respiratory agents - Magellan Health Services || TennCare Portal

RESPIRATORY AGENTSPREFERREDAll generic, prescription first generationantihistaminesBROMPHENIRAMINECHLORPHENIRAMINECLEMASTINEDEXCHLORPHENIRAMINEDIPHENHYDRAMINEHYDROXYZINEPROMETHAZINENEW: FIRST GENERATION ANTIHISTAMINESNON-PREFERREDAll branded, prescription first generationantihistaminesALDEX AN ® (doxylamine)ZYMINE ® (triprolidine)ZYMINE XR ® (triprolidine)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.BACKGROUNDRE-REVIEW: MINIMALLY SEDATNG ANTIHISTAMINES• Rhinitis is defined as inflammation of the nasal membranes, and it is associated withnasal congestion, rhinorrhea, sneezing, itching of the nose and/or postnasal drainage.Rhinitis may be caused by non-allergic or allergic factors; however most rhinitis is allergicin nature. Since rhinitis is often associated with nasal congestion, many of the drugmanufacturers have added pseudoephedrine to the minimally sedating antihistamines.• Minimally sedating antihistamines inhibit the release of allergic mediators such ashistamine, leukotrienes, and prostaglandins by selectively and competitively blocking H 1receptors. These agents have little to no central or autonomic nervous system activity.Pseudoephedrine causes vasoconstriction by acting on the adrenergic receptors in thenasal mucosa.• The FDA-Approved indications are as follows:Drug Seasonal AR* Perennial AR CIU**Acrivastine/PSE***√Cetirizine √ √ √Cetirizine/PSE √ √Desloratadine √ √ √Desloratadine/PSE√Fexofenadine √ √Fexofenadine/PSE√Levocetirizine √ √Loratadine √ √Loratadine/PSE √ √*AR = Allergic Rhinitis ** CIU = Chronic Idiopathic Urticaria *** PSE = Pseudoephedrine• The most common adverse effects seen in patients using minimally sedatingantihistamines include somnolence, headache, fatigue, dry mouth, dyspepsia andnausea. The pseudoephedrine component often causes insomnia. Below is a chartlisting the incidence of somnolence for each agent within this category.Page 5 of 85November 8, 2007 Tennessee PAC

DrugRESPIRATORY AGENTSSomnolenceCompared toPlaceboDrugSomnolenceCompared to PlaceboAcrivastine/PSE 12%-Adults Fexofenadine 1.3-2.2%-Adults

RESPIRATORY AGENTSo One randomized controlled double-blind trial compared desloratadine tofexofenadine among 49 patients with SAR. The main outcomes examined werepeak nasal inspiratory flow, nasal symptoms, and eye symptoms. The studyshowed no significant difference in symptom reduction among treatment groups.• The American Academy of Allergy, Asthma and Immunology (AAAAI) recommends astepwise approach to managing allergic rhinitis. Patients with persistent, mild tomoderate allergic rhinitis should be treated with an oral, minimally sedating antihistamine(± decongestant) and/or an inhaled nasal corticosteroid. Patients with severe allergicrhinitis should be treated with combination therapy including a nasal corticosteroid and aminimally sedating antihistamine (± decongestant). Children or those with perennialallergic rhinitis may alternately be treated with an inhaled nasal antihistamine or nasalcromolyn.RECOMMENDATIONAll of the minimally sedating antihistamines are effective at reducing the symptoms of allergicrhinitis (AR) and chronic idiopathic urticaria (CIU). While comparative data show mixed results,some studies indicate cetirizine may be more effective than loratadine or fexofenadine at providingsymptomatic relief; however, cetirizine is associated with more sedation (up to 14% incidence).According to the AAAAI guidelines, there is similar efficacy among the agents in this class.Therefore, it is recommended that at least one minimally sedating antihistamine and one minimallysedating antihistamine/pseudoephedrine combination product be available for use in patients withAR or CIU. In order to meet the needs of pediatric patients, it is recommended that at least oneoral solution or syrup formulation be available.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONREREVIEW: MINIMALLY SEDATNG ANTIHISTAMINESNON-PREFERREDPREFERREDLORATADINE QL (Compares to Claritin)LORATADINE/PSEUDOEPHEDRINE QL(Compares to Claritin-D)ALLEGRA ® QL (fexofenadine)ALLEGRA-D 12 HOUR ® QL(fexofenadine/pseudoephedrine)ALLERGRA-D 24 HOUR ® QL(fexofenadine/pseudoephedrine)CLARITIN ® QL (loratadine)CLARITIN-D 12 HOUR ® QL(loratadine/pseudoephedrine)CLARITIN-D 24 HOUR ® QL(loratadine/pseudoephedrine)CLARITIN REDITABS ® QL (loratadine)CLARINEX ® QL (desloratadine)CLARINEX-D 12 HOUR ® QL(desloratadine/pseudoephedrine)CLARINEX-D 24 HOUR ® QL(desloratadine/pseudoephedrine)CLARINEX REDITABS ® QL (desloratadine)SEMPREX D ® QL (acrivastine/pseudoephedrine)FEXOFENADINE QL (Compares to Allegra)ZYRTEC ® QL (cetirizine)ZYRTEC-D ® QL (cetirizine/pseudoephedrine)XYZAL ® QL (levocetirizine)Page 7 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSQuantity LimitsAllegra ® 30 mg, 60 mg = 2/day; 180 mg = 1/dayAllegra-D 12 Hour ® = 2/dayAllegra-D 24 Hour ® = 1/dayClaritin ® = 1/dayClaritin-D 12 Hour ® =2/dayClaritin-D 24 Hour ® = 1/dayClaritin Reditabs ® = 1/dayClarinex ® = 1/dayClarinex-D12 Hour ® = 2/dayClarinex-D 24 Hour ® = 1/dayClarinex Reditabs ® = 1/dayFexofenadine 30 mg, 60 mg = 2/day; 180 mg = 1/dayLoratadine = 1/dayLoratadine/Pseudoephedrine = 2/daySemprex D ® =4/dayXyzal ® = 1/dayZyrtec ® = 1/dayZyrtec-D ® = 2/dayReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Antihistamines, Minimally Sedating Review. Sept 17, 2007.4. Dykewicz MS, Fineman S, Nicklas R, et al. Joint Task Force Algorithm and Annotations forDiagnosis and Management of Rhinitis. Ann Allergy Asthma Immunol. 1998;81:469-73.BACKGROUNDRE-REVIEW: INTRANASAL STEROIDS• Seasonal allergic rhinitis develops when patients inhale airborne allergens to which theyhave made antibodies. These antibodies bind to receptors on mast cells and basophilsgenerating granule-associated chemical mediators and cytokines which lead toinflammation. Seasonal allergic rhinitis is usually characterized by sneezing, itching ofthe nose, eyes and palate, rhinorrhea, and nasal obstruction. Perennial allergic rhinitis isa persistent, chronic IgE-mediated condition which shows no relation to seasonalchanges, and it is usually less severe than allergic rhinitis. Vasomotor rhinitis, alsoknown as irritant rhinitis, is aggravated by environmental agents such as fumes, odors,temperature, atmospheric changes, or smoke. Vasomotor rhinitis causes year-roundsymptoms, including congestion and headache, and usually occurs in adults.• The intranasal corticosteroids produce anti-inflammatory and vasoconstrictor effects bygaining entry into the cell cytoplasm and interacting with the glucocorticoid receptor tocause a reduction in the cytokine-induced production of pro-inflammatory mediators.Page 8 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• FDA-Approved Indications are as follows:DrugPerennialallergicrhinitisSeasonalallergicrhinitisPerennialnonallergicrhinitisSeasonalnonallergicrhinitisNasal Polypsbeclomethasone √ √ √ √ √Prophylaxisbudesonide √ √flunisolide √ √fluticasone√√fuoratefluticasoneproprionatemometasone √ √Alsoprophylaxis(≥ 12)√ √ √ √√(adults only)triamcinolone √ √√ Indicates treatment unless otherwise stated• Intranasal steroids are generally well-tolerated. Common side effects include pharyngitis,epistaxis, cough and nasal irritation. In rare cases, nasal septal perforation has occurred.o Flunisolide is contraindicated in patients with untreated localized infectioninvolving the nasal mucosa.o Intranasal steroids should be used in the lowest effective dose in children and theFDA recommends that height be routinely monitored. Clinicians should also becautious of signs of adrenal insufficiency when replacing a systemiccorticosteroid with a nasal corticosteroid. Those receiving corticosteroids asimmunosuppressive therapy may experience more serious or fatal responses toinfection. All of the intranasal steroids are pregnancy category C except forbudesonide (B).o Fluticasone propionate is metabolized by the cytochrome P450 3A4 enzyme;therefore, coadministration with ritonavir is not recommended due to possibleincrease in plasma fluticasone exposure and a possible reduction in serumcortisol concentrations.• Many head-to-head clinical trials have been performed with the intranasal steroids.o Patients (n=501) with moderate-to-severe seasonal allergic rhinitis were enrolledin a double-blind, placebo-controlled study comparing a four week trial of eithermometasone 100 mcg QAM or 200 mcg QAM, beclomethasone 200 mcg BID, orplacebo. Loratadine 10 mg daily was allowed as a rescue medication in the caseof intolerable symptoms related to rhinitis. Results showed that bothmometasone and beclomethasone were more effective than placebo; however,no difference was seen between study medications. Rescue antihistamine usewas reduced as well for all treatment groups compared to placebo. There wasno statistical difference in adverse effects between mometasone- andbeclomethasone- treated patients.o Thirty-eight patients with allergic rhinitis participated in a double-blind, crossoverstudy in which they received budesonide 64 mcg, budesonide 256 mcg, andmometasone 200 mcg 3 days prior to an allergen challenge. The allergenchallenge was administered daily for seven days while treatment continued.Active treatments reduced nasal symptoms and improved nasal peak inspiratoryflow (PIF) (p =

