse regimen f fluticasne/salmeterl and the adjustable maintenance dsing regimen f budesnide/frmterl. The mean change frm baseline in the Asthma Quality f Life Questinnaire s (AQLQ) verall scre was nt statistically different between the tw grups (p=0.121). Hwever, a pst hc regressin analysis did identify a statistically significant difference in AQLQ scre at 28 (p=0.038) and 52 (p=0.009) weeks in favr f the fluticasne/salmeterl grup. A randmized, duble-blind, duble-dummy, placeb-cntrlled trial was cmpleted ver a 12 week perid t cmpare the efficacy and safety f budesnide/frmterl t budesnide, frmterl and placeb. Patients 12 years f age (n=596) with mderate t severe persistent asthma wh were previusly receiving an ICS were placed n budesnide 160 mcg BID. After tw weeks, patients were randmized t the cmb prduct (160/4.5 mcg BID), budesnide (160 mcg BID), frmterl (4.5 mcg BID), budesnide (160 mcg BID) + frmterl (4.5 mcg BID), r placeb BID. The primary efficacy endpints were mean change frm baseline f FEV 1 and mean change frm baseline in 12-hur FEV 1. The results were similar fr all utcmes measures in the budesnide/frmterl and the budesnide + frmterl grups. The cmbinatin shwed greater imprvement in FEV 1 than the budesnide, frmterl, r placeb grups (p= 0.049). Fewer patients n the cmbined agents experienced wrsening asthma symptms (p 0.025). All f the treatments had similar safety prfiles. The 2007 NHLBI guidelines recmmend the additin f a LABA t an ICS fr thse whse asthma cannt be cntrlled n an ICS alne. The 2007 GOLD guidelines suggest the additin f an ICS t a LABA fr patients with severe COPD whse symptms cannt be cntrlled n an as needed dsage f a SABA and a scheduled dse f a LABA. RECOMMENDATION: The cmbinatin f an ICS and LABA is a reasnable agent fr the treatment f asthma and COPD. There is insufficient evidence t shw that ne cmbinatin prduct is superir t anther; therefre, these agents are assumed t be therapeutically equivalent. The 2007 NHLBI guidelines recmmend the additin f a LABA t an ICS fr patients f all ages whse asthma is nt cntrlled n an ICS alne. The 2007 GOLD guidelines suggest the additin f an ICS t a LABA fr patients with severe COPD whse symptms cannt be cntrlled n a LABA and an as needed SABA. Based n these guidelines and the current medical literature, it is recmmended that the cmbinatin LABA/ICS agents be reserved fr asthma patients wh require frequent use f an inhaled shrt-acting brnchdilatr while maintained n an ptimal dse f an inhaled sterid, and fr COPD patients wh have symptms despite ptimal dses f a LABA. PAC: Apprved the prpsed recmmendatin as stated by First Health. TennCare: Accepted the PAC s recmmendatins. Page 10 f 56

11 RESPIRATORY AGENTS REREVIEW: LONG-ACTING BETA 2 AGONIST/INHALED CORTICOSTEROID COMBINATIONS PREFERRED NON-PREFERRED N/A ADVAIR DISKUS CC,QL (salmeterl/fluticasne DPI) ADVAIR HFA CC,QL (salmeterl/fluticasne MDI) SYMBICORT CC,QL (frmterl/budesnide MDI) Quantity Limits Advair Diskus = 1/mnth (billing units f 28 r 60) Advair HFA = 1/mnth (billing units f 12) Symbicrt = 1/mnth (billing units f 10.2) PAC: Apprved the quantity limits as submitted; hwever, asked that the billing units be added t the criteria dcument. TennCare: Accepted the PAC s recmmendatins. Clinical Criteria fr Advair / Symbicrt Advair / Symbicrt will nly be apprved if ONE f the fllwing criteria is met: Fr the treatment f asthma r the treatment f ther reversible airway disease(s) where ptimal dses f inhaled sterids are being used and breakthrugh symptms require frequent use f inhaled shrt-acting brnchdilatrs; OR Fr the treatment f COPD where ptimal dses f a lng-acting beta agnist are being used and symptms are still uncntrlled. PAC: Recmmended that these criteria be tabled until First Health culd determine if the system is capable f ding an aut lk back fr: [an ICS r a LABA] and a SABA. TennCare: Accepted the recmmendatin f the PAC t table the criteria until First Health culd determine if the aut lk back was pssible. Page 11 f 56