RESPIRATORY AGENTSo Patients (n=550) with perennial allergic rhinitis were randomized in a doubleblind,placebo-controlled study to receive nasal mometasone 200 mcg,fluticasone 200 mcg, or placebo daily for 3 months. The mean percent reductionfrom baseline in patient-recorded nasal symptoms was 37-63% in themometasone group, 39-60% in the fluticasone group, and 22-39% in the placebogroup. Both active drugs were better than placebo; however, physicianevaluatedreduction of nasal discharge and congestion was best withmometasone. Patients were symptom free 10 days with mometasone, 11 dayswith fluticasone and 4 days with placebo.• The American Academy of Allergy, Asthma and Immunology (AAAAI) recommends astepwise approach to managing allergic rhinitis.Seasonal Allergic Rhinitis Perennial Allergic Rhinitis Non-Allergic RhinitisPersistent, mild to moderate:Minimally sedating antihistamine(± decongestant) or an inhalednasal corticosteroidSevere: Combination therapyincluding a nasal corticosteroidand a minimally sedatingantihistamine (± decongestant)Alternatives: Minimally sedatingantihistamine may be substitutedwith a nasal antihistamine ornasal cromolyn for childrenPersistent, mild to moderate:Minimally sedating antihistamine(± decongestant) and/or aninhaled nasal corticosteroidSevere: Combination therapyincluding a nasal corticosteroidand a minimally sedatingantihistamine (± decongestant)Alternatives: Minimally sedatingantihistamine may be substitutedwith a nasal antihistamine ornasal cromolyn for childrenIntranasalcorticosteroid, oraldecongestants, or acombination of bothRECOMMENDATION:According to the AAAAI, the intranasal corticosteroids are the most effective single agents forcontrolling allergic rhinitis symptoms. In addition, the intranasal steroids are among the agents ofchoice for non-allergic rhinitis, as well. While differences in approved indications, dosingregimens, and patient preference may exist, clinical trials have shown the intranasalcorticosteroids to be similar in efficacy and the AAAAI makes no differentiation between theagents. In order to allow for patient and prescriber choice, it is recommended that at least threeintranasal corticosteroids be available.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONRE-REVIEW: INTRANASAL STEROIDSPREFERREDNON-PREFERREDFLUNISOLIDE QL (compares to Nasarel ® ) BECONASE AQ ® QL (beclomethasone)NASACORT AQ ® QL (triamcinolone)NASONEX ® QL (mometasone)FLONASE ® QL (fluticasone proprionate)FLUTICISONE PROPIONATE QL (compares toFlonase ® )NASACORT HFA ® QL (triamcinolone)NASAREL ® QL (flunisolide)RHINOCORT AQUA ® QL (budesonide)VERAMYST ® QL (fluticasone fuorate)Page 10 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSQuantity LimitsBeconase AQ ® 2 canisters/monthFlonase ® 1 canister/monthflunisolide 2 canisters/monthfluticasone propionate 1 canister/monthNasacort AQ ® 2 canisters/monthNasarel ® 2 canisters/monthNasonex ® 1 canisters/monthRhinocort Aqua ® 2 canisters/monthTri-Nasal ® 2 canisters/monthVeramyst ® 1 canister/monthReferences:1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Intranasal Rhinitis Agents Review. May, 15 2007.4. Dykewicz MS, Fineman S, Nicklas R, et al. Joint Task Force Algorithm and Annotations forDiagnosis and Management of Rhinitis. Ann Allergy Asthma Immunol. 1998;81:469-73.5. Ahlstrom-Emanuelsson C, Persson C, Svensson C, et al. Establishing a model of seasonalallergic rhinitis and demonstrating dose-response to a topical glucocorticosteroid. Ann AllergyAsthma Immunol. 2002;89(2):159-65.6. Herbert JR, et al. Once-daily mometasone fuorate aqueous nasal spray in seasonal allergicrhinitis: an active and placebo controlled study. Allergy. 1996;51:569-76.RE-REVIEW: NASAL ANTIHISTAMINESBACKGROUND• Rhinitis affects 40 million Americans and is characterized by sneezing, itching of theeyes, nose and palate, rhinorrhea, and nasal obstruction. Rhinitis can be perennialallergic, perennial non-allergic, seasonal allergic or seasonal non-allergic.• Azelastine, the only nasal antihistamine product available, exerts is physiological effectsby blocking histamine (H 1 ) resulting in an inhibitory effect on the release of inflammatorymediators from mast cells. It also inhibits other mediators of allergic reactions such asleukotrienes and platelet-aggregating factor (PAF), and it reduces chemotaxis and theactivation of eosinophils.• Azelastine is FDA-approved for the symptomatic treatment of seasonal allergic rhinitis inindividuals ≥ 5 years old and vasomotor rhinitis in those ≥12 years old.• The most common adverse effects seen with azelastine include a bitter taste (19.7%),headache (14.8%), somnolence (11.5%), and nasal burning (4.1%).o Azelastine is contraindicated with other CNS depressants as it may cause CNSdepression as well. Patients should be cautioned to assess their individualresponse to azelastine before participating in activities requiring mentalalertness, and they should be cautious when coadministering azelastine withother CNS depressants including alcohol.• A multicenter, double-blind trial involving 334 patients with moderate-to-severe seasonalallergic rhinitis compared symptom scores after 2 weeks of treatment with the followingregimens: azelastine 2 sprays per nostril BID, azelastine 2 sprays per nostril BID plusfexofenadine 60 mg BID, or placebo. There was a one week run-in period usingfexofenadine 60 mg BID. Patients whose total nasal symptom score improved less than25-33% were randomized to one of the three treatment arms. Both the azelastine group(p=0.007) and the azelastine plus fexofenadine group (p=0.003) experienced statisticallysignificant improvements in total nasal symptom scores. Azelastine alone was aseffective as the combination of azelastine and fexofenadine.Page 11 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• The American Academy of Allergy, Asthma and Immunology (AAAAI) recommends astepwise approach to managing allergic rhinitis.Seasonal Allergic Rhinitis Perennial Allergic Rhinitis Non-Allergic RhinitisPersistent, mild to moderate:Minimally sedating antihistamine(± decongestant) or an inhalednasal corticosteroidSevere: Combination therapyincluding a nasal corticosteroidand a minimally sedatingantihistamine (± decongestant)Alternatives: Minimally sedatingantihistamine may be substitutedwith a nasal antihistamine ornasal cromolyn for childrenPersistent, mild to moderate:Minimally sedating antihistamine(± decongestant) and/or aninhaled nasal corticosteroidSevere: Combination therapyincluding a nasal corticosteroidand a minimally sedatingantihistamine (± decongestant)Alternatives: Minimally sedatingantihistamine may be substitutedwith a nasal antihistamine ornasal cromolyn for childrenIntranasalcorticosteroid, oraldecongestants, or acombination of bothRECOMMENDATION:Azelastine is effective in the symptomatic treatment of seasonal allergic rhinitis and can beconsidered an alternative to oral antihistamine therapy. Although an alternative therapy,azelastine offers advantages over systemic antihistamines with regards to lessened systemicadverse effects such as sedation, and it may be beneficial in those intolerant to, or not wellcontrolledon, intranasal corticosteroids. Therefore, it is recommended that azelastine be availablefor use in allergic rhinitis patients.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDASTELIN ® QL (azelastine)REREVIEW: NASAL ANTIHISAMINESNON-PREFERREDN/AQuantity LimitsAstelin Nasal Spray = 3 bottles per monthReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Intranasal Rhinitis Agents Review. May 15, 2007.4. Ahlstrom-Emanuelsson C, Persson C, Svensson C, et al. Establishing a model of seasonalallergic rhinitis and demonstrating dose-response to a topical glucocorticosteroid. Ann AllergyAsthma Immunol. 2002;89(2):159-65.5. LaForce CF, Corren J, Wheeler WJ, et al. Efficacy of azelastine nasal spray in seasonalallergic rhinitis patients who remain symptomatic after treatment with fexofenadine. AnnAllergy Asthma Immunol. 2004; 93(2):154-59.Page 12 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSNEW: NASAL ANTICHOLINERICSBACKGROUND• Ipratropium 0.03% nasal spray is FDA approved for the symptomatic relief of rhinorrheaassociated with perennial rhinitis, both allergic and non-allergic, in those ≥ 6 years of age.Ipratropium 0.06% is indicated for symptomatic relief of rhinorrhea associated with thecommon cold or seasonal allergic rhinitis for patients ≥ 5 years of age. Ipratropium nasalspray does not relieve nasal congestion, sneezing, or postnasal drip associated withallergic or non-allergic perennial rhinitis.• Ipratropium works by blocking cholinergic receptors and reflex-mediated hypersecretionfrom nasal glands. Systemic anticholinergic effects are minimized because ipratropium isa quaternary amine resulting in reduced movement across the nasal and gastrointestinalmembrane and blood-brain barrier.• The most common adverse events associated with ipratropium are epistaxis (8.2-9%),nasal dryness (4.8-5.1%), dry mouth or throat (1.4-2%), and nasal irritation (1-2%).o The safety and efficacy of ipratropium bromide 0.06% nasal spray used beyond 4days in patients with the common cold or used beyond 3 weeks in patients withseasonal allergic rhinitis have not been established.o Because ipratropium has anticholinergic effects, it should be used with caution inpatients with narrow-angle glaucoma, prostatic hypertrophy or bladder neckobstruction.• A multicenter, randomized trial including 533 patients with perennial allergic rhinitiscompared the use of ipratropium 0.03% nasal spray TID, beclomethasone nasal spray 84mcg BID, the combination of both treatment regimens, and placebo. The primaryendpoints were severity and duration of rhinorrhea and patient and physician symptomassessment. During the four weeks of treatment, combination therapy was moreeffective than either agent alone in reducing the average severity and duration ofrhinorrhea. Ipratropium had a faster onset of action and reduced rhinorrhea more thanbeclomethasone during the first week, but beclomethasone was more effective inreducing the severity of congestion and sneezing. Combination therapy caused no moreadverse reactions than monotherapy.• The American Academy of Allergy, Asthma and Immunology (AAAAI) recommends astepwise approach to managing allergic rhinitis. Their 1998 treatment guidelines suggestthat the nasal anticholinergics effectively reduce rhinorrhea, but may cause dryness ofthe nasal membranes and have no effect on other nasal symptoms, such as nasalcongestion, sneezing, and itching.RECOMMENDATION:Nasal anticholinergics represent a reasonable option for patients with rhinorrhea symptomsassociated with either allergic rhinitis, non-allergic rhinitis, or the common cold. While currentclinical guidelines recommend antihistamines and nasal steroids as first line treatments for allergicrhinitis, nasal anticholinergics are effective at reducing rhinorrhea symptoms with few side effects.Therefore, it is recommended that at least one nasal anticholinergic be available.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: NASAL ANTICHOLINERGICSPREFERREDNON-PREFERREDIPRATROPIUM QL (Compares to Atrovent ® ) ATROVENT ® QL (ipratropium)Page 13 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSQuantity LimitsAtrovent 0.03% = 2 bottles/monthAtrovent 0.06% = = 3 bottles/monthIpratropium 0.03% = 2 bottles/monthIpratropium 0.06% = 3 bottles/monthCOMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences:1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Intranasal Rhinitis Agents Review. May 15, 2007.4. Ahlstrom-Emanuelsson C, Persson C, Svensson C, et al. Establishing a model of seasonalallergic rhinitis and demonstrating dose-response to a topical glucocorticosteroid. Ann AllergyAsthma Immunol. 2002;89(2):159-65.5. Dockhorn R, Aaronson D, Bronsky E et al. Ipratropium bromide nasal spray 0.03% andbeclomethasone nasal spray alone and in combination for the treatment of rhinorrhea inperennial rhinitis. Ann Allergy Asthma Immunol. 1999; 82(4):349-59.BACKGROUNDNEW: NON-NARCOTIC ANTITUSSIVES• For the purpose of this review, we will consider prescription agents only. The prescriptionnon-narcotic antitussives include benzonatate and one formulation of dextromethorphan.(All other dosage forms of dextromethorphan are over-the-counter and are covered forrecipients who are less than 21 years of age.)• Benzonatate suppresses cough by anesthetizing the stretch or cough receptors locatedin the respiratory passages, lungs, and pleura, and may also suppress transmission ofthe cough reflex in the medulla. Dextromethorphan works by suppressing transmissionof the cough reflex in the medulla.• Both agents in this class are FDA approved for the temporary treatment of cough.• Common adverse effects for both benzonatate and dextromethorphan include dizziness,GI upset, somnolence, and sedation. Benzonatate may also cause hallucinations andheadache. If chewed or crushed, benzonatate may act as an anesthetic causingnumbness in the tongue and throat.o The use of dextromethorphan and an MAOI may cause hyperpyrexia, abnormalmuscle movement, hypotension, coma, and death; therefore, the concomitantuse of these two agents within 14 days of each other is contraindicated.o Benzonatate should not be used in children less than 10 years of age.Dextromethorphan should not be used for chronic persistent cough in conditionssuch as asthma or emphysema. While the abuse potential has not been fullyinvestigated, there have been an increasing number of cases of abuse ofdextromethorphan-containing products, especially among the teenagepopulation.Page 14 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• Sixteen patients with chronic, stable cough were given codeine 20 mg ordextromethorphan 20 mg in a double-blind crossover comparison trial. Outcomes weremeasured using both an objective and subjective assessment of efficacy. Bothpreparations were similarly effective in reducing cough frequency; however,dextromethorphan lowered cough intensity to a greater degree than codeine and wasconsidered the better antitussive by the majority of patients. Dextromethorphan alsoproduced fewer CNS and gastrointestinal side effects.• Benzonatate is an effective alternative to opioid antitussives, such as codeine, and itappears to have a more sustained cough-suppressing effect. Dextromethorphan is aseffective as codeine, but is not associated with the high incidence of drowsiness and GIdisturbances.RECOMMENDATION:Benzonatate and dextromethorphan are effective prescription options to codeine for the treatmentof cough. Benzonatate should not be used in children less than 10 years old; therefore,dextromethorphan must be available. In order to ensure adequate prescriber choice, isrecommended that both benzonatate and dextromethorphan products be available for use.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDAll generic, prescription dextromethorphanproductsBENZONATATE (compares to Tessalon ® ,Tessalon Perles ® )NEW: NON-NARCOTIC ANTITUSSIVESNON-PREFERREDAll branded, prescription dextromethorphanproductsAEROTUSS ® (dextromethorphan)TESSALON ® (benzonatate)TESSALON PERLES ® (benzonatate)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Matthys H, Bleicher B, & Bleicher U: Dextromethorphan and codeine: objective assessment ofantitussive activity in patients with chronic cough. J Int Med Res 1983; 11(2):92-100.BACKGROUNDNEW: EXPECTORANTS• For the purposes of this review, we will consider prescription agents only. This classconsists of two agents, guaifenesin and potassium iodide.• While potassium iodide is most commonly used as a thyroid gland protectant duringradiation therapy or topically as a disinfectant, it can also be used as an expectorant.• Guaifenesin increases respiratory tract secretions and helps to loosen phlegm andbronchial secretions causing an increase in the efficiency of the cough reflex. As anexpectorant, potassium iodide decreases mucus viscosity by enhancing the secretion ofrespiratory fluids. Potassium iodide also protects the thyroid gland against injury as aresult of radiation therapy by blocking the thyroidal uptake of radioactive isotopes ofiodine.Page 15 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• Guaifenesin is FDA approved as an expectorant for the treatment of sinusitis, bronchitis,asthma, and pharyngitis. Potassium iodide is approved to prevent thyroid gland injurydue to radiation sources and as an expectorant in the treatment of chronic pulmonarydiseases such as bronchial asthma, chronic bronchitis, pulmonary emphysema and sinuscongestion.• The most common adverse reaction associated with expectorants is GI upset.Guaifenesin also commonly causes dizziness, headache, and rash or urticaria.Potassium iodide commonly causes metallic taste and skin eruptions, andhypothyroidism occurs infrequently with chronic use.o Potassium iodide is contraindicated in patients with renal disorders or iodineinduced goiter.o Expectorants should be used with caution in patients with conditions in whichchronic persistent cough is seen, such as asthma, chronic bronchitis oremphysema, unless the underlying condition has been properly treated.Guaifenesin should also be used with caution in patients who are predisposed tokidney stone formation and in children less than 6 (immediate release products)or less than 12 (sustained release products). Potassium iodide should be usedwith caution in patients with Addison’s disease, dehydration, or hyperthyroidism,and in patients who are pregnant or breastfeeding.• There are currently no head to head studies comparing the expectorants, or treatmentguidelines addressing appropriate use of guaifenesin or potassium iodide asexpectorants.RECOMMENDATION:While guaifenesin is more commonly used, both guaifenesin and potassium iodide are reasonableoptions when an expectorant is needed. Since potassium iodide is used as a disinfectant and toprevent thyroid injury during radiation therapy, it is recommended that both guaifenesin andpotassium iodide products be available. In order to best meet patient and prescriber needs, it isrecommended that at least one liquid formulation be available.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDAll generic, prescription guaifenesinproductsGUAIFENESIN (compares to Allefen Jr ® ,Ganidin ® , Liquibid ® , Organidin NR ® )POTASSIUM IODIDE (compares to Pima ® ,SSKI ® )NEW: EXPECTORANTSNON-PREFERREDAll branded, prescription guaifenesin productsALLFEN JR ® (guaifenesin)GANIDIN ® (guaifenesin)LIQUIBID ® (guaifenesin)ORGANIDIN NR ® (guaifenesin)PIMA ® (potassium iodide)SSKI ® (potassium iodide)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.Page 16 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSoDue to their rapid onset of action, the short-acting beta 2 adrenergic agonists areuseful for temporary relief of bronchoconstriction and the accompanyingsymptoms, such as wheezing, chest tightness, and cough.oBronchodilator medications are central to the symptomatic management ofCOPD. They improve emptying of the lungs, tend to reduce dynamichyperinflation at rest and during exercise, and improve exercise performance.They are given either on an as needed basis for relief of persistent or worseningsymptoms or on a regular basis to prevent or reduce symptoms. Regularbronchodilation with these drugs does not modify the decline of function in mildCOPD or the prognosis of the disease. The principal bronchodilator treatmentsare beta 2 -agonists, anticholinergics, and theophylline. These are given either asmonotherapy or in combination with the inhaled agents being preferred. Whileshort-acting beta 2 -agonists can be used on an as needed basis in mild COPD,regular treatment with a long-acting agent is required as the disease progresses.• The beta 2 -agonists relieve reversible bronchospasm by relaxing the smooth muscles ofthe bronchioles in conditions associated with asthma, COPD or bronchitis.Bronchodilation may additionally facilitate expectoration. Although there are both beta 1and beta 2 receptors in the heart, the latter are more predominant in the lungs, where theyserve as the primary adrenergic receptors in bronchial smooth muscle. In order to reducecardiac toxicities (e.g., tachyarrhythmias), the use of beta 2 specific agonists is preferredin the treatment of bronchospasm. This has minimized the use of less specific and lesssafe agents such as epinephrine (Primatene®) and isoproterenol. To further reducecardiac toxicities, non-systemic dosage forms given by inhalation are preferred to oraldosage forms.• FDA Approved Indications:Drug NameAlbuterol CFC MDI(Proventil ® )Albuterol HFA MDI(Proventil HFA ® ,Ventolin HFA ® )ManufacturergenericProventil HFA®ScheringVentolin HFA®GlaxoSmithKlineReversibleBronchospasmPrevention and ReliefTreatmentPrevention ofEIBX X XX X XCOPDAlbuterol HFA MDI(ProAir HFA ® )Albuterol inhalationsolution (Accuneb ® )Ivax X X XgenericXDeyXLevalbuterolinhalation solution(Xopenex ® )Levalbuterol HFA MDI(Xopenex ® )metaproterenolinhalation solutionmetaproterenol MDI(Alupent ® )Pirbuterol MDI(Maxair Autohaler ® )SepracorSepracorXXGeneric X X XBoehringer-Ingelheim3MCFC=Chlorofluorocarbon HFA=hydrofluroalkane MDI=metered-dose inhalerXXXPage 19 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• No specific contraindications exist for the short-acting beta agonists.• Significant drug interactions for the short-acting beta 2 agonists include increased risk ofventricular arrhythmias with MAOIs, increased risk of ventricular arrhythmias withTricyclic antidepressants (TCA), potential for severe bronchospasm in asthmatic patientswith beta-blockers, and potentiation of adrenergic effects with other adrenergic drugs.• Given recent efforts to phase out CFC-containing inhalers by the end of 2008 due toenvironmental concerns, most short-acting beta 2 agonists are now available as an HFAinhaler. There appears to be no difference in tolerability or efficacy between the two MDItypes.• This year the GINA guidelines from the NLBHI and the NAEPP Guidelines for AsthmaManagement were updated to reflect a change in focus from asthma severity to asthmacontrol. Asthma control is defined as no or minimal daytime symptoms; no limitations inactivity; no nocturnal symptoms; no or minimal need for rescue medications; normal ornear normal lung function; and no exacerbations. A five-step treatment approach isintroduced in these guidelines that offers flexibility to step up treatment when asthma isuncontrolled or step down treatment when asthma is controlled. These new guidelinesrecommend treatment with short acting beta 2 -agonists only on an as-needed basisparticularly if patients experience only occasional daytime symptoms of short duration.When symptoms are more frequent and/or worsen periodically, patients require regularcontroller therapy.• Current guidelines from the AAAAI also recommend reserving short-acting beta 2 agonistsfor as needed use to relieve symptoms. They state that use of a short-acting beta 2agonist more than twice weekly may indicate the need to initiate or increase long-termcontrol therapy.• Current treatment guidelines from the Medical Advisory Panel for the Pharmacy BenefitsManagement Strategic Healthcare Group state that short-acting beta 2 agonist should beused as needed for the majority of symptomatic patients with COPD. These agents mayalso be administered on a scheduled basis for those patients uncontrolled on ipratropiumalone. These guidelines further state that all short-acting agents have similar efficacyand selection could be based on cost.• None of the guidelines specify which short-acting beta 2 agonist should be used; however,the following should be taken into consideration:o Metaproterenol is neither beta 2 selective nor as long acting as albuterol;therefore, it should not be considered for first-line therapy.o Pirbuterol is similar in both efficacy and safety to the generically availablealbuterol CFC inhalers, although it is somewhat less beta 2 selective. Maxair® is aCFC containing product, but it will continue to be available in that formulation atleast through the end of 2009.o Levalbuterol is the R-enantiomer form of albuterol. Current clinical trials withlevalbuterol offer mixed results. The majority of available studies indicate thatlevalbuterol inhalation solution has similar efficacy with fewer adverse effectswhen given in equivalent doses to albuterol inhalation solution.• A randomized, double-blind clinical trial comparing levalbuterol (0.31 mgand 0.63 mg) to racemic albuterol (1.25 mg and 2.5 mg) in pediatricasthma patients (n=338) aged 4-11 years found that levalbuterol 0.31 mgwas no different from placebo with regards to changes in ventricularheart rate, QTc interval, or glucose. The more favorable side effectprofile of levalbuterol at low doses suggests that it may have a potentialbenefit in the pediatric population.RECOMMENDATION:Short acting beta 2 agonists (SABAs) are the therapy of choice for relief of acute symptoms ofasthma and prevention of Exercise-Induced Bronchospasm (EIB). Clinical guidelines do notdistinguish between the available SABAs when it comes to safety or efficacy. Due to the phasingout of CFC inhalers in response to environmental concerns, it is suggested that there be at leastone HFA product available as preferred. Given the potential for fewer side effects withlevalbuterol, it should be available for those with intolerance to albuterol products.Page 20 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSCOMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONRE-REVIEW: SHORT ACTING BETA 2 ADRENERGIC AGENTS, INHALEDPREFERREDNON-PREFERREDALBUTEROL CFC QL (Compares to ALBUTEROL HFA QL (Compares to ProAir HFA ® ,Proventil ® )Proventil HFA ® , Ventolin HFA ® )MAXAIR AUTOHALER ® QL (pirbuterol) ALUPENT MDI ® QL (metaproterenol)VENTOLIN HFA ® QL (albuterol HFA) PROAIR ® HFA QL (albuterol HFA)ALBUTEROL SOLUTION QL (Compares to PROVENTIL ® QL (albuterol CFC)Proventil ® )PROVENTIL HFA ® QL (albuterol HFA)XOPENEX HFA ® CC, QL (levalbuterol)XOPENEX ® CC, QLNEBULIZER SOLUTION(levalbuterol)Quantity LimitsAlbuterol MDI Up to 3 inhalers/month ProAir ® HFA Up to 3 inhalers/monthAlbuterol HFA Up o 3 inhalers/month Alupent ® Up to 2 inhalers/monthMaxair Autohaler ® 1 inhaler every 60 days Proventil ® Up to 3 inhalers/monthProventil HFA ® Up to 3 inhalers/month Ventolin HFA ® Up to 3 inhalers/monthXopenex ® 2 canisters/monthXopenex ® Nebulizer Soln Up to 96 vials/monthAlbuterol solution Up to 120 vials/monthClinical CriteriaXopenex HFA ® MDI :• No prior authorization required for beneficiaries ages 10 and under.• Prior authorization is required for all beneficiaries ages 11 and older and will be approvedfor those experiencing side effects with albuterol or whose cardiovascular status isconsidered to be in severely deteriorating condition (in this situation, a trial of one otheragent is not required).Xopenex ® Nebulizer Solution :• No prior authorization required for beneficiaries ages 10 and under and ages 60 andolder.• Prior authorization is required for all beneficiaries age 11 through 59 experiencing sideeffects with albuterol or whose cardiovascular status is considered to be in severelydeteriorating condition (in this situation, a trial of one other agent is not required).COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Beta 2 Adrenergic Agents-Inhaled Short Acting Review. Sept 24, 20074. National Asthma Education and Prevention Program Expert Panel Report: Guidelines for theDiagnosis and Management of Asthma. Expert Panel Report 3. Available athttp://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.html. Accessed October 3, 2007.5. Medical Advisory Panel for the Pharmacy Benefits Management Strategic Healthcare Group.The pharmacologic management of chronic obstructive pulmonary disease. Washington (DC):Veterans Health Administration, Department of Veterans Affairs; 2002 Sep. 31 p.http://www.guideline.gov/summary/summary.aspx?doc_id=5186&nbr=003568&string=copd#s23.6. Milgrom H, et al. Low-dose levalbuterol in children with asthma: Safety and efficacy incomparison with placebo and racemic albuterol. J Allergy Clin Immunol. 2001 Dec; 108(6):938-45.Page 21 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSBACKGROUNDNEW: BETA 2 AGONISTS, ORAL• Beta 2 -agonists are the most effective bronchodilators available for the treatment ofbronchospasms; however, inhaled short-acting beta 2 -agonists are preferred over oralformulations because the oral agents are associated with more systemic effects.• The oral beta 2 agonists include albuterol, metaproterenol and terbutaline.• Beta 2 -agonists stimulate beta-adrenergic receptors of intracellular adenyl cyclase causingrelaxation of bronchial smooth muscle and inhibition of mediator release from mast cells.• Albuterol is FDA approved for acute relief of bronchospasm in asthma and for prophylaxisof exercise-induced asthma. Metaproterenol and terbutaline are indicated for acute reliefof bronchospasm in asthma and bronchospasms associated with bronchitis andemphysema.• Common adverse reactions include: headache, tachyarrhythmias, tremor, andnervousness.o Albuterol can also cause erythema multiforme / Stevens-Johnson syndrome,hypokalemia, myocardial infarction, and pulmonary edema.o Metaproterenol has been known to cause hypertension and paradoxicalbronchospasms.oTerbutaline can also cause paradoxical bronchospasms or seizure.• Metaproterenol is contraindicated in patients with chronic tachyarrhythmias, and thesyrup is contraindicated in patients with allergy to parabens.• These agents should be used with caution in patients with cardiovascular or convulsivedisorders, diabetes mellitus, hyperthyroidism, or hypokalemia. Terbutaline should alsobe used with caution in those with hypertension. Albuterol and metaproterenol arepregnancy category C; however, terbutaline is category B.• It is recommended that albuterol be started at lower doses initially and increased astolerated in children and in the elderly. The dose of terbutaline should be reduced inpatients with CrCl 10-50 mL/min, and it is contraindicated in those patients with CrCl < 10mL/min.• Head to Head Trials:ooA double-blind, 3-way crossover, single dose study examined the effects of oralalbuterol 4 mg, metaproterenol sulfate 20 mg, and terbutaline sulfate 5 mg in 20moderate-to-severe asthmatic patients. The study found oral metaproterenol hada more rapid onset of action, producing greater improvements in FEV 1 at 30minutes than albuterol or terbutaline. Albuterol and terbutaline, however,produced a significantly greater improvements in FEV 1 than metaproterenolbetween 6 and 8 hours after administration. The incidence of side effects was41% in the albuterol group, 59% in the metaproterenol group, and 73% in thegroup treated with terbutaline.65 children with asthma were given albuterol syrup 2 mg three times daily ormetaproterenol syrup 10 mg three times daily. The albuterol treatment groupshowed a greater change in baseline FEV 1 (29% vs. 20%) on treatment days 1and 28, a greater bronchodilation from hours 2 to 8 post administration, and asmaller chronotropic effect 1 and 1.5 hours post administration on both days 1and 8. Similar safety profiles were seen between the two drugs.Page 22 of 85November 8, 2007 Tennessee PAC

• Place in Therapy:RESPIRATORY AGENTSoMetaproterenol and terbutaline have similar efficacy to albuterol; however,metaproterenol and terbutaline possess more beta 1 -activity therefore they areassociated with a greater incidence of tachycardia.o While metaproterenol and terbutaline seem to have a quicker onset of action (30minutes, 30-45 minutes respectively compared to 15-180 minutes with albuterol),albuterol has a longer duration of action (6-8 hours compared to 4-8 withterbutaline and 4 hrs with metaproterenol).oTerbutaline has also found utility in the management of preterm labor.• Because beta 2- agonists relieve intermittent episodes of asthma as well as preventexercise-induced asthma, current treatment guidelines published by the National AsthmaEducation and Prevention Program (NAEPP), the National Institutes of Health (NIH),National, Heart, Lung, Blood Institute (NLBHI), as well as the Global Initiative for Asthma(GINA), Global Strategy for Asthma Management and Prevention advocate the use of aninhaled short- acting beta 2 agonist for all patients with asthma Oral beta 2 agonists have alimited place in chronic asthma management due to their greater incidence of side effectsand longer onset of action.• Current treatment guidelines from the Medical Advisory Panel for the Pharmacy BenefitsManagement Strategic Healthcare Group state that short-acting beta 2 agonists should beused as needed for the majority of symptomatic patients with COPD. These agents mayalso be administered on a scheduled basis for those patients uncontrolled on ipratropiumalone. Oral beta2 agonists can be useful for patients who cannot use any inhaled form,although such cases are rare and the risk of systemic adverse reactions is increasedsignificantly. These guidelines further state that all short-acting agents have similarefficacy and selection could be based on cost.RECOMMENDATION:The use of beta 2 -agonists to relieve intermittent episodes of asthma and COPD is the standard ofpractice. However, the lower incidence of systemic adverse events makes inhaled beta 2 -agonistspreferred over oral agents. While the use of oral beta 2 agonists is rare in the treatment ofbronchospasms, this route of administration provides a useful alternative for those patients whoare unable to use the inhaled medications. All agents in this class seem to have similar efficacy;however, due to the increased beta 1 activity, tolerability with metaproterenol and terbutalineseems to be lessened. While metaproterenol and terbutaline have a quicker onset of action,albuterol has a longer duration of action. In order to ensure provider choice among agents and toallow for the use of terbutaline in pre term labor, it is recommended that at least albuterol andterbutaline be available for use.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDALBUTEROL, syrup, tablets (compares toProventil ® , VoSpire ® )ALBUTEROL ER, tablets (compares toVoSpire ® ER)TERBUTALINE, tablets (compare toBrethine ® )NEW: BETA 2 AGONIST, ORALNON-PREFERREDBRETHINE ® (terbutaline)METAPROTERENOL, syrup, tabletsPROVENTIL ® (albuterol)VOSPIRE® (albuterol)VOSPIRE ER ® (albuterol ER)Page 23 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedAugust, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed August, 2007.3. National Heart Lung and Blood Institute. Expert Panel Report 3: Guidelines for The Diagnosisand Management of Asthma. 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf4. Medical Advisory Panel for the Pharmacy Benefits Management Strategic Healthcare Group.The pharmacologic management of chronic obstructive pulmonary disease. Washington (DC):Veterans Health Administration, Department of Veterans Affairs; 2002 Sep. 31 p.http://www.guideline.gov/summary/summary.aspx?doc_id=5186&nbr=003568&string=copd#s23.5. National Asthma Education and Prevention Program Expert Panel Report: Guidelines for theDiagnosis and Management of Asthma. Expert Panel Report 3. Available athttp://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.html. Accessed October 3, 2007.6. Formgren H: A clinical comparison of the effect of oral terbutaline and orciprenaline. Scand JResp Dis 1970; 51:195-202.7. Wolfe JD, Yamate M, Biedermann AA, et al: Comparison of the acute cardiopulmonary effects oforal albuterol, metaproterenol, and terbutaline in asthmatics. JAMA 1985a; 253:2068-2072.8. Kreukniet J: Clinical comparison of two beta-receptor stimulants and on parasympatholytic Drugin chronic obstructive lung disease. Scand J Resp Dis 1971; 52:137.9. Legge JS, Gaddie J, & Palmer KNV: Comparison of two oral selective beta 2-adrenergicstimulant drugs in bronchial asthma. Br Med J 1971a; 1:637-639.10. Maranetra N & Pain MC: Action of Bricanyl(R) (terbutaline) on ventilatory capacity in patientswith asthma. Med J Aust 1973; 1:988-990.11. Mattila MJ & Muittari A: Effect of bronchodilator drugs on the peak expiratory flow rate ofasthmatic patients: oral orciprenaline and terbutaline (KWD 2019). Ann Med Exp Biol Fenn1969; 47:298-302.12. Wolfe JD, Shapiro GG, & Ratner PH: Comparison of albuterol and metaproterenol syrup in thetreatment of childhood asthma. Pediatrics 1991; 88:312-319.BACKGROUNDRE-REVIEW: INHALED STEROIDS• Asthma is defined as a chronic inflammatory disease of the bronchial tubes or airwayswhich involves a cellular component. This inflammation of the air passages can causerecurrent episodes of breathlessness, chest tightness, coughing and wheezing. Inaddition, inflamed airways may cause an increase in bronchial hyperresponsiveness oroverreaction to various triggers (i.e. colds, allergies, cigarette smoke, and weatherchanges). This hyperresponsiveness causes a series of events involving muscletightening around the bronchial tubes, bronchial wall swelling and production of increasedmucus. This reaction increases the narrowing of the bronchial tubes to further obstructairflow.• The inhaled corticosteroids decrease the metabolism of arachidonic acid (an antiinflammatorycompound), reduce proinflammatory prostaglandin and leukotrienesynthesis and increase the number and responsiveness of beta-adrenergic receptors. Inaddition, the late phase reaction to allergies is blocked causing a reduction in airwayhyperresponsiveness and inhibiting inflammatory cell migration and activation.• All inhaled steroids are FDA approved for asthma maintenance treatment as prophylactictherapy, and all except budesonide are also approved for systemic corticosteroidreduction.Page 24 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• The most commonly reported side effects of inhaled corticosteroids include cough,headache, nausea, oral candidiasis, pharyngitis and upper respiratory infection (URI).o A detailed questionnaire sent to pediatricians and adult endocrinologists in theUnited Kingdom asked physicians to recall any cases of adrenal crisis suspectedto be due to ICS use in asthma. Among 33 cases identified as acute adrenalcrisis, 28 were reported in children and 5 were reported in adults. The childrengenerally presented with acute hypoglycemia, while adults usually showed amore insidious onset characterized by lethargy and nausea. Thirty cases wereassociated with fluticasone, one with both fluticasone and budesonide, and twowith beclomethasone. Almost all cases were associated with high doses ofsteroid; however, the majority of doses were still within accepted treatmentrecommendations.o Budesonide is the only agent in this class with a Pregnancy Category B. Allother agents in this class are classified as Pregnancy Category C.o Inhaled corticosteroids are contraindicated as primary treatment for statusasthmaticus or any other acute asthma episode. However, they are consideredfirst line treatment for persistent asthma.o Prolonged use of inhaled corticosteroids has the potential to reduce verticalgrowth. The Childhood Asthma Management Program (CAMP) trial, whichcompared budesonide with nedocromil and placebo in 1,041 children followed for4 to 6 years, found a 1 centimeter difference between study groups at the end oftreatment. This reduction was related to the dose and length of use ofcorticosteroids. These height changes are consistent with the NAEPPguidelines, which report an average reduction in height of 1 centimeter over thefirst year; however, this effect is not sustained and may be reversible.o Many corticosteroids are primarily metabolized by the cytochrome P450isoenzyme 3A4. Fluticasone has been associated with Cushing’s syndrome andadrenal suppression when coadministered with ritonavir. Close monitoring isrecommended for patients with hepatic impairment to avoid accumulation of theactive ingredient.• There are limited head to head clinical trials that compare the agents within this class.However, numerous studies have shown inhaled corticosteroids to be superior toplacebo.o An eight week, randomized, multicenter, placebo-controlled, double-blind,double-dummy study was conducted to compare the safety and efficacy of oncedaily mometasone 440 mcg, budesonide 400 mcg, and placebo in 262 patientswith moderate persistent asthma. The percent change in FEV 1 from baseline tofinal evaluable visit was used as the primary efficacy endpoint. The FEV 1endpoint was significantly greater (p

RESPIRATORY AGENTSSeverity Birth to 4 years Ages 5 to 11 years Ages ≥ 12 yearsStep 1 No daily meds needed No daily meds needed No daily meds neededIntermittentStep 2PersistentStep 3PersistentStep 4PersistentStep 5PersistentStep 6PersistentLow dose inhaled steroid Low dose inhaled steroid Low dose inhaled steroidMedium dose inhaledsteroidMedium dose inhaledsteroid AND long-actinginhaled B 2 agonist ORmontelukast (Singulair)High dose inhaledsteroid AND long actinginhaled B 2 agonist ORmontelukast (Singulair)High dose inhaledsteroid AND long-actinginhaled B 2 agonist ORmontelukast (Singulair)AND oral steroidLow dose inhaled steroidAND long acting inhaled B 2agonist OR leukotrienereceptor antagonist ORtheophylline OR mediumdose steroidMedium dose inhaledsteroid AND long actinginhaled B 2 agonistHigh dose inhaled steroidAND long acting inhaled B 2agonistHigh dose inhaled steroidAND long acting inhaled B 2agonist AND oral steroidLow dose inhaled steroidAND long acting inhaledB 2 agonist OR mediumdoseinhaled steroidMedium dose inhaledsteroid AND long actinginhaled B 2 agonistHigh dose inhaledsteroid AND long-actinginhaled B 2 agonistHigh dose inhaledsteroid AND long-actinginhaled B 2 agonist ANDoral corticosteroidRECOMMENDATION:Efficacy studies clearly show inhaled corticosteroids reduce symptoms, frequency, and severity ofasthma exacerbations. As a result, improvements in lung function and quality of life have beenobserved by asthmatic patients. The 2007 National, Heart, Lung, and Blood Institute of Health,National Institutes of Health (NHLBI, NIH) Global Initiative for Asthma (GINA) list inhaledcorticosteroids as the preferred treatment for patients with persistent asthma at every level ofseverity. Although differences exist between agents in the class in dosage frequency and numberof inhalations required for each dose, all inhaled corticosteroids appear to be equally effectivewhen given in equipotent dosages. In order to allow provider choice among the various agentsand delivery systems, it is recommended that at least three unique agents be available.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDASMANEX ® QL (mometasone furoate powderfor inhalation)AZMACORT ® QL (triamcinolone acetonide MDI)FLOVENT HFA ® QL (fluticasone propionateMDI)FLOVENT DISKUS ® QL (fluticasone propionatepowder for inhalation)FLOVENT ROTADISK ® QL (fluticasonepropionate powder for inhalation)QVAR ® QL (beclomethasone dipropionate MDI)REREVIEW: INHALED STEROIDSNON-PREFERREDAEROBID ® QL (flunisolide MDI)AEROBID-M ® QL (flunisolide MDI)AEROSPAN TM QL (flunisolide hemihydrate MDI)PULMICORT FLEXHALER ® QL (budesonidepowder for inhalationPULMICORT TURBUHALER ®QL (budesonidepowder for inhalation)PULMICORT RESPULES ® CC, QL (budesonidesuspension for inhalation)Page 26 of 85November 8, 2007 Tennessee PAC