12 RESPIRATORY AGENTS References 1. Facts and Cmparisns n-line. Versin 4.0; Wlters Kluwer Health, Inc.; Accessed September, Thmpsn MICROMEDEX n-line Accessed September, Natinal Heart Lung and Bld Institute. Expert Panel Reprt 3: Guidelines fr The Diagnsis and Management f Asthma Rabe KF, Hurd S, Anzuet A, et al. Glbal strategy fr the diagnsis, management, and preventin f chrnic bstructive pulmnary disease: GOLD Executive Summary. Am J Respir Crit Care Med 2007;176: Natinal Asthma Educatin and Preventin Prgram Expert Panel Reprt: Guidelines fr the Diagnsis and Management f Asthma. Expert Panel Reprt 3. Available at Accessed Octber 3, Fitzgerald JM, Bulet LP, Fllws RM. The CONCEPT trial: a 1-year, multicenter, randmized, duble-blind, duble-dummy cmparisn f a stable dsing regimen f salmeterl/fluticasne prpinate with an adjustable maintenance dsing regimen f frmterl/budesnide in adults with persistent asthma. Clin Ther. 2005;27(4): Nnan M, Rsenwasser L, Martin P, et al. Efficacy and safety f budesnide and frmterl in ne pressurized metered-dse inhaler in adults and adlescents with mderate t severe asthma: a randmized clinical trial. Drugs. 2006;66(17): Prince DB, Williams AE, Yxall S. Salmeterl/fluticasne stable-dse treatment cmpared with frmterl/budesnide adjustable maintenance dsing: impact n health-related quality f life. Respir Res. 207;8:46. Page 12 f 56

13 GASTROINTESTINAL AGENTS Drug REREVIEW: PROTON PUMP INHIBITORS BACKGROUND Gastresphageal reflux refers t the retrgrade mvement f gastric cntents frm the stmach int the esphagus. When the esphagus is repeatedly expsed t refluxed material fr prlnged perids f time, inflammatin f the esphagus can ccur. In severe cases, reflux may lead t serius cmplicatins such as esphageal strictures, esphageal ulcers, mtility disrders, perfratin, hemrrhage, aspiratin and Barrett s Esphagus. Peptic ulcer disease, n the ther hand, refers t a grup f ulcerative disrders f the upper gastrintestinal tract that require acid and pepsin fr their frmatin. There are three cmmn frms f peptic ulcer: H. pylri assciated, nnsteridal anti-inflammatry drug (NSAID) assciated, and stress ulcers. Chrnic ulcers (H. pylri - and NSAIDassciated) differ frm acute ulcers (stress ulcers) in their depth, etilgy, clinical presentatin and tendency t recur. After ral administratin, Prtn Pump Inhibitrs (PPIs) enter actively secreting parietal cells. At highly acidic ph, the agents are cnverted t a sulfnamide miety which binds + + t the luminal surface f H /K -ATPase resulting in irreversible inhibitin f the gastric prtn pump and a lng-lasting antisecretry effect. FDA-Apprved Indicatins fr Adults: Dudenal Ulcer Dyspepsia H. pylri GERD Ersive esphagitis esmeprazle Treatment and Maintenance lansprazle meprazle meprazle OTC meprazle / sdium bicarbnate Treatment and Maintenance Treatment Treatment Treatment and Maintenance Treatment and Maintenance Treatment and Maintenance pantprazle Treatment and Maintenance rabeprazle Treatment Treatment and Maintenance Gastric Ulcers Hypersecretry cnditins NSAIDinduced ulcers Other FDA-Apprved Indicatins: Esmeprazle is indicated fr the shrt term treatment f GERD in children years ld. Lansprazle is indicated fr the shrt term treatment f GERD in children >1 years ld and fr shrt term treatment f ersive esphagitis in children 1-11 years ld. Omeprazle is indicated fr the treatment f GERD and ther acid related disrders in children 2 years ld. Omeprazle/sdium bicarbnate 40/1100 mg is indicated fr upper GI bleeding prphylaxis in critically ill patients. Page 13 f 56