Quantity LimitsRESPIRATORY AGENTSAerobid ® , Aerobid-M ® 3 inhalers/monthAerospan TM 2 inhalers/monthAsmanex ® 1 inhaler/monthAzmacort ® 2 inhalers/monthFlovent HFA ® 2 inhalers/monthFlovent Diskus ® 50mcg:2/day, 100mcg:4/day, 250 mcg:8/dayFlovent Rotadisk ® 50mcg:2/day, 100mcg:4/day, 250 mcg:8/dayPulmicort Turbuhaler ® 2 inhalers/monthPulmicort Respules ® 2 vials/dayPulmicort Turbuhaler 2 inhaler/monthQVAR ® 2 inhalers/monthClinical or Step TherapyPulmicort Respules ® PA not required for recipients ages 6 and under.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed October, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed October, 2007.3. Provider Synergies. Inhaled Glucocorticoids Agents Review. September 25, 2007.4. National Heart Lung and Blood Institute. Expert Panel Report 3: Guidelines for TheDiagnosis and Management of Asthma. 2007.http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf5. National Asthma Education and Prevention Program Expert Panel Report: Guidelines forthe Diagnosis and Management of Asthma. Expert Panel Report 3. Available athttp://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.html. Accessed October 3, 2007.6. Todd GRG, Acerini CL, Ross-Russell R, et al: Survey of adrenal crisis associated with inhaledcorticosteroids in the United Kingdom. Arch Dis Child 2002; 87:457-461.7. Berger WE, Milgrom H, Chervinsky P, et al. Effects of treatment with mometasonefuroate dry powder inhaler in children with persistent asthma. Ann Allergy AsthmaImmunol. 2006;97(5):672-80.8. Corren J, Berkowitz R, Murray J, et al. Comparison of once-daily mometasone furoateversus once daily budesonide in patients with moderate persistent asthma. Int J ClinPract. 2003; 57 (7):567-72.BACKGROUNDRE-REVIEW: LONG-ACTING INHALED BETA 2 ADRENERGIC AGENTS• Bronchospasms are due to smooth muscle contraction resulting from airway obstructionin asthma and Chronic Obstructive Pulmonary Disease (COPD). Beta-agonists preventbronchospasm by stimulation of adenyl cyclase, the enzyme that forms cyclic AMP fromATP. The increased levels of cyclic AMP cause relaxation of bronchial smooth muscleand inhibition of the release of inflammatory mediators. There are beta 1 and beta 2receptors in the heart; however, the beta 2 receptors are more prominent in the lungs.The inhaled beta agonists are beta 2 selective.Page 27 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• Arformoterol and formoterol nebulized solutions are indicated for the long-termmaintenance treatment of bronchoconstriction in patients with COPD. They are notindicated for the acute treatment of COPD exacerbations or the management of asthma.Formoterol and salmeterol dry powder for inhalation (DPI) are indicated for the treatmentof COPD, prevention of exercise induced bronchospasm (EIB), and the prevention andtreatment of bronchospasm associated with asthma.• The most common adverse effects resulting from the use of LABAs are headache, GIupset, nervousness, palpitations, tachycardia, and tremor.o All of the LABAs carry similar black box warnings stating, “Long-acting beta 2adrenergic agonists may increase the risk of asthma-related death. Therefore,when treating patients with asthma, only use LABAs as additional therapy forpatients not adequately controlled on other asthma-controller medications (e.g.,low- to medium-dose inhaled corticosteroids) or patients whose disease severityclearly warrants initiation of treatment with 2 maintenance therapies, including aLABA. Data from a large, placebo-controlled US study that compared the safetyof salmeterol or placebo added with the usual asthma therapy showed anincrease in asthma-related deaths in patients receiving salmeterol (13 deaths outof 13,176 patients treated for 28 weeks on salmeterol versus 3 deaths out of13,179 patients on placebo).”o The LABAs should be used with caution in patients with cardiovascular disease,seizure disorders or thyrotoxicosis. All LABAs are Pregnancy Category C.o The cardiovascular adverse reactions of the LABAs may be potentiated byMAOIs, TCAs or drugs known to prolong the QTc interval. MAOIs should bediscontinued for 14 days before initiation of a LABA. Caution should be used inpatients who are treated with beta blockers and LABAs to prevent inhibition ofthe bronchodilatory effects of the LABAs. To minimize this interaction, patientsshould be treated with cardioselective beta blockers, if treatment with a betablocker is unavoidable, such as with prophylaxis after MI. The hypokalemiceffects of adrenergic agonists may be potentiated by the coadministration ofxanthine derivatives, steroids, or diuretics, particularly potassium wastingdiuretics.• Formoterol and salmeterol have been compared head to head in 3 studies.o A double-blind, double-dummy, placebo-controlled, randomized, four-periodcrossover study was conducted involving 25 patients with asthma and a historyof EIB defined as mean fall in FEV 1 of 31% from baseline. After 12 days,participants were subjected to exercise challenge at 5, 30 or 60 minutes afterinhalation of a single dose of formoterol 12 mcg, salmeterol 50 mcg, terbutaline500 mcg or placebo. There was no difference between active treatments at anytime in EIB (measured by maximum fall in FEV 1 or area under the curve);however, the onset of bronchodilation was slower after salmeterol compared toterbutaline (p=

RESPIRATORY AGENTS• Arformoterol (15 mcg BID, 25 mcg BID, or 50 MCG BID via nebulizer) and salmeterol (42mcg BID via MDI) were compared in a 12-week, double-blind, randomized, doubledummy,placebo-controlled trial including 717 COPD patients. Mean percentage changein FEV 1 from the predose value over 12 weeks was significantly greater with all threearformoterol doses. All groups, including placebo, had similar rates of adverse effectsand COPD exacerbations.• The mainstay of asthma therapy includes an inhaled glucocorticoid and LABA ascontroller medications. These agents improve lung function, reduce asthma symptoms,and reduce the need for SABA as rescue medications. However, LABAs should never beused as monotherapy for controlling asthma. The 2007 guidelines from the NHLBI andNAEPP advocate the use of a LABA for prevention of exercised-induced asthma. Theyrecommend that patients >5 years old with moderate persistent asthma or patientswhose asthma is not controlled by low-dose corticosteroid be considered as candidatesfor the addition of a LABA or an increase in their inhaled corticosteroid. Patients whohave severe persistent asthma should be treated with a combination of a LABA andinhaled corticosteroid. The 2006 GINA guidelines recommend the use of a LABA whenasthma sufferers require their SABA more frequently than occasionally during thedaytime and bronchospasms are longer in duration.• Bronchodilators are also the mainstay of COPD treatment because they improveemptying of the lungs, reduce dynamic hyperinflation, and improve exercise performance.These agents do not modify the decline in lung function or the prognosis associated withCOPD, but they can be used early in the disease on an as needed or on a scheduledbasis as COPD progresses. The 2006 GOLD guidelines state SABA are among theprincipal treatments for symptomatic management of COPD, but regular treatment usinga LABA is more effective and convenient.RECOMMENDATION:Long acting beta 2 agonists are a mainstay in the treatment of both asthma and COPD. The 2007guidelines from the NHLBI and NAEPP recommend a combination of a LABA and an inhaledcorticosteroid for patients who have severe persistent asthma. These guidelines also advocatethe use of a LABA for prevention of exercise-induced asthma. The 2006 GOLD guidelines stateregular treatment using a LABA is more effective and convenient than a SABA. These clinicalguidelines do not distinguish between the available LABAs when it comes to safety or efficacy.While proven effective, these agents may increase the risk of asthma-related death; therefore,they should only be used as additional therapy in patients with asthma. Given the safety concernsassociated with these agents, it is recommended that they be subject to clinical criteria to ensuretheir appropriate use. The nebulized forms may be beneficial in patients who have difficultysynchronizing breath and actuation using the dry powder inhalers. For this reason, it isrecommended that at least one nebulized formulation be available for individuals who havedifficulty using a DPI.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONRE-REVIEW: LONG-ACTING INHALED BETA 2 ADRENERGIC AGENTSREFERREDNON-PREFERREDFORADIL ® ST, QL (formoterol DPI)BROVANA ® CC, QL (arformoterol inhalation solution)SEREVENT DISKUS ® ST, QL (salmeterol DPI) PERFOROMIST TM CC, QL (formoterol inhalationsolution)Quantity LimitsBrovana ® 120 mL/monthForadil ® 1 inhaler/monthPerforomist TM 120 mL/monthSerevent Diskus ® 1 inhalers/monthPage 29 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSStep Therapy for Serevent Diskus ® and Foradil ®Serevent® or Foradil® will be approved if ONE of the following criteria are met:• A diagnosis of asthma (step 3 or higher or moderate persistent to more severe) andcurrently treated with an inhaled steroid and an inhaled short-acting beta agonist; OR• A diagnosis of Exercise Induced Bronchospasm and a short-acting beta agonist has beentried and failed (note: a SABA should still be provided for acute relief of symptoms); OR• A diagnosis of COPDCOMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONClinical Criteria for Brovana ® or Perforomist TMBrovana ® or Perforomist TM will be approved for individuals who meet the following criteria:Recipient has tried and failed (or been intolerant to) treatment with salmeterol DPI or formoterolDPI, or for patients who have difficulty using a dry powder inhaler (DPI).COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Beta 2 Adrenergic Agents-Inhaled Long Acting Review. Sept 17, 2007.4. National Asthma Education and Prevention Program Expert Panel Report: Guidelines for theDiagnosis and Management of Asthma. Expert Panel Report 3. Available athttp://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.html. Accessed October 3, 2007.5. Bumgartner RA, Hanania NA, Calhoun WJ, et al. Nebulized arformoterol in patients withCOPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo and activecontrolledtrial. Clin Ther. 2007;29(2):261-78.6. DiMarco F, Milic-Emili J, Boveri B, et al. Effect of inhaled bronchodilators on inspiratorycapacity and dyspnoea at rest in COPD. Eur Respir J. 2003;21:86-94.7. Kottakis J, Cioppa GD, Creemers J, et al. Faster onset of bronchodilation with formoterol thanwith salmeterol in patients with stable, moderate to severe COPD: results of a randomized,double-blind clinical stud. Can Respir J. 2002;9:107-15.8. Richter K, Janicki S, Jorres RA, et al. Acute protection against exercise-inducedbronchoconstriction by formoterol, salmeterol and terbutaline. Eur Respir J. 2002;19:865-71.RE-REVIEW: LONG-ACTING BETA 2 AGONIST/INHALED CORTICOSTEROIDCOMBINATIONSBACKGROUND• For the treatment of asthma at any age, it is recommended to add a long acting beta 2agonist to an inhaled corticosteroid if the asthma cannot be controlled on an inhaledcorticosteroid alone (ICS). Therefore, two products are now available which combine anICS and long-acting beta2 agonist (LABA): fluticasone with salmeterol (Advair ® ) andbudesonide with formoterol (Symbicort ® ).Page 30 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• Salmeterol and formoterol selectively bind to the beta 2 receptors in bronchial smoothmuscle resulting in bronchial relaxation and inhibition of the release of hypersensitivitymediators from mast cells. Corticosteroids, budesonide and fluticasone, decrease themetabolism of arachidonic acid and reduce the synthesis of proinflammatoryprostaglandins and leukotrienes. Corticosteroids also increase the number andresponsiveness of beta-adrenergic receptors, block the late-phase reaction to allergens,reduce airway hyperresponsiveness, and inhibit inflammatory cell migration andactivation.• The combination beta 2 agonist ICS products are approved for the chronic treatment ofasthma. The dry powder formulation (DPI) of fluticasone (250 mcg) and salmeterol (50mcg) is also approved for the treatment of chronic obstructive pulmonary disease(COPD) associated with chronic bronchitis. These agents should not be used for acuteasthma exacerbations.• The most common adverse events associated with these combination products includecough, headache, nausea, oral candidiasis, pharyngitis, and upper respiratory infection.o Both of these products carry a black box warning about a small, but significant,increased risk of life-threatening asthma episodes or asthma related deathsobserved in patients taking salmeterol in the Salmeterol Multi-center AsthmaResearch Trial (SMART).o Caution should be used in patients with hepatic impairment who takefluticasone/salmeterol due to possible accumulation of both active ingredients.This product should also be used cautiously in patients with milk allergy, becausethe lactose in the salmeterol component contains milk proteins. Formoterol hasbeen associated with exacerbation of convulsive disorders, hypokalemia orthyrotoxicosis, and should be used cautiously in these patient populations. Thesteroid components may cause an inadequate adrenal response, bone mineraldensity loss or small growth velocity reduction in children and adolescents. Thebeta agonist component may cause cardiovascular disorders such as palpitationsor tachycardia due to stimulation of beta receptors in the heart.• A randomized, double-blind, double-dummy study compared the efficacy offluticasone/salmeterol (250/50 mcg BID) to budesonide/formoterol (200/6 mcg BID) in688 adults with persistent asthma and a FEV 1 of 81% (CONCEPT trial). After 4 weekson stable dosing both groups continued for an additional 48 weeks on either a stabledose of fluticasone/salmeterol or an adjustable dosing regimen of budesonide/formoterolthat required either halving the dose and stepping up or down as indicated by thepercentage of symptom free days (primary endpoint), presence or absence of nocturnalawakenings due to asthma, frequency of rescue medication use, or changes in morningpeak expiratory flow (PEF). Patients receiving stable doses of fluticasone/salmeterol hada greater percentage of symptom-free days compared to those receiving adjustablebudesonide/formoterol (p=0.034) and fewer emergency room visits or hospitalizations(p=0.008). Patients in the adjustable budesonide/formoterol group used an average of1.8 inhalations daily with nearly 83% stepping down to one inhalation daily.• A follow up to the CONCEPT trial looked at long-term efficacy as well as impact onhealth-related quality of life of the stable-dose regimen of fluticasone/salmeterol and theadjustable maintenance dosing regimen of budesonide/formoterol. The mean changefrom baseline in the Asthma Quality of Live Questionnaire (AQLQ) overall score was notstatistically different between the two groups (p=0.121). However, a post hoc regressionanalysis did identify a statistically significant difference in AQLQ score at 28 (p=0.038)and 52 (p=0.009) weeks in favor of the fluticasone/salmeterol group.Page 31 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• A randomized, double-blind, double-dummy, placebo-controlled trial was completed overa 12 week period to compare the efficacy and safety of budesonide/formoterol tobudesonide, formoterol and placebo. Patients ≥12 years of age (n=596) with moderate tosevere persistent asthma who were previously receiving an ICS were placed onbudesonide 160 mcg BID. After two weeks, patients were randomized to the comboproduct (160/4.5 mcg BID), budesonide (160 mcg BID), formoterol (4.5 mcg BID),budesonide (160 mcg BID) + formoterol (4.5 mcg BID), or placebo BID. The primaryefficacy endpoints were mean change from baseline of FEV 1 and mean change frombaseline in 12-hour FEV 1 . The results were similar for all outcomes measures in thebudesonide/formoterol and the budesonide + formoterol groups. The combinationshowed greater improvement in FEV 1 than the budesonide, formoterol, or placebo groups(p=≤0.049). Fewer patients on the combined agents experienced worsening asthmasymptoms (p≤0.025). All of the treatments had similar safety profiles.• The 2007 NHLBI and NAEPP guidelines recommend the addition of a long acting beta 2agonist to an ICS for those with persistent asthma that cannot be controlled on an ICSalone. The 2007 GOLD guidelines suggest the addition of an ICS to a long acting beta 2agonist for patients with severe COPD whose symptoms cannot be controlled on an asneeded dosage of a short acting beta 2 agonist and a scheduled dose of a long actingbeta 2 agonist. However, neither of these guidelines suggests that the fixed dosecombination products be used over the agents given individually.RECOMMENDATION:The combination of an ICS and long acting beta 2 agonist are reasonable agents for the treatmentof asthma and COPD; however, there is insufficient evidence to show that one combinationproduct is superior to another. The 2007 NHLBI and NAEPP guidelines recommend the additionof a long-acting beta 2 agonist to an ICS for patients of all ages whose asthma is not controlled onan ICS alone. The 2007 GOLD guidelines suggest the addition of an ICS to a long-acting beta 2agonist for patients with severe COPD whose symptoms cannot be controlled on a long-actingbeta 2 agonist and an as needed short acting beta 2 agonist. Based on these guidelines and thecurrent medical literature, it is recommended that the combination LABA/ICS agents be reservedfor asthma patients who require frequent use of an inhaled short-acting bronchodilator whilemaintained on an optimal dose of an inhaled steroid, and for COPD patients who have symptomsdespite optimal doses of a LABA.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONRE-REVIEW: LONG-ACTING BETA 2 AGONIST/INHALED CORTICOSTEROIDCOMBINATIONSPREFERREDNON-PREFERREDN/AADVAIR DISKUS ® CC,QL (salmeterol/fluticasone DPI)ADVAIR HFA ® CC,QL (salmeterol/fluticasone MDI)SYMBICORT ® CC,QL (formoterol/budesonide MDI)Quantity LimitsAdvair ® = 1/monthSymbicort = 1/monthClinical Criteria for Advair ® / Symbicort ®Advair ® / Symbicort ® will only be approved if ONE of the following criteria is met:• For the treatment of asthma or the treatment of other reversible airway disease(s) whereoptimal doses of inhaled steroids are being used and breakthrough symptoms requirefrequent use of inhaled short-acting bronchodilators; OR• For the treatment of COPD where optimal doses of a long-acting beta agonist are beingused and symptoms are still uncontrolled.Page 32 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSCOMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. National Heart Lung and Blood Institute. Expert Panel Report 3: Guidelines for The Diagnosisand Management of Asthma. 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf4. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, andprevention of chronic obstructive pulmonary disease: GOLD Executive Summary. Am J RespirCrit Care Med 2007;176:532–555.5. National Asthma Education and Prevention Program Expert Panel Report: Guidelines for theDiagnosis and Management of Asthma. Expert Panel Report 3. Available athttp://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.html. Accessed October 3, 2007.6. Fitzgerald JM, Boulet LP, Follows RM. The CONCEPT trial: a 1-year, multicenter,randomized, double-blind, double-dummy comparison of a stable dosing regimen ofsalmeterol/fluticasone propionate with an adjustable maintenance dosing regimen offormoterol/budesonide in adults with persistent asthma. Clin Ther. 2005;27(4):393-4067. Noonan M, Rosenwasser L, Martin P, et al. Efficacy and safety of budesonide and formoterolin one pressurized metered-dose inhaler in adults and adolescents with moderate to severeasthma: a randomized clinical trial. Drugs. 2006;66(17):2235-54.8. Prince DB, Williams AE, Yoxall S. Salmeterol/fluticasone stable-dose treatment comparedwith formoterol/budesonide adjustable maintenance dosing: impact on health-related qualityof life. Respir Res. 207;8:46.BACKGROUNDRE-REVIEW: INHALED ANTICHOLINERGICS• Chronic Obstructive Pulmonary Disease (COPD) is characterized by progressive,possibly hyperactive, airflow obstruction due to chronic bronchitis or emphysema.Chronic bronchitis specifically causes intermittent airway inflammation and excessivemucus production which leads to frequent, prolonged episodes of productive cough.Emphysema is caused by the destruction of alveoli and distal airspaces resulting indecreased ventilation and a loss of the capillary network essential for perfusion.• Ipratropium inhibits vagally mediated reflexes by antagonizing the action of acetylcholineon bronchial smooth muscle preventing secretions in the nasal mucosa. Albuterolactivates beta 2 receptors on airway smooth muscle leading to smooth muscle relaxation.Two agents in this category, Combivent ® and DuoNeb ® , utilize the combination ofipratropium and albuterol. Tiotropium inhibits M(3) receptors at the smooth musclepromoting bronchodilation.• Ipratropium and tiotropium are approved for the maintenance treatment of bronchospasmassociated with COPD. The combination of albuterol and ipratropium is indicated for thetreatment of bronchospasm associated with COPD in patients who require more than onebronchodilator.• Ipratropium and the ipratropium/albuterol combination most commonly cause headache,dry mouth, GI upset, nervousness/tremor, palpitations or chest pain. The most commonadverse events reported with tiotropium are dry mouth (16%) and anticholinergic typeside effects such as constipation (4%) and blurred vision. Glaucoma and urinaryretention/difficulty occurred in less than 1% of the tiotropium treated population.o Combivent ® is contraindicated in patients with hypersensitivity to soy lecithin orrelated food products such as soybean or peanut.Page 33 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSo All of these agents should be used with caution in patients with narrow-angleglaucoma, prostatic hyperplasia or bladder neck obstruction due to theiranticholinergic activities. Tiotropium should be used with caution in patients withrenal impairment (CrCl ≤ 50 mL/min) as accumulation of drug may occur.Ipratropium is pregnancy category B while albuterol containing products andtiotropium are pregnancy category C.o The cardiovascular effects of albuterol or albuterol containing products may bepotentiated by MAOIs and TCAs if given concurrently; therefore, MAOIs shouldbe discontinued for 14 days prior to starting therapy with albuterol or albuterolcontaining products. Tiotropium is metabolized via the cytochrome P450 3A4and 2D6 isoenzymes; therefore, caution should be used if patients are takingtiotropium along with 3A4 or 2D6 inhibitors such as ketoconazole or quinidine.• Tiotropium was compared to ipratropium in three studies:o Tiotropium (18 mcg daily) was compared to ipratropium (40 mcg QID) duringlong-term treatment of 288 patients with stable COPD in a 14-center, doubleblind,double-dummy, parallel group 13 week study . Tiotropium showedsuperiority over ipratropium in trough, average and peak FEV 1 levels, trough andaverage FVC levels, and weekly mean morning and evening PEF. The use ofconcomitant albuterol was also lower in the tiotropium treated patients. Drymouth was seen in 14.7% of tiotropium treated patients versus 10.3% ofipratropium treated patients.o Two randomized, double-blind, double-dummy studies of one year in lengthevaluated tiotropium (18 mcg daily) or ipratropium (50 mcg QID). Mean baselineFEV 1 values were 41.9% of predicted value for tiotropium and 39.4% of predictedvalue for ipratropium. An improvement in trough FEV 1 at one year of 0.12 ±0.01L was seen in the tiotropium group compared to a decline of 0.03 ± 0.02 L inthe ipratropium group (p=

PREFERREDATROVENT HFA ® QL (ipratropium)COMBIVENT ® QL (albuterol/ipratropium)IPRATROPIUM, solution (Compares toAtrovent ® )DUONEB ® QL (albuterol/ipratropium)SPIRIVA ® QL (tiotropium)Quantity LimitsAlbuterol/Ipratropium 180 nebs/monthAtrovent HFA ® 2 inhalers/monthCombivent ® 2 inhalers/monthDuoNeb ® 180 nebs/monthSpiriva ® 1/dayRESPIRATORY AGENTSREREVIEW: INHALED ANTICHOLINERGICSNON-PREFERREDALBUTEROL/IPRATROPIUM SOLUTION QL(Compares to DuoNeb)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Bronchodilators, Anticholinergic Review. Sept 19, 20074. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, andprevention of chronic obstructive pulmonary disease: GOLD Executive Summary. Am JRespir Crit Care Med 2007;176:532–555.BACKGROUNDRE-REVIEW: LEUKOTRIENE MODIFIERS• There are two classes of agents in the leukotriene modifiers. Zileuton and zileutonextended-release block the synthesis of leukotrienes by inhibiting 5-lipoxygenase.Montelukast and zafirlukast selectively inhibit the cysteinyl leukotriene receptor.Reductions in cysteinyl leukotrienes result in bronchodilation and a reduction insymptoms of asthma and allergic rhinitis.• FDA-approved inidications are as follows:oMontelukast is FDA approved for treatment of seasonal allergic rhinitis in adultsand children ≥2 years, treatment of perennial allergic rhinitis in adults andchildren ≥6 months, prophylaxis and chronic management of asthma in adultsand children ≥12 months, and prevention of exercise-induced bronchospasm(EIB) for patients ≥15 years.ooZafirlukast is indicated for prophylaxis and chronic management of asthma inadults and children 5 years and older.Zileuton and zileuton extended-release are indicated for prophylaxis and chronictreatment of asthma in adults and children 12 years and older.• Dosing is once daily for montelukast, twice daily for zafirlukast, and up to four times dailyfor zileuton.• Zileuton and Zileuton ER are contraindicated in patients with active liver disease.Zileuton ER is also contraindicated with ALT elevations ≥ 3 times upper limit of normal.• Warnings / Precautions – these agents are not indicated for reversal of bronchospasmduring an acute asthma attack. Short-acting inhaled beta-agonists should be availablefor these situations.Page 35 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• Common side effects for montelukast include otitis, pharyngitis, influenza, fever, sinusitis,cough, upper respiratory infection, headache, and diarrhea. Common side effects forzafirlukast include headache and abdominal pain. Common side effects of zileuton andzileuton ER include abdominal pain, dyspepsia, N/V, myalgia and elevated liver enzymes.• Drug-Drug Interactions:oooMontelukast – CYP450 enzyme inducers may decrease montelukast levelsZafirlukast – aspirin may increase zafirlukast levels, erythromycin andtheophylline may decrease zafirlukast levels, and zafirlukast may increase theeffects of warfarin.Zileuton and zileuton ER may increase the activity of propranolol, theophyllineand warfarin.• No published trials are available comparing the leukotriene modifiers head to head.Studies have been conducted comparing the leukotriene modifiers with other agentsused for asthma and AR. These comparative studies do not provide conclusive evidenceto suggest that one leukotriene modifier is more effective than the others.• Leukotriene modifiers are beneficial in the treatment and prophylaxis of asthma. Thefollowing chart outlines the 2007 NAEPP guidelines:Severity Birth to 4 years Ages 5 to 11 years Ages ≥ 12 yearsStep 1 No daily meds needed No daily meds needed No daily meds neededIntermittentStep 2 Low dose inhaled steroid Low dose inhaled steroid Low dose inhaled steroidPersistentStep 3PersistentMedium dose inhaled steroidStep 4PersistentStep 5PersistentStep 6PersistentMedium dose inhaled steroidAND long-acting inhaled B 2agonist OR montelukast(Singulair)High dose inhaled steroidAND long acting inhaled B 2agonist OR montelukast(Singulair)High dose inhaled steroidAND long-acting inhaled B 2agonist OR montelukast(Singulair) AND oral steroidLow dose inhaled steroid ANDlong acting inhaled B 2 agonistOR leukotriene receptorantagonist OR theophyllineOR medium dose steroidMedium dose inhaled steroidAND long acting inhaled B 2agonistHigh dose inhaled steroidAND long acting inhaled B 2agonistHigh dose inhaled steroidAND long acting inhaled B 2agonist AND oral steroidLow dose inhaled steroidAND long acting inhaled B 2agonist OR medium-doseinhaled steroidMedium dose inhaledsteroid AND long actinginhaled B 2 agonistHigh dose inhaled steroidAND long-acting inhaled B 2agonistHigh dose inhaled steroidAND long-acting inhaled B 2agonist AND oralcorticosteroid• While not specifically recommended in AAAAI allergic rhinitis guidelines (which have notbeen updated since 1998), the leukotriene modifiers are useful in the treatment of AR forthose patients who also have asthma or for those individuals who do not respond totreatment with oral antihistamines or nasal steroids.RECOMMENDATION:According to the NAEPP, inhaled corticosteroids are the cornerstone treatment for asthma.Leukotriene modifiers should be considered as a potential alternative or add-on therapy for thosepatients with persistent asthma. Guidelines indicate that leukotriene modifiers can be used ascontroller medications in the treatment of asthma particularly for those ages four and under. Forpatients ages five and older, the preferred adjunctive therapy to inhaled corticosteroids is a longactinginhaled beta agonists (rather than a leukotriene modifier). Leukotriene modifiers arebeneficial in the treatment of AR, but should be considered second line medications after trial andfailure of topical nasal steroids and minimally sedating antihistamines.Page 36 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSCOMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONRE-REVIEW: LEUKOTRIENE MODIFIERSPREFERREDNON-PREFERREDSINGULAIR ® ST, QL (montelukast)ACCOLATE ® QL (zafirlukast)ZYFLO ® (zileuton)ZYFLO ® CR (zileuton controlled release)Quantity LimitsAccolate ® 2 per daySingulair ® 1 per dayStep Therapy for Singulair ®• For the treatment of asthma in patients