14 GASTROINTESTINAL AGENTS The mst cmmn adverse reactins seen with PPIs include abdminal pain, diarrhea, headache and nausea. All f the PPIs may rarely cause hip fracture and rhabdmylysis. Other rare but serius side effects include: Severe skin rashes with esmeprazle, pantprazle and rabeprazle. Pancreatitis, hepattxicity and interstitial nephritis with meprazle. Hyperglycemia with pantprazle. PPIs shuld be used with cautin in thse with hepatic disease as dsage adjustments may be required. Lansprazle, meprazle and rabeprazle shuld be used with cautin in patients with gastric malignancy as symptmatic respnse des nt preclude the presence f gastric malignancy. The ral disintegrating lansprazle tablets cntain phenylalanine; therefre, this dsage frm shuld be used with cautin in phenylketnurics. The lng term use f meprazle may cause atrphic gastritis. Sdium bicarbnate (ne f the cmpnents f Zegerid ) shuld be used with cautin in patients with acid base balance prblems, Bartter s syndrme, hypcalcemia, hypkalemia, metablic alkalsis and respiratry alkalsis. Omeprazle is Pregnancy Categry C; hwever, all ther agents in this class are Pregnancy Categry B. All PPIs have the ptential t cause ph-dependent drug interactins resulting in a significant decrease in the absrptin f weak bases, such as ketcnazle r itracnazle. Omeprazle inhibits CYP2C19 resulting in ptential interactins with diazepam, phenytin, and warfarin; hwever, esmeprazle dse nt seem t have this interactin. Rabeprazle and pantprazle d nt interact with the CYP450 system significantly. There have been numerus cmparative studies invlving the varius PPIs; hwever, the data has failed t clearly indicate clinical superirity fr ne agent ver the thers. Furthermre, studies have shwn that mst patients can be switched frm ne PPI t anther withut significant impact n efficacy r tlerability. A duble-blind, duble-dummy, crssver trial randmized 240 patients t receive daily treatment, first fr 4 weeks with meprazle 20 mg, and then fr 4 weeks with rabeprazle 20 mg. Each phase f 4 weeks was separately assessed by patients thrugh questinnaires and by nn-directed questining abut psitive and negative side effects. At the end f the study perid patients cmpared the tw medicatins in seven treatment characteristics. Participants were als asked abut their further attitude tward changing medicatins within the class. Results shwed the majrity f patients culd be switched t anther PPI withut nticeable differences in nging primary symptm cntrl. Abut 1/3 f patients were able t express a preference fr ne f the treatments. Favr was shwn t rabeprazle fr absence f unwanted side effects (p=0.0467) and presence f psitive side effects (p=0.0188). Hwever, n difference between the tw PPIs was detected in the primary utcme variable f ttal treatment preference scre. Mst f the patients already cntrlled n a PPI (83.6%) indicated they wuld be willing t try anther medicatin within the drug class. There are tw main treatment strategies fr GERD: The step up apprach uses an H 2 -receptr antagnist (H 2 RA) as initial therapy, and if it fails t relieve symptms, the H 2 RA is changed t a PPI. The step dwn apprach uses a PPI as initial therapy, and if the patient is symptm-free after 8 weeks, therapy is changed t an H 2 RA. The H 2 RA may then be stepped dwn ver time t n medicatin depending n symptms. The 2005 guidelines frm the American Cllege f Gastrenterlgy (ACG) and the 2006 guidelines fr the Institute fr Clinical Systems Imprvement (ICSI) recmmend a step dwn apprach t GERD. They recmmend empiric therapy (therapy withut diagnstic testing) with a trial f a standard-dse PPI fr 4-8 weeks alng with antacids and lifestyle mdificatins unless alarm symptms are present such as dysphagia, dynphagia, bleeding, weight lss, r anemia are present. Patients with alarm symptms, persistent symptms f GERD r thse wh d nt respnd t a curse f standard-dse PPI shuld underg further diagnstic testing. Page 14 f 56