oRESPIRATORY AGENTSXanthine derivatives are contraindicated in patients with active peptic ulcerdisease or underlying, untreated seizure disorder because aminophylline ortheophylline may actually exacerbate these co-morbid conditions.o Clinicians should cautiously monitor for potentially fatal theophylline toxicity inpatients with CHF, fever ≥ 102 for ≥ 24 hours, liver disease, hypothyroidism,acute pulmonary edema or cor pulmonale, sepsis, and shock. In addition,caution should be used in patients 60 years old, and in patients who arediscontinuing smoking, because their clearance of theophylline is reduced.There is also a risk of exacerbations of cardiac tachyarrhythmias or seizures inpatients with these co-morbid conditions who take a xanthine derivative.o Concomitant use with ephedrine or other sympathomimetic bronchodilators maycause toxic effects of xanthine derivatives. Aminophylline and theophylline aremetabolized by the cytochrome P450 enzyme system, specifically CYP1A2,CYP2E1 and CYP3A3. This leads to several drug to drug interactions. Theremay be decreased serum levels of xanthine derivatives if administered along withautoinducers such as carbamazepine, phenytoin or rifampin. There may beincreased serum levels and possibly toxicity if xanthine derivative arecoadministered with enzyme inhibitors such as cimetidine, ciprofloxacin, ormacrolides. Xanthine derivatives will increase the renal clearance of lithium anddecrease the clearance of alcohol.• The pharmacokinetic properties of xanthine derivatives are altered based on age and comorbidcondition; therefore, dosing should be recommended using specific patientparameters. Aminophylline and theophylline doses should be increased in patientsundergoing hemodialysis, as these agents are dialyzed. Doses should also be reducedin geriatric patients and those with liver disease.• Patients with mild persistent asthma (23-46 years old) who were stable on the equivalentof budesonide 200 mcg daily were randomized to receive either inhaled budesonide 400mcg daily (n=25), montelukast 10 mg daily (n=25) or sustained release theophylline 400mg daily after a 3-week run-in period. At the end of the 3-month study, there we nostatistically significant differences between the groups with regard to change frombaseline in initial morning peak expiratory flow (PEF) or forced expiratory volume in 1second (FEV 1 ), daytime and nighttime symptom scores, or supplemental beta-agonistuse. Asthma exacerbations occurred in 4 of 25 (16%) patients receiving montelukast and3 of 24 (12.5%) patients receiving theophylline. No asthma exacerbations were reportedin the patients receiving budesonide• According to the 2007 NHLBI guidelines, sustained-release theophylline is a long-termcontroller medication recommended as an alternative or as an adjunct to inhaledcorticosteroids (ICS) in patients who are not candidates for higher doses of inhaledcorticosteroids or long acting beta agonists. Theophylline is less desirable as adjunctivetherapy than a leukotriene receptor antagonist, cromolyn, or nedocromil because of itssafety profile and the need to adjust doses based on diet, drug interactions and variablemetabolism with age. Aminophylline is generally only recommended in the IV form forthe management of asthma exacerbations.RECOMMENDATION:Both aminophylline and theophylline are indicated for the symptomatic treatment or prevention ofchronic asthma and COPD. Theophylline is recommended as an alternative to low-dose inhaledcorticosteroids (ICS) or as an adjunct to inhaled corticosteroids (ICS) in patients who are notcandidates for higher doses of inhaled corticosteroids or long acting beta agonists. While bothagents are clinically equivalent, aminophylline is generally only used IV for the management ofasthma exacerbations. Therefore, it is recommended that at least theophylline be available foruse in asthma patients.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPage 38 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTSPREFERREDTHEO-24 ® (theophylline ER)THEOPHYLLINE ER/IR(compares toElixophyllin ® , Theo-24 ® , TheoCap ® , Theochron ® ,Theo-Dur ® , Theo-Time ® , Quinron-T ® , Uniphyl ® )AMINOPHYLLINE (Compares to Norphyl ® ,Phyllocontin ® , Truphylline ® )NEW: XANTHINE DERIVATIVESNON-PREFERREDELIXOPHYLLIN ® (theophylline)NORPHYL ® (aminophylline)PHYLLOCONTIN ® (aminophylline)THEOCAP ® (theophylline)THEOCHRON ® (theophylline)THEO-DUR ® (theophylline)THEO-TIME ® (theophylline)TRUPHYLLINE ® (aminophylline)QUINRON-T ® (theophylline)UNIPHYL ® (theophylline)References:1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. National Heart Lung and Blood Institute. Expert Panel Report 3: Guidelines for The Diagnosisand Management of Asthma. 2007. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.4. Yurdakul AS, Taci N, Eren A, et al: Comparative efficacy of once-daily therapy with inhaledcorticosteroid, leukotriene antagonist or sustained-release theophylline in patients with mildpersistent asthma. Respir Med 2003; 97(12):1247-1327.BACKGROUNDNEW: MAST CELL STABILIZERS• Mast cell degranulation is important in the initiation of immediate responses followingexposure to allergens. Asthmatics with an allergic component usually have increasednumbers of mast cells within the walls of their respiratory tact. Currently, there are twomast cell stabilizers, cromolyn and nedocromil, available for use in these patients.• After exposure to specific antigens, the mast cells release histamine, and the slowreactingsubstance of anaphylaxis (SRS-A), a leukotriene. Cromolyn inhibits the releaseof histamine and SRS-A from the mast cells. Nedocromil sodium inhibits the in vitroactivation of, and mediator release from, a variety of inflammatory cells, includingeosinophils, neutrophils, macrophages, mast cells, monocytes, and platelets.• Cromolyn is FDA approved for prophylactic management of bronchial asthma andprevention of bronchospasms in patients 2 years and older. Nedocromil is FDA approvedfor prophylactic management of asthma in patients 6 years or older.• Both agents in this class can cause throat irritation, dry mouth, bad taste,nausea/vomiting, and cough. Cromolyn should be used with caution in patients less than2 years old, and those with coronary artery disease and cardiac arrhythmias. Mast cellstabilizers are not for use in acute asthma attacks.• Head to Head StudiesoA multicenter, double-blind, group comparative trial compared nedocromil tocromolyn and placebo in patients already receiving short-acting inhaled beta 2 -agonists and inhaled corticosteroids for asthma. Both mast cell stabilizersreduced symptoms, but nedocromil was found to be more effective thancromolyn in reducing asthma symptoms in patients who were maintained onregimens of low to moderate doses of inhaled corticosteroids.o A double-blind, cross-over study involving 12 children, ages 6.5 years to 13.5years, with known exercise induced asthma (EIA), compared nedocromil 4 mg,cromolyn 10 mg, and placebo. Participants exercised for 6 minutes on a 10%grade treadmill adjusted to maintain a maximum heart rate of 180 beats/min.FEV 1 was measured before administration and post-exercise. Both drugsprovided equal protection from EIAPage 39 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• Current treatment guidelines published by the National Asthma Education and PreventionProgram (NAEPP), the National Institutes of Health (NIH), National, Heart, Lung, BloodInstitute (NLBHI), as well as the Global Initiative for Asthma (GINA), Global Strategy forAsthma Management and Prevention, emphasize the use of inhaled corticosteroids (ICS)as first-line therapy for managing persistent asthma symptoms. However, cromolyn andnedocromil are recommended as alternatives to ICS as long-term control medicationsparticularly in those younger than 5 years of age, with mild persistent asthma. Theseagents may also be used to prevent exercise-induced bronchospasm.RECOMMENDATION:Cromolyn and nedocromil provide alternatives to inhaled corticosteroids in the management ofmild persistent asthma. While current guidelines make no differentiation between the twoproducts, studies have shown that nedocromil may be more effective than cromolyn in thetreatment of asthma. Cromolyn is supplied in a nebulizer solution as well as a MDI and isapproved in younger patients than nedocromil. Therefore, it is recommended that both nedocromiland cromolyn products be available for use in patients with asthma.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: MAST CELL STABILIZERSPREFERREDNON-PREFERREDCROMOLYN nebulizer solution QL (compares to Intal ® ) INTAL ® QL nebulizer solution (cromolyn)INTAL ® MDI QL (cromolyn)TILADE ® MDI QL (nedocromil)Quantity LimitsCromolyn 20 mg/2mL nebulizer solution 120 vials/monthIntal ® 20mg/mL nebulizer solution 120 vials/monthIntal ® 800 mcg/actuation 8.1 g (112 sprays) MDI 2 inhalers/monthIntal ® 800 mcg/actuation 14.2 g (200 spays) MDI 2 inhalers/monthTilade ® 1.75 mg/actuation 16.2 g (104 sprays) MDI 3 inhalers/monthReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. National Heart Lung and Blood Institute. Expert Panel Report 3: Guidelines for TheDiagnosis and Management of Asthma. 2007.http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf4. National Asthma Education and Prevention Program Expert Panel Report: Guidelines forthe Diagnosis and Management of Asthma. Expert Panel Report 3. Available athttp://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.html. Accessed October 3, 2007.5. Comis A, Valletta EA, Sette L, et al: Comparison of nedocromil sodium and sodiumcromoglycate administered by pressurized aerosol, with and without a spacer device inexercise-induced asthma in children. Eur Respir J 1993; 6:523-526.6. Lal S, Dorow PD, Venho KK, et al: Nedocromil sodium is more effective than cromolynsodium for the treatment of chronic reversible obstructive airway disease. Chest 1993;104:438-447.Page 40 of 85November 8, 2007 Tennessee PAC

RESPIRATORY AGENTS• The 2007 NHLBI Guidelines states that omalizumab may be used as adjunctive therapyin step 5 or 6 care for patients who have allergies and severe persistent asthma which isinadequately controlled using the combination of an inhaled corticosteroid and a longactingbeta agonist.RECOMMENDATION:Omalizumab is used in allergic asthma because it limits the release of the mediators of the allergicresponse. Omalizumab has been shown to reduce asthma related symptoms and improve qualityof life in patients with severe persistent allergic asthma. It is recommended that omalizumab beavailable for patients with moderate or severe persistent asthma who have a positive skin test or invitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled withthe combination of an inhaled corticosteroid and a long acting beta agonist.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDN/ANEW: ANTI-ASTHMA MONOCLONAL ANTIBODIESNON-PREFERREDXOLAIR ® CC (omalizumab)Class CCClinical Criteria for Xolair ® (omalizumab)Omalizumab will be approved if ALL of the following criteria are met:• Diagnosis of moderate to severe persistent asthma; AND• Inadequately controlled asthma despite therapy with an inhaled or oral corticosteroid;AND a long acting beta agonist (unless there is a documented intolerance orcontraindication); AND• Patient has a positive skin test or in vitro reactivity (RAST test) to a perennialaeroallergen**NOTE: Safety and efficacy have not been established in children less than 12 years of age.Length of authorization: 6 months, subsequent renewals will be granted upon verification ofmarked clinical improvement.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Xolair [package insert]. San Francisco, CA: Genentech, Inc.; July 2007.4. National Heart Lung and Blood Institute. Expert Panel Report 3: Guidelines for TheDiagnosis and Management of Asthma. 2007.http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf5. Chipps B, Buhl R, Beeh, KM, et al. Improvement in quality of life with omalizumab inpatients with severe allergic asthma. Current Medical Research & Opinion. 22(11);2201-8. 2006 Nov.Page 42 of 85November 8, 2007 Tennessee PAC

BACKGROUNDRESPIRATORY AGENTSNEW: ANTI-VIRAL MONOCLONAL ANTIBODIES• Respiratory Syncytial Virus (RSV) causes an upper respiratory tract infection similar tothe common cold. RSV is self-limiting in otherwise healthy individuals, but it can causeserious complications in babies born prematurely who are less than 6 months of ageduring RSV season, and in infants and children with comorbid conditions such as chroniclung disease (CLD), congenital heat disease (CHD), and immunodeficiency. The RSVseason tends to occur October through April each year in Tennessee, and infants andchildren at increased risk for severe disease may require prophylactic treatment againstRSV during the RSV season.• Palivizumab, the only prophylactic medication against RSV, neutralizes RSV and inhibitsits fusion activity. This results in the inhibition of RSV replication.• Palivizumab is indicated for prophylaxis against severe lower respiratory tract diseasecaused by RSV in high-risk pediatric patients.• The most common adverse reactions seen in palivizumab-treated patients are injectionsite reactions, cough, GI upset, fever, rash, rhinitis, upper respiratory tract infection, andwheezing. Anaphylaxis is rare (< 1 case per 100,000 patients).o Clinicians should be warned to use palivizumab with caution in patients withthrombocytopenia or coagulation disorders as it is an IM injection. In addition,palivizumab is not indicated for the treatment of RSV infections.• Two randomized, double-blind, placebo-controlled trials examined the safety and efficacyof palivizumab for prophylaxis against RSV infection in pediatric patients at high risk of anRSV-related hospitalization.oOne trial was conducted during a single RSV season and included 1,502 patients≤ 24 months of age with CLD or infants who were born at ≤ 35 weeks’ gestationand were ≤ 6 months of age at study entry. Patients were given 15 mg/kg ofpalivizumab versus placebo IM monthly for 5 injections and were followed for 30days after the last injection. Monthly prophylaxis with palivizumab wasassociated with a 55% reduction in hospitalization as a result of RSV(p=0.00004). Significant reductions were observed in both children with CLD(p=0.038) and premature children without CLD (p=

RESPIRATORY AGENTS• The American Academy of Pediatrics (AAP) states that prophylaxis using palivizumab orRespiratory Syncytial Virus Globulin Intravenous (RSV-IVIG) should be considered forinfants and children younger than 2 years with CLD who have required medical therapyfor CLD within 6 months prior to the start of RSV season. The AAP prefers palivizumabover RSV-IVIG because of its ease of administration, safety and effectiveness. The AAPfurther states that patients with more severe CLD may benefit from prophylaxis withpalivizumab during a second RSV season if they continue to require medical therapy forpulmonary or cardiac dysfunction. The guidelines further state that infants born at ≤32weeks' gestation may benefit from RSV prophylaxis even if they do not have CLD.Infants born at ≤ 28 weeks may benefit from prophylaxis during their first RSV up to 12months of age, and infants born at 29-32 weeks gestation may benefit from prophylaxisup to 6 months of age. For infants born between 32 and 35 weeks gestation, prophylaxisshould be reserved for infants who are younger than 6 months and have at least two riskfactors for RSV such as day care enrollment, school-aged siblings, exposure toenvironmental air pollutants, congenital abnormalities of the airways, or severeneuromuscular disease. Children < 24 months with hemodynamically significant cyanoticand acyanotic CHD will benefit from prophylaxis with palivizumab if they are receivingmedication to control CHF, have moderate to severe pulmonary hypertension, or havecyanotic heart disease.RECOMMENDATION:Palivizumab is effective as a preventative therapy against severe viral lower respiratory tractinfection in pediatric patients at high risk for RSV. The American Academy of Pediatrics (AAP) hasvery specific recommendations about the patient population that has been shown to benefit frompalivizumab therapy. Therefore, it is recommended that palivizumab be available for use duringRSV season in patients who meet the high-risk criteria set forward by the AAP.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDN/ANEW: ANTI-VIRAL MONOCLONAL ANTIBODIESNON-PREFERREDSYNAGIS ® (palivizumab) CCClinical Criteria for Synagis ®Synagis ® may be approved for patients under the age of 2 years meeting the following criteria:• For patients < 6 months of age at the onset of the RSV season:o If patient was born at less than 32 weeks gestation- May approve therapybeginning October 1 st with a last date of therapy not after the end of the RSVseason (April 30 th ).o If the patient was born at 32-35 weeks gestation, the patient must have two ormore of the following risk factors for severe RSV disease:• Exposure to environmental air pollutants, including tobacco smoke• Child care out of the home (> 4 hours per week)• Siblings attending school or day-care• Congenital abnormalities of the airways• Severe neuromuscular disease• Long distance from hospital care, defined as 30 miles or 30 minutes• Low birth weight (