15 GASTROINTESTINAL AGENTS In cntrast, the current guidelines frm the Veteran Health Administratin/Department f Defense (VHA/DD) Medical Advisry Panel fr the Pharmacy Benefits Management Strategic Healthcare Grup state that empiric initial treatment may cnsist f either a H 2 RA r PPI. They state that there is a lack f evidence and cnsensus t supprt using ne treatment apprach (step up, step dwn, r n step therapy) ver the thers. Accrding t the VHA/DD guidelines, expert pinin cnsiders an H 2 RA t be an apprpriate first-line therapeutic ptin in patients withut alarm symptms r histry f cmplicated GERD, and wh have nt undergne endscpy, have negative endscpy r have mild esphagitis. The recmmended acute dses f H 2 RA are as fllws: Cimetidine 400 mg BID r 800 mg QHS Famtidine 20 mg BID r 40 mg QHS Nizatidine 150 mg BID r 300 mg QHS Ranitidine 150 mg BID r 300 mg QHS The VHA/DD guidelines als state that symptm relief with standard dses f H 2 RA usually ccurs within 2 weeks and escalating the dse prduces minimal t n benefit ver switching t a PPI. All 3 guidelines (ACG, ICSI and VAH/DD) recmmend endscpy t screen fr Barrett s esphagus r esphageal adencarcinma in patients with a lng duratin f GERD symptms (>5-10 years). They als cncur that there is little evidence favring ne PPI ver anther. RECOMMENDATION Prtn Pump Inhibitrs (PPIs) are a useful class f acid-suppressing drugs used fr a variety f GI diagnses. All agents within the PPI class have been shwn t display similar safety and efficacy, and current guidelines d nt differentiate between the available agents. Therefre, the PPIs can be cnsidered therapeutic alternatives t ne anther. In rder t ensure adequate patient and prescriber chice, it is recmmended that at least 2 agents be available. Given that there are many different indicatins fr the PPIs, including diagnses fr which H 2 RAs have been shwn t be effective, diagnses requiring twice daily dsing, and diagnses requiring specific tests t cnfirm them, it is recmmended that this class f drugs be subject t clinical criteria t ensure apprpriate use. PREFERRED NEXIUM ST, QL (esmeprazle) PREVACID ST, QL (lansprazle) PRILOSEC OTC ST, QL (meprazle) REREVIEW: PROTON PUMP INHIBITORS NON-PREFERRED ACIPHEX ST, QL (rabeprazle) OMEPRAZOLE ST, QL (cmpares t meprazle) PANTOPRAZOLE ST, QL (Cmpares t Prtnix ) PREVACID SOLUTABS ST, QL (lansprazle) ST, QL PREVACID NAPRAPAC (lansprazle/naprxen) PRILOSEC ST, QL (meprazle) PROTONIX ST, QL (pantprazle) ZEGERID ST, QL (meprazle/sdium bicarbnate) Page 15 f 56

16 Clinical Criteria GASTROINTESTINAL AGENTS Prtn pump inhibitrs will be apprved as described fr the fllwing diagnses: Ersive Esphagitis (includes esphageal strictures) If diagnsed by an endscpy r ther testing, then may apprve fr ne year. Renewals will be made n a yearly basis withut requirement f repeat testing. If diagnsed by symptms, a dcumented trial and failure f an H 2 -receptr antagnist (H 2 RA) (minimum trial perid f 2 weeks) will be required befre a PPI will be apprved. At ne year, the recipient will be asked t attempt step dwn therapy either frm multiple t single daily dse PPI r frm single daily dse PPI t an H 2 RA. If therapy fails during the taper perid, the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. Barrett s Esphagus, Schatzki s ring If diagnsed by endscpy, apprve fr ne year. Renewals will be made n a yearly basis withut requirement f repeat testing r step dwn/taper therapy. Laryngpharyngeal Reflux (LPR) If diagnsed by laryngscpy r ther testing, may apprve fr ne year. At ne year, the recipient will be asked t step dwn/taper therapy (see details under Ersive Esphagitis nt diagnsed by testing). If therapy fails during the taper perid the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. If diagnsed by symptms, a dcumented trial and failure f an H 2 -receptr antagnist (H 2 RA) (minimum trial perid f 2 weeks) will be required befre a PPI will be apprved. At ne year, the recipient will be asked t step dwn/taper therapy (see details under Ersive Esphagitis nt diagnsed by testing). If therapy fails during the taper perid, the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. Pathlgical Hypersecretry Cnditin (i.e. Zllinger-Ellisn syndrme, Multiple Endcrine Adenma, Systemic Mastcytsis) If diagnsed by any f the fllwing mechanisms: UGI r EGD with bipsy, serum gastrin r serum secretin stimulatin test, may apprve fr ne year. Renewals will be made n a yearly basis withut requirement f repeat testing r step dwn/taper therapy. GERD, r GERD, atypical with symptms f chrnic laryngitis, harseness, r cugh due t reflux If diagnsed by symptms, a dcumented trial and failure f an H 2 -receptr antagnist (H 2 RA) (minimum trial perid f 2 weeks) will be required befre a PPI will be apprved. At ne year, the recipient will be asked t step dwn/taper therapy (see details under Ersive Esphagitis nt diagnsed by testing). If therapy fails during the taper perid, the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. If diagnsed by endscpy, esphagram, upper GI series r barium swallw within the last year, may apprve fr ne year. At ne year, the recipient will be asked t step dwn/taper therapy (see details under Ersive Esphagitis nt diagnsed by testing). If therapy fails during the taper perid, the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. H. pylri psitive May apprve fr 1 mnth at bid dsing. May renew nly if repeat testing cnfirms initial treatment failure r there has been a dcumented trial and failure f an H 2 RA (minimum trial perid f 2 weeks). Page 16 f 56

17 GASTROINTESTINAL AGENTS NSAID gastrpathy If diagnsed by recent endscpy r by symptmatlgy, may apprve fr 3 mnths. If still n current NSAID, may be apprved fr the duratin f the NSAID therapy. Chrnic NSAID r Aspirin Use May apprve a PPI fr up t 1 year fr individuals using NSAIDs r aspirin n a chrnic basis (daily fr > 2 weeks) AND meeting at least ne f the risk factrs belw: Prir histry f gastrintestinal event (ulcer, hemrrhage); OR Age > 60 years; OR Receiving an anti-inflammatry dse f the NSAID; OR Cncurrent use f crticsterids; OR Cncurrent use f anticagulants; OR Cncmitant use f tw NSAIDs, r an NSAID plus aspirin. Upper GI Bleed/Hemrrhagic Gastritis Apprve fr up t ne year at dsing given (qd r bid). Fr renewals, the recipient will be asked t step dwn/taper therapy (see details under Ersive Esphagitis nt diagnsed by testing). If therapy fails during the taper perid, the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. Hyperacidity in Cystic Fibrsis Recipients, Achalasia, CREST syndrme, Sclerderma, Sarcid May apprve fr 1 year. Renewals will be made n a yearly basis withut requirement f repeat testing r step dwn/taper therapy. Gastric r Dudenal Ulcer If diagnsed by an upper GI prcedure within the last mnth, apprve fr 3 mnths. If diagnsed by symptms, recipient must have a dcumented trial and failure f an H 2 RA (minimum trial perid f 2 weeks). Apprve fr 3 mnths nly. Fr