RESPIRATORY AGENTS• For patients

CENTRAL NERVOUS SYSTEM AGENTSLENGTH OF AUTHORIZATIONS:Dependent upon diagnosis and length oftherapy needed to treat. (Most medicationsin this class are used chronically, and thuswould be approved for 1 year.)1. Is there any reason the patient cannot be changed to a medication not requiringprior approval within the same class?Acceptable reasons include:• Allergy to medications not requiring prior approval• Contraindication to or drug-to-drug interaction with medications notrequiring prior approval• History of unacceptable/toxic side effects to medications not requiring priorapproval2. The requested medication may be approved if both of the following are true:• If there has been a therapeutic failure of at least two medications within thesame class not requiring prior approval (unless otherwise specified)• The requested medication’s corresponding generic (if a generic is availableand preferred by the State) has been attempted and failed or iscontraindicated3. The requested medication may be approved if the following is true:• An indication which is unique to a non-preferred agent and is supported bypeer-reviewed literature or an FDA approved indication exists.--------------------------------------------------------------------------------------------------------------------------------The information provided for each drug class within the Central Nervous System Agentsis organized into the following sections when applicable:BACKGROUND:• General overview• Pharmacology• Therapeutic effect(s)• Adverse reactions• Outcomes data• Place in therapy according to current Treatment GuidelinesRECOMMENDATION:• General recommendation regarding utility and therapeutic equivalence among the agentsin the class, as well as requirements for product availability (PDL placement).Page 46 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSBACKGROUNDNEW: ANTICONVULSANTS: HYDANTOINS• During a seizure, excessive excitability spreads locally (partial) or more widely(generalized). Partial seizures are called simple if there is no loss of consciousness andcomplex if consciousness is lost. Complex partial seizures are most commonly seen inteens and adults. In generalized seizures, motor symptoms are bilateral and there is aloss of consciousness. Generalized seizures are made up of tonic-clonic seizurescharacterized by body stiffness followed by jerking movements and absence seizurescharacterized by an abrupt onset and interruption of activities which ends abruptly. If atonic clonic seizure is preceded by an aura, it is likely that the seizure started as a partialseizure that generalized secondarily.• The hydantoins work by stabilizing the seizure threshold and preventing the spread ofseizure activity by promoting sodium efflux from neurons and stabilizing the thresholdagainst hyperexcitability.• Ethotoin is approved for the control of tonic-clonic or complex seizures. Phenytoin isFDA-Approved for the control of generalized tonic-clonic and complex partial seizuresinvolving the psychomotor and temporal lobes as well as for the treatment and preventionof seizures during neurosurgery.• The most common adverse effects seen with hydantoins are signs and symptoms of CNSdepression such as ataxia, dizziness, and slurred speech. Hydantoins may also causeGI upset, gingival hyperplasia and dermatologic disorders such as rash or pruritis. Rarelyhydantoins may cause Stevens-Johnson syndrome or disorders of the hematopoieticstructure. Phenytoin may also cause nephrotoxicity or osteomalacia.o Ethotoin is contraindicated in patients with hematologic and hepatic disorders.o Abrupt discontinuation of hydantoins may precipitate a seizure. Caution shouldbe used when administering phenytoin in patients with diabetes, liverdysfunction, and porphyria. Hydantoins are Pregnancy Category D.o The use of ethotoin should be avoided with other drugs that will adversely affectthe hematopoietic structure. Both phenytoin and ethotoin interact with warfarincausing decreased levels of warfarin and increased levels of phenytoin orethotoin. Phenytoin is a highly protein bound drug and drug levels should bemonitored closely when administered with other highly protein bound drugs suchas digoxin, rifampin, and isoniazid to name a few. Chronic alcohol consumptionmay decrease phenytoin levels while acute consumption will increase levels.Tricyclic antidepressants may precipitate seizures.• The sodium salt of phenytoin is used to make Dilantin Kapseals and Phenytek extendedrelease capsules. Dilantin-125 Suspension and Dilantin Infatabs are manufactured usingthe free acid form of phenytoin. There is an 8% increase in drug with the free acidproducts; therefore, dosage adjustments and serum level monitoring will be necessarywhen switching from the sodium salt to the free acid form and vice versa.• A randomized double-blind parallel-group study involving 181 individuals with newlydiagnosed untreated partial seizures or secondarily or primary generalized tonic-clonicseizures was conducted. Participants were treated with lamotrigine titrated from 100 mgor phenytoin titrated from 200 mg over 6 weeks and continued for ≤ 48 weeks. The twostudy arms did not differ significantly in percentages of patients remaining on treatmentand seizure free during the last 24 and 40 weeks of the study or in time to first seizureafter the first 6 weeks of therapy. Discontinuation of study medication due to adverseevents occurred in 15% of patients treated with lamotrigine compared to 19% of thephenytoin treated patients. The adverse event most commonly seen with lamotriginewas skin rash while phenytoin patients had more trouble with CNS side effects such asasthenia, somnolence, and ataxia. The SEALS inventory, a quality of life instrument,favored the lamotrigine group.Page 47 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• According to the 2004 NICE guidelines for the Diagnosis and Management of theEpilepsies in Adults and Children in Primary and Secondary Care, phenytoin is a secondline therapy for focal seizures with or without secondary generalization. Phenytoin is athird line agent for the treatment of generalized tonic-clonic or tonic type seizures.Phenytoin may worsen atonic and childhood or juvenile absence seizures and thereforeshould be avoided in these patient populations. These guidelines make no mention ofappropriate use for ethotoin.RECOMMENDATION:Phenytoin is the most commonly prescribed agent in the hydantoin class due to its availability inmultiple dosage forms and pediatric indication. Ethotoin possesses no advantage over phenytoinand is not mentioned in the current treatment guidelines; therefore, it is recommended that atleast phenytoin and all of its available dosage forms be available for use.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDDILANTIN INFATAB ® (phenytoin)DILANTIN KAPSEAL ® 30 mg capsules(phenytoin)PHENYTEK ® (phenytoin)PHENYTOIN (Compares to DilantinKapseal ® 100 mg, Dilantin-125 ® )NEW: ANTICONVULSANTS: HYDANTOINSNON-PREFERREDDILANTIN-125 ® (phenytoin)DILANTIN KAPSEAL ® (phenytoin) 100 mg capsulesPEGANONE ® (ethotoin)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. National Institute for Clinical Excellence. The epilepsies: The diagnosis and management ofthe epilepsies in adults and children in primary and secondary care. October 2004.http://guidance.nice.org.uk/CG20/niceguidance/pdf/English4. Steiner J, Dellaportas CI, Findley LJ, et al. Lamotrigine monotherapy in newly diagnoseduntreated epilepsy: a double-blind comparison with phenytoin. Epilepsia. May 1999;40(5):601-7.BACKGROUNDNEW: ANTICONVULSANTS: SUCCINIMIDES• Epilepsy can develop at any age; however, the risk is estimated to be only 1% from birthto 20 years old and 3% at 75 years old. Absence seizures are more common in youngchildren and adolescents. Lennox-Gastaut syndrome, one of the hardest forms ofepilepsy to treat, is characterized by mental retardation and daily seizures of multipletypes. The succinimides, ethosuximide and methsuximide, can be used to treat absenceseizures and Lennox-Gastaut syndrome.• The succinimides suppress the paroxysmal three cycles per second spike and waveactivity associated with lapses of consciousness, and they depress the seizure threshold.• Both agents in this class are FDA approved for the control of absence seizures.Methsuximide is approved for refractory absence seizures in particular.• The most common adverse reactions with succinimides include ataxia, dizziness, GIupset, loss of appetite and somnolence. Rare but severe adverse effects includedisorders of the hematopoietic structure and Stevens-Johnson syndrome. Methsuximidemay cause hematuria and proteinuria.Page 48 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSo Succinimides should be withdrawn slowly to prevent precipitation of seizures.Particular caution should be used if succinimides are being used as monotherapybecause they may precipitate absence seizures. Patients with renal and liverdisease should be monitored closely while on therapy with a succinimide.o Succinimides are often used as an adjunctive therapy; however, caution shouldbe used if succinimides are used with phenytoin and phenobarbital assuccinimides may increase serum levels of phenytoin and phenobarbital.Ethosuximide may also decrease or increase valproic acid levels.• There have been no head-to-head trials comparing ethosuximide and methsuximide.• The 2004 NICE guidelines for the Diagnosis and Management of the Epilepsies in Adultsand Children in Primary and Secondary Care states that ethosuximide is among the firstline agents for the treatment of absence seizures in children and adults. Whilelamotrigine, sodium valproate and topiramate are first line, ethosuximide is among thesecond line agents for the treatment of Lennox-Gastaut syndrome. The guidelines makeno mention of methsuximide. Since succinimides do not precipitate tonic-clonic seizures,they may be of particular benefit as an adjunct to other anticonvulsants in controllingcombined absence and tonic-clonic seizures.RECOMMENDATION:Succinimides are effective in the treatment of absence seizures by suppressing the paroxysmalthree cycles per second spike and wave activity associated with lapses of consciousness anddepressing the seizure threshold. Current clinical guidelines identify ethosuximide as a first lineagent for the treatment of absence seizures in children and adults and as a second line agent forthe treatment of Lennox-Gastaut syndrome. Succinimides are also beneficial in the treatment ofmixed seizure types as an adjunctive therapy. Therefore, it is recommended that at leastethosuximide be available for use in patients with these seizure types.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: ANTICONVULSANTS: SUCCINIMIDESPREFERREDNON-PREFERREDETHOSUXIMIDE (Compares to Zarontin ® ) CELONTIN ® (methsuximide)ZARONTIN ® (ethosuximide)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. National Institute for Clinical Excellence. The epilepsies: The diagnosis and management ofthe epilepsies in adults and children in primary and secondary care. October 2004.http://guidance.nice.org.uk/CG20/niceguidance/pdf/EnglishPage 49 of 85November 8, 2007 Tennessee PAC

BACKGROUNDCENTRAL NERVOUS SYSTEM AGENTSNEW: ANTICONVULSANTS, MISCELLANEOUS• There are several agents used to treat epilepsy which do not fit into a specific drug class.Theses agents include carbamazepine, felbamate, gabapentin, lamotrigine,levetiracetam, oxcarbazepine, pregabalin, primidone, tiagabine, topiramate, valproicacid/divalproex sodium, and zonisamide.• The major goals of therapy for epilepsy are to reduce the frequency of seizures whileproviding the best quality of life possible. Ideally those goals will be met with the leastamount of medication with the most benign adverse effect profile. Unfortunately, the typeof seizure will dictate the medication necessary for treatment and many patients willrequire combination therapy for seizure control.• These agents utilize several unique mechanisms of action in order to prevent seizureactivity.o Carbamazepine works by reducing the polysynaptic responses and blockingpost-tetanic potentiation. The exact mechanism associated with the treatment ofbipolar disease is unknown.o Felbamate appears to antagonize the GABA-receptor resulting in blockage of theeffects of the excitatory amino acids.o Gabapentin and pregabalin bind to the presynaptic α 2 -delta subunit of voltagesensitive calcium channels.o Lamotrigine inhibits voltage-sensitive sodium channels resulting in stabilization ofneuronal membranes.o Levetiracetam inhibits burst firing without affecting normal neuronal excitabilityand prevents propagation of seizure activity.o Oxcarbazepine blocks voltage-sensitive sodium channels causing stabilization inhyperexcited neural membranes, inhibition of repetitive neuronal firing anddiminution of propagation of synaptic impulses.o The exact mechanism by which primidone exerts it’s physiological effects isunknown, but anticonvulsant effects are thought to be due to the parentcompound, primidone, as well as its two active metabolites, phenobarbital andphenylethylmalonamide (PEMA), whose actions may be synergistic.o Tiagabine and valproic acid/divalproex increase GABA activity.o Topiramate blocks sodium channels, potentates activity of GABA, antagonizesglutamate and inhibits carbonic anhydrase.o Zonisamide is thought to block sodium channels causing stabilization of neuronalmembranes and suppression of neuronal hypersynchronization, or it maysuppress synaptically-driven electrical activity without affecting postsynapticGABA or glutamate responses.Page 50 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• FDA-Approved seizure indications are as follows:Drug Absence Myoclonic Partial Tonic-ClonicMixedSeizurePatternsLennox-GastautSyndromecarbamazepine √ √ √felbamate** √ √-Adjunctivegabapentin √-Adjunctivelamotrigine √-Adjunctivelevetiracetam √-Adjunctive √-Adjunctiveoxcarbazepine √-AdjunctiveMonotherapypregabalin √-Adjunctiveprimidone √-AdjunctiveMonotherapytiagabine √-Adjunctivetopiramate √-AdjunctiveInitialmonotherapyvalproic acid √-AdjunctiveMonotherapy√-AdjunctiveMonotherapydivalproex √ √-AdjunctiveMonotherapy√-Adjunctive√-Adjunctive√-AdjunctiveMonotherapy√-AdjunctiveInitialmonotherapy√-Adjunctive√-Adjunctive√-Adjunctive√-Adjunctivezonisamide √-Adjunctive** Felbamate is not indicated as first line antiepileptic therapy. The FDA recommends that this agent only be used inpatients who have had an inadequate response to alternative therapy and whose epilepsy is so severe that the benefits ofthis therapy out weigh the risk of aplastic anemia and/or liver failure.• Anticonvulsant drugs have also found utility in a host of other disease states.ooooCarbamazepine is also indicated for the treatment of acute manic and mixedepisodes associated with bipolar I disorder, pain associated with trigeminalneuralgia and glossopharyngeal neuralgia.Gabapentin is also approved for the treatment of pain associated with postherpeticneuralgia.Lamotrigine is approved for maintenance therapy of bipolar I disorder.Pregabalin has an FDA indication for the management of fibromyalgia and for thetreatment of pain associated with diabetic peripheral neuropathy or post-herpeticneuralgia.Page 51 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSoTopiramate is also approved for prophylaxis against migraine headaches.o Divalproex sodium is also FDA indicated for the treatment of acute manic ormixed episodes associated with bipolar disorder with or without psychoticfeatures and prophylaxis against migraines.• The adverse effect profiles of this class of anticonvulsants are as diverse as theirapproved indications. Anticonvulsants in general are associated with GI upset, weightchanges, tremor, somnolence and dizziness.o Carbamazepine may cause hyponatremia, rashes (9.9%), thrombocytopenia(

CENTRAL NERVOUS SYSTEM AGENTS• The following chart conveys the 2004 NICE, AAN and AES recommendations for first andsecond line anticonvulsant therapies according to seizure type.Seizure Type First Line Second Line ContraindicatedGeneralized Tonic-Cloniccarbamazepinelamotriginesodium valproatelevetiracetamoxcarbazepinetiagabineAbsenceMyoclonictopiramatelamotriginesodium valproatesodium valproatetopiramate (children)topiramatelamotriginelevetiracetamtopiramatecarbamazepinegabapentinoxcarbazepinetiagabinecarbamazepinegabapentinoxcarbazepinetiagabinecarbamazepineoxcarbazepinecarbamazepineoxcarbazepineN/AToniclamotriginesodium valproatelevetiracetamtopiramateAtoniclamotriginelevetiracetamsodium valproate topiramateFocal with or carbamazepinegabapentinwithout secondary lamotriginelevetiracetamgeneralization oxcarbazepinetiagabinesodium valproatetopiramateSodium valproate encompasses both valproic acid and divalproex sodium.• The 2002 American Psychiatric Association considers the first-line pharmacologicaltreatment for more severe manic or mixed episodes of bipolar disorder to be either:lithium plus an antipsychotic or valproate plus an antipsychotic. The recommendation forless ill patients is monotherapy with lithium, valproate, or an antipsychotic such asolanzapine. Lithium or lamotrigine are also considered first-line therapy for the treatmentof depressive episodes associated with bipolar disorder. The initial treatment for patientswho experience rapid cycling should include lithium or valproate; however, many patientswill require combination therapy. The American Psychiatric Association also states thatlithium and valproate are the medications with the best empirical evidence to supporttheir use for chronic maintenance therapy in patients with bipolar disorder.RECOMMENDATION:Given the differences in mechanism of action, side effect profiles, and FDA approved indicationsbetween the different agents in this category, these agents cannot be deemed therapeuticalternatives to one another. Due to the safety concerns (aplastic anemia, hepatotoxicity) and lackof endorsement by current treatment guidelines, felbamate can be considered an inferior agent inthis class. Patient responses may vary from agent to agent; therefore, it is necessary to havemultiple agents for each seizure type. For this reason, it is recommended that the various uniquechemical entities and dosages forms included in the miscellaneous anticonvulsant class all bemade available with the exception of felbamate which will be reserved for patients with refractoryseizures in which the benefits of therapy outweigh the risks.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPage 53 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSNEW: ANTICONVULSANTS, MISCELLANEOUSNON-PREFERREDPREFERREDCARBAMAZEPINE immediate release,chewable, suspension (Compares toEpitol ® , Tegretol ® )DEPAKOTE ® (divalproex sodium)DEPAKOTE ER ® (divalproex sodium)DEPAKOTE SPRINKLES ® (divalproexsodium)GABITRIL ® (tiagabine)GABAPENTIN (Compares to Neurontin ® ,Gabarone ® )KEPPRA ® (levetiracetam)LAMICTAL ® (lamotrigine) tablets onlyLAMOTRIGINE chewable tablets(Compares to Lamictal ® )LYRICA ® (pregabalin)NEURONTIN ® (gabapentin), oral solutiononlyPRIMIDONE (Compares to Mysoline ® )TEGRETOL-XR ® (extended releasecarbamazepine)TOPAMAX ® CC (topiramate)TRILEPTAL ® (oxcarbazepine)VALPROIC ACID immediate releasecapsules and oral syrup (Compares toDepakene ® )ZONISAMIDE (Compares to Zonegran ® )CARBATROL ® (carbamazepine extended releasecapsules)DEPAKENE ® (valproic acid)EPITOL ® (carbamazepine immediate release)EQUETRO ® (carbamazepine extended releasecapsules)FELBATOL ® CC (felbamate)GABARONE ® (gabapentin)LAMICTAL ® (lamotrigine), chewable/dispersibletablets onlyMYSOLINE (primidone)NEURONTIN ® (gabapentin tablets, capsules)OXCARBAZEPINE (Compares to Trileptal ® )TEGRETOL ® (carbamazepine immediate release)ZONEGRAN ® (zonisamide)Step Therapy for Felbatol ®Felbatol ® will be approved if ONE of the following criteria have been met:1. Used as adjunctive therapy in Lennox-Gastaut Syndrome AND there has been acontraindication to, or trial and failure of, all of the following medications:• Lamotrigine; AND• Topiramate2. Used for the treatment of partial seizures AND there has been a contraindication to ortrial and failure of all of the following medications:• Carbamazepine; AND• Gabapentin; AND• Lamotrigine; AND• Topiramate; AND• Valproic acid/divalproex sodiumOf note, Felbatol ® will not be approved for patients with a history of blood dyscrasia or liverdisease unless the prescriber can make a compelling clinical case demonstrating that thebenefits of the drug outweigh the risks.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPage 54 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSClinical Criteria for Topamax ®Topamax ® is unrestricted in patient ≤ 20 years old for all indications.For those > 20 years old, Topamax ® is unrestricted in the treatment of seizures. The patientmust have in their medication history (a past 3 month computer review) prior use of anantiepileptic medication.For migraine prophylaxis:Patients requesting Topamax ® for treatment of migraines must meet all of the following criteria:• Diagnosis of frequent migraines (defined as 4 or more migraines per month) that failtypical abortive therapy or are so severe that having one leads to debility (hemiplegicmigraine, seizure, etc.); AND• Has tried and failed migraine prophylaxis with a beta-blocker and amitriptyline• Approval may also be given if the prescriber has a reason not to try both classes ofmedications prior to prescribing Topamax ® . Reasons not to try both classes ofmedications may include1. Intolerance to one or more medications.2. Failure of a similar medication within the class.3. History of seizure and would like to combine therapy.For Bipolar Disorder:Patients requesting Topamax ® for treatment of bipolar disorder must meet the following criteria:• Has tried and failed treatment with lithium, AND lamotrigine OR valproate(NOTE: Failure on valproate due to weight gain would be indicated by an increase inbaseline weight by ≥ 10 pounds or > 7%.)• Use of Topamax ® therapy must be in combination with an atypical antipsychotic (unlessthe recipient has a history of intolerance or contraindication to atypical antipsychotics)COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. National Institute for Clinical Excellence. The epilepsies: The diagnosis andmanagement of the epilepsies in adults and children in primary and secondary care.October 2004. http://guidance.nice.org.uk/CG20/niceguidance/pdf/English4. Practice guideline for the treatment of patients with bipolar disorder (revision). Am JPsychiatry 2002 Apr;159(4 Suppl):1-50.5. French KA. Kanner A, Bautista K. et al. Efficacy and tolerability of the new antiepilepticdrugs I: treatment of new onset epilepsy: report of the Therapeutic and TechnologyAssessment Subcommittee and Quality Standards Subcommittee of the AmericanAcademy of Neurology and the American Epilepsy Society. Neurology 2004 Apr27;62(8):1252-60.6. French KA. Kanner A, Bautista K. et al. Efficacy and tolerability of the new antiepilepticdrugs II: treatment of refractory epilepsy: report of the Therapeutic and TechnologyAssessment Subcommittee and Quality Standards Subcommittee of the AmericanAcademy of Neurology and the American Epilepsy Society. Neurology 2004 Apr27;62(8):1261-73.7. Modi S, Lowder D. Medication for migraine prophylaxis. Am Fam Phys. 2006;73(1):72-8.Page 55 of 85November 8, 2007 Tennessee PAC