renewals, the recipient will be asked t step dwn/taper therapy (see details under Ersive Esphagitis nt diagnsed by testing). If therapy fails during the taper perid, the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. Of nte, nn-healing ulcers shuld be reassessed peridically t ensure the PPI has nt masked a mre serius medical cnditin. Fr diagnses nt specifically mentined abve: A dcumented trial and failure f an H 2 -receptr antagnist (H 2 RA) (minimum trial perid f 2 weeks) will be required befre a PPI will be apprved. May apprve fr 6 mnths nly. At 6 mnths, the recipient will be asked t step dwn/taper therapy (see details under Ersive Esphagitis nt diagnsed by testing). If therapy fails during the taper perid, the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. Twice Daily Dsing Criteria r Greater May apprve fr a maximum f 6 mnths, unless stated therwise abve, f therapy when symptms are nt cntrlled. Re-evaluate at 6 mnths t determine if the dse may be decreased t a step lwer in therapy. If therapy fails during the taper perid, the recipient will nt be asked t taper again. Once tapering has been dcumented as failing, PPI renewals will be apprved n a yearly basis at the lwest tlerated dse. Diagnstic criteria must be established via a phne call/fax t the call center Page 17 f 56

18 GASTROINTESTINAL AGENTS Quantity Limits Aciphex 1/day Prevacid NapraPAC up t 84 Nexium 1/day Prevpac 14/mnth Omeprazle 1/day Prilsec 1/day Pantprazle 1/day Prilsec OTC 2/day Prevacid 1/day Prtnix 1/day Prevacid Slutabs 1/day Zegerid 1/day References 1. Facts and Cmparisns n-line. Versin 4.0; Wlters Kluwer Health, Inc.; Accessed Nvember, Thmpsn MICROMEDEX n-line Accessed Nvember, Prvider Synergies. Prtn Pump Inhibitrs Review. May 2, Talley JN. American Gastrenterlgical Assciatin medial psitin statement: evaluatin f dyspepsia. Gastrenterlgy 2005;129(5): Institute fr Clinical Systems Imprvement (ICSI). Initial management f dyspepsia and GERD. Blmingtn (MN): Institute fr Clinical Systems Imprvement (ICSI);2006 Jul. 53p. 6. VHA/DO Clinical Practice Guideline fr the Management f Adults with Gastresphageal Reflux Disease in Primary Care Practice. March 12, Accessed December Jhnsn M, Guilfrd, Librett SE. Patients have treatment preferences: a multicentre, duble-blind, crssver study cmparing rabeprazle and meprazle. Curr Med Res Opin. 2002;18: Krmer W. Relative efficacies f gastric prtn-pump inhibitrs n a milligram basis: desired and undesired SH reactins. Impact f chiralty. Scand J Gastrenterl Suppl. 2001;234: DeVault KR, Castell DO. Updated guidelines fr the diagnsis and treatment f gastresphageal reflux disease. American Jurnal f Gastrenterlgy. 2005; 100: REREVIEW: ORAL ANTI-EMETICS-5-HT 3 ANTAGONISTS BACKGROUND Nausea is assciated with altered physilgic activity, including the gastric hypmtility and increased parasympathetic tne that precede and accmpany vmiting. Nausea may represent the awareness f the medullary vmiting center t the afferent stimuli such as systemic r ingested txins, disturbance f the vestibular system, peritneal inflammatin r bwel bstructin. Psychgenic vmiting may be self-induced r may ccur invluntarily in situatins that are anxiety-inducing, threatening r in sme way distasteful. The cntrl f nausea and vmiting is much like the cntrl f pain in that if nausea and vmiting is well cntrlled during the first expsure t an ffending stimuli psychgenic nausea and vmiting is less likely t ccur during subsequent expsures t the same stimuli. Page 18 f 56

19 GASTROINTESTINAL AGENTS Nausea and vmiting during chemtherapy appears t be assciated with the release f sertnin frm the enterchrmaffin cells f the small intestine resulting in stimulatin f vagal afferents thrugh the 5-HT 3 receptrs initiating the vmiting reflex. The ral 5-HT 3 antagnists, dlasetrn, granisetrn and ndansetrn, selectively blck the 5-HT 3 receptrs which are fund centrally in the chemreceptr trigger zne and peripherally at vagal nerve terminals in the intestines. All agents in this class are indicated fr the preventin f chemtherapy induced nausea and vmiting (CINV). Dlasetrn is als indicated fr the preventin and treatment f pstperative nausea and vmiting (PONV); hwever, ndansetrn is nly indicated fr the preventin f PONV. In additin, granisetrn and ndansetrn are indicated fr the preventin f nausea and vmiting as a result f radiatin therapy. While prescribing infrmatin states that ndansetrn can be used fr patients ver 4 years ld, there are data t supprt its use in patients 6 mnths and lder fr PONV. Granisetrn has been studied in limited randmized, cntrlled trials fr PONV in patients lder than 4 years ld. Dlasetrn is indicated fr use in patients ver 2 years ld. The mst cmmn adverse effects seen with the 5-HT 3 antagnists are headache, fatigue, diarrhea, hepatic functin abnrmalities and hyptensin. Dlasetrn may als cause tachycardia in 2% f patients. All f the 5-HT 3 antagnists shuld be used with cautin in patients wh have r may develp prlngatin f cardiac cnductin intervals such as QTc. All agents in this categry are Pregnancy Categry B. The dse f ndansetrn shuld nt exceed 8 mg per day in patients with severe hepatic impairment (Child-Pugh scre >10). Due t variatin f pharmackinetic parameters in children, higher weight-based dses f 5-HT 3 antagnists than thse used in adults may be required fr antiemetic prtectin in children. Several head-t-head cmparative trials have been perfrmed amng the 5-HT 3 antagnists. A multicenter, randmized, duble-blind study cmparing dlasetrn (single ral dses f 25, 50, 100 r 200 mg 1 hur prir t chem) t ndansetrn (8 mg given 1.5 hurs prir, and 6.5, 14.5 and 22.5 hurs after chem) shwed the tw were therapeutically equivalent in the preventin f nausea and vmiting fllwing mderately emetgenic chemtherapy. Granisetrn (1 mg PO Q12H given n days 1 and 2) was cmpared t ndansetrn (8 mg PO Q8H r 32 mg IV Q24H n days 1 and 2) in 102 patients prir t hematpietic stem cell transplantatin fr the preventin f nausea and vmiting assciated with high-dse chemtherapy r raditherapy. There was n difference between the grups in verall cmplete respnse rates, verall majr efficacy rates and mean visual analg scales (VAS) scres. Anther duble-blind, randmized, crssver study cmpared granisetrn (3 mg/day) t ndansetrn (24 mg/day) in 309 patients receiving tw cycles f identical chemtherapy ver 5 days. There was n statistical difference in the achievement f gd cntrl f emetic symptms; hwever, patients preferred granisetrn ver ndansetrn (p=0.048). An additinal study cmpared ndansetrn (4 mg, n=30), granisetrn (1 mg, n= 30) r granisetrn (0.1 mg, n=28) in patients wh experienced PONV, despite the preperative use f ndansetrn 4 mg, at the end f a surgical prcedure requiring general anesthesia. There was n statistical difference between the three grups. The 2006 guidelines frm the American Sciety f Clinical Onclgists (ASCO) recmmend a 5-HT 3 antagnist as first-line therapy in cmbinatin with aprepitant and dexamethasne fr patients n chemtherapy f high r mderate emetic risk and thse receiving an anthracycline (dxrubicin r epirubicin) and cyclphsphamide. Fr thse patients receiving radiatin therapy f all emetic risks, 5-TH 3 antagnists are recmmended. These guidelines further state that at equivalent dses, sertnin receptr antagnists have equivalent safety and efficacy and can be used interchangeably. Page 19 f 56