BACKGROUNDCENTRAL NERVOUS SYSTEM AGENTSRE-REVIEW: SEDATIVE HYPNOTICS• Insomnia can be characterized by difficulties falling asleep, staying asleep ornonrefreshing sleep combined with daytime dysfunction or distress. Insomnia can beprimary or secondary. Primary insomnia is an independent disorder while secondaryinsomnia is the result of another condition such as stress or noise. The sedativehypnotics are most commonly used to treat insomnia. However, nonpharmacologicalmeasures such as stimulus control or progressive muscle relaxation should be triedbefore using a sedative hypnotic to treat insomnia.• The cyclopyrrolone hypnotics, eszopiclone, zaleplon and zolpidem, selectively bind to thebenzodiazepine-1 (BZ-1) receptor subunit of the GABA-BZD receptor complex resultingin sedation and the preservation of deep sleep (stages 3 and 4). Ramelteon is a potent,selective agonist of the MT1 and MT2 melatonin receptors resulting in sleep-promotionand maintenance of the circadian rhythm. The exact mechanism of chloral hydrate isunknown, but it is thought to have nonspecific CNS depressant activities due to its activemetabolite, trichloroethanol. Hypnotic doses produce mild cerebral depression, buthigher doses induce respiratory and vasomotor depression.• Eszopiclone and zolpidem ER are approved for the treatment of insomnia of anyduration. Ramelteon is approved for the treatment of chronic or transient insomniacharacterized by difficulty with falling asleep. Chloral hydrate is approved as an adjunctto anesthesia and perioperative sedation as well as for the short term (7-10 days)treatment of insomnia.• Zaleplon and zolpidem are indicated for the short-term (7-10 days) treatment of insomnia.Zolpidem is commonly used off label for the treatment of SSRI-induced insomnia or forlong-term treatment of insomnia.• The most common adverse effects seen with this class are headache, myalgia, amnesia,dizziness, and daytime drowsiness or somnolence. Sedative hypnotics may also causeshort-term memory impairment, hallucinations, impaired coordination, dizziness, andlight-headedness. In addition, eszopiclone-treated patients may experience dose-relatedunpleasant taste (34%), respiratory infection (-10%), and anxiety (3.7%).o All agents in this class carry a warning regarding complex sleep-relatedbehaviors such as sleep-driving, making phone calls, and preparing and eatingfood while asleep. Many times patients have no memory of these events. Allagents in this class are scheduled IV narcotics, with the exception of ramelteon.o Chloral hydrate is contraindicated in patients with severe cardiovascular, hepaticor renal disease, and the elderly.o The sedative hypnotics may cause anaphylaxis or angioedema as early as thefirst dose. The plasma concentrations are significantly increased if patients withsevere liver impairment take eszopiclone, zaleplon or zolpidem. Increasedplasma concentrations of zaleplon were also observed in Japanese adults. Allagents in this class are Pregnancy Category C except for immediate releasezolpidem (B).o Agents in this category (except ramelteon) should be used with caution inpatients receiving other CNS depressants as the effects may be additive.CYP450 3A4 inducers (rifampin) will increase the clearance and reduce thebioavailability of eszopiclone, ramelteon, zaleplon, and zolpidem by 80%.CYP450 3A4 inhibitors (cimetidine, clarithromycin, ketoconazole) will increasethe bioavailability of eszopiclone, ramelteon, zaleplon and zolpidem by 84%.Ramelteon administered conjointly with fluvoxamine is contraindicated as thebioavailability of ramelteon may be increased.o The onset and duration of action is quite important in this class of drugs todetermine timing of pre-bed dosing and expected length of sleep.Page 56 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSDrug Onset Durationchloral hydrate 30-60 minutes 4-8 hourseszopiclone ≤ 30 minutes 6-8 hrsramelteon ≤ 30 minutes NR*zaleplon 10-30 minutes 4 hourszolpidem

CENTRAL NERVOUS SYSTEM AGENTS• The incidence of insomnia in children ranges for 1-6%, and that incidence is increased to50-75% in children with neurodevelopmental or psychiatric illnesses. Chloral hydrate isthe only agent in this class that is indicated for the treatment of insomnia in children of allages; however, the American Academy of Sleep Medicine’s task force onPharmacotherapy in Pediatric Sleep Medicine published guidelines in 2005 that do notprefer one sedative hypnotic over another for use in children.RECOMMENDATION:The ideal sedative hypnotic would induce sleep within 30 minutes, maintain a normal pattern ofsleep for 6-8 hours, have no residual effects the next morning, be safe upon overdose, and notinduce tolerance, abuse or dependence. Chloral hydrate can be considered an inferior agent inthis class, because it is associated with tolerance, dependence, GI effects, drug interactions andfatalities in overdose. Although it is the only agent in this class approved for children, the currentguidelines do not recommend it over any other sedative hypnotic. The other sedative hypnoticsseem to be equally effective and tolerated, and thus can be considered therapeutic alternatives toone another. In order to best meet patient needs, it is recommended that at least one agent withthe following characteristics be available: indication for long term use, a quick onset (≤30minutes), and a long duration of action (up to 8 hours).COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDLUNESTA ® QL (eszopiclone)ZOLPIDEM QL (Compares to Ambien ® )REREVIEW: SEDATIVE HYPNOTICSNON-PREFERREDQuantity LimitsAmbien ® = 14/monthAmbien CR ® = 1/dayChloral Hydrate = 15/month, liquid 150 mL/monthLunesta ® = 1/dayRozerem ® = 1/daySonata ® = 1/dayZolpidem = 14/monthAMBIEN ® QL (zolpidem)AMBIEN CR ® QL (zolpidem)CHLORAL HYDRATE QL (Compares to Somnote ® )ROZEREM ® QL (ramelteon)SOMNOTE ® QL (chloral hydrate)SONATA ® QL (zaleplon)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Elie R. Ruther E, Farr I, et al. Sleep latency is shortened during 4 weeks of treatment withzaleplon, a novel nonbenzodiazepine hypnotic, J Clin Psychiatry. 1999;60:536-44.4. Zammit GK, Corser B, Doghramji K, et al. Sleep and residual sedation afteradministration of zaleplon, zolpidem, and placebo during experimental middle-of-the-nightawakening. J Clin Sleep Med. 2006;2(4):417-23.Page 58 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSBACKGROUNDRE-REVIEW: ANTI-MIGRAINE: 5-HT 1 RECEPTOR AGONISTS• Migraines result from activity within the trigeminovascular system causing a release ofvasoactive neuropeptides, vasodilation, dural plasma extravasation and perivascularinflammation.• It is sometimes difficult to distinguish migraine headache from tension-type headache;however, migraines are usually episodic, lasting from 4-72 hours with at least 2 of thefollowing symptoms: unilateral pain, throbbing, aggravation of pain upon moving, pain ofmoderate to severe intensity accompanied by nausea, vomiting, photophobia orphonophobia. Acetaminophen, NSAIDs, ergot alkaloids, and 5-HT 1 Receptor agonists or“triptans” can all be used to treat migraines.• Triptans stimulate vascular 5-HT 1B receptors resulting in intracranial vessel constriction,presynaptic 5-HT 1D receptors resulting in inhibition of vasoactive neuropeptide releaseand 5-HT 1D receptors within the brainstem causing interruption of pain signaltransmission.• All triptans are FDA approved for the acute treatment of migraine attacks with or withoutaura in adults. Injectable sumatriptan is also indicated for the acute treatment of clusterheadache in adults. Triptans are not intended for the prophylactic therapy of migraine orfor use in the management of hemiplegic or basilar migraine• The most common adverse events seen in triptan users are dizziness, nausea,somnolence, flushing, palpitations, pain and pressure sensations or paresthesia. Thenasal sprays commonly cause unusual taste or nasal irritation.oTriptans are contraindicated in patients with ischemic heart disease or patientswho have symptoms or findings consistent with ischemic heart disease, coronaryartery vasospasm or other significant underlying cardiovascular disease.Naratriptan is also contraindicated in patients with severe renal impairment (CrCl

CENTRAL NERVOUS SYSTEM AGENTSooFour trials compared almotriptan to sumatriptan. All concluded that the productshad similar efficacy; however, 3 found that almotriptan was associated with fewerside effects than sumatriptan.Three trials compared rizatriptan use to other triptans (2 compared it tosumatriptan, 1 to naratriptan, and 1 to zolmitriptan). The studies found rizatriptanto have superior efficacy compared to naratriptan, similar efficacy but a fasteronset of action compared to sumatriptan, and similar efficacy to zolmitriptan.• The US Headache Consortium, the American Academy of Family Physicians, and theAmerican College of Physicians-American Society of Internal Medicine recommendsNSAIDs as first-line therapy for patients with mild to moderate migraine pain. Triptansand dihydroergotamines should be used for migraines that do not respond to NSAIDs.They further recommend a non-oral route of administration when nausea or vomiting areparticularly troublesome early in the migraine. These groups recognize that naratriptanhas a slightly delayed onset of pain relief, but they do not recommend any specific triptanover another. They also state that it is reasonable to switch to another triptan if there isan inadequate pain response or intolerable adverse reaction. Frovatriptan and eletriptanwere not available when these guidelines were published.RECOMMENDATION:Triptans are approved for the acute treatment of migraine attacks with or without aura in adults,and they are recommended as possible alternatives to NSAIDs. All of the triptans have similarefficacy and adverse event rates; however, it is reasonable to switch to another triptan if there isan inadequate pain response or intolerable adverse reaction to a single agent. Therefore, it isrecommended that at least two distinct agents be available. In order to ensure patient andprovider choice, it is recommended that at least two non-oral dosage forms be available forpatients with migraines associated with nausea.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONRE-REVIEW: ANTI-MIGRAINE: 5-HT 1 RECEPTOR AGONISTSPREFERREDNON-PREFERREDMAXALT ® QL (rizatriptan)AMERGE ® QL (naratriptan)MAXALT MLT ® QL (rizatriptan)AXERT ® QL (almotriptan)ZOMIG ® QL (zolmitriptan)FROVA ® QL (frovatriptan)ZOMIG NASAL SPRAY ® QL (zolmitriptan) IMITREX ® QL (sumatriptan)ZOMIG ZMT ® QL (Zolmitriptan)IMITREX KIT ® QL (sumatriptan)IMITREX ® QL INJECTABLE (sumatriptan) IMITREX ® QL NASAL(sumatriptan)RELPAX ® QL (eletriptan)Quantity LimitsAmerge 9/monthAxert 12/monthFrova 9/monthImitrex 9/monthImitrex Injectable 0.5 4/month, 1 8/monthImitrex Kit 8/monthImitrex Nasal 1/monthMaxalt 12/monthMaxalt MLT 12/monthRelpax 6/monthZomig 6/monthZomig Nasal Spray 1/monthZomig ZMT 6/monthPage 60 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Antimigraine Agents, Triptans Review. May 4, 2007.4. Goadsby PJ, Massiou H, Pascual J. et al. Almotriptan and zolmitriptan in the acutetreatment of migraine. Acta Neurol Scand. 2007;115(1):34-40.5. Steiner TJ, Diener HC, MacGregor Ea, et al. Comparative efficacy of eletriptan andzolmitriptan in the acute treatment of migraine. Cephalalgia. 2003;23(10):942-52.BACKGROUNDNEW: ERGOTAMINE DERIVATIVES• The pathophysiology behind migraine headaches can be described by two theories. Thevascular theory implies that migraines are caused by stimulation of sensory nerves in thelarge cerebral arteries and meningeal circulation. The neuronal theory implies thatmigraines are caused by the interplay between the trigeminal nerve and a variety ofinflammatory neurotransmitters resulting in plasma protein extravasation stimulatingnerve endings thereby resulting in pain.• The ergotamine derivatives, ergotamine tartrate and dihydroergotamine, constrictperipheral and cranial blood vessels and depress central vasomotor centers by acting asa partial agonist or antagonist against tryptaminergic, dopaminergic, and alphaadrenergicreceptors.• Ergotamine is FDA approved for the treatment or prophylaxis of vascular headaches andmigraines, while dihydroergotamine is approved for the treatment of cluster headachesand migraines, with or without an aura.• Common adverse reactions for ergotamine include: GI upset, pruritis and rash.Dihydroergotamine can cause dizziness, euphoria, GI upset, rhinitis, topical sitereactions, and alterations in taste.o Ergotamine and dihydroergotamine both carry the following black box warning,“Serious and/or life-threatening peripheral ischemia has been associated with thecoadministration of ergotamine/dihydroergotamine with potent CYP3A4inhibitors, including protease inhibitors and macrolide antibiotics. BecauseCYP3A4 inhibition elevates the serum levels of ergotamine/dihydroergotamine,the risk for vasospasm leading to cerebral ischemia and/or ischemia of theextremities is increased. Hence, concomitant use of these medications iscontraindicated.”o Both agents in this class are also contraindicated in patients with ischemic heartdisease, uncontrolled hypertension, hepatic failure or hemiplegic or basilarmigraine. Pregnancy and lactation are also contraindications for the use ofergotamine or dihydroergotamine.o Ergotamine should be used cautiously in patient with basilar/hemiplegic migraineand in those who require a prolonged duration of therapy. Dihydroergotamineshould be used cautiously in patients at risk for cerebrovascular event orcardiovascular disease.• Currently there are no head to head trials comparing ergotamine to dihydroergotamine.Page 61 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• A prospective, double-blind, randomized, crossover study comparing intranasalsumatriptan 20 mg (n=185) with intranasal dihydroergotamine 1 mg (n=183)demonstrated that therapy with sumatriptan obtained significantly better headache reliefafter 45 minutes and retained better relief until study endpoint of 2 hours (p < 0.05). Sixtyminutes after drug administration, significantly more patients experienced headache reliefwith sumatriptan (53%) than with dihydroergotamine (31%) Significantly moresumatriptan patients experienced relief of nausea at 45 minutes (55%), 60 minutes(64%), and 90 minutes (67%) compared to dihydroergotamine patients (40%, 40%, and53%, respectively; p < 0.015). At 120 minutes, the relief from nausea became no differentbetween treatment groups. No statistical difference in the ability of either drug to improveclinical disability associated with migraine episodes was observed. After the initial andoptional dose of study medication, both treatment groups were similarly well-tolerated.Bitter or unpleasant taste was the most common adverse event reported in thesumatriptan group (5%) while DHE patients most commonly reported sinus symptoms(4%), nausea and vomiting (3%).• According to the European Federation of Neurological Societies (EFNS) guidelines,ergotamine should be used short term to prevent cluster headache when therapy withverapamil or steroids is ineffective, contraindicated, or not well tolerated. According to aEuropean consensus on the use of ergotamine in the acute treatment of migraine,patients who should use ergotamine rather than a triptan include the following: patientsestablished on ergotamine with continuing satisfactory response, no contraindications toan ergot, and no signs of dose escalation; patients with very long attacks, lasting morethan 48 hours; patients with frequent headache recurrence. For patients who needmigraine-specific therapy or who have failed analgesics and non-steroidal agents, atriptan is probably a better choice for first-line migraine therapy. The main place intherapy of dihydroergotamine mesylate remains as an alternative to other measures(including ergotamine) in acute attacks of migraine headache.RECOMMENDATION:The ergotamine derivatives relieve the pain associated with migraine headaches by constrictingperipheral and cranial blood vessels and depressing central vasomotor centers. Ergotamineshould be used short term to prevent cluster headaches when therapy with verapamil or steroidsis ineffective, contraindicated, or not well tolerated. Dihydroergotamine can be considered secondline behind ergotamine since it should be used as an alternative to other measures (includingergotamine) in acute attacks of migraine headache. Therefore, it is recommended that at leastergotamine be available as an alternative therapy for patients experiencing headaches.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: ERGOTAMINE DERIVATIVESPREFERREDNON-PREFERREDERGOMAR ® QL (ergotamine)MIGRANAL ® QL (dihydroergotamine)Quantity LimitsErgomar ® 2 mg SL tablets = 20 tabs/monthMigranal ® 4 mg/mL (0.5 mg/spray) in 3.5 mL vial nasal spray = 1 vial/monthPage 62 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. AccessedSeptember, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Biondi D, Mendes P. Treatment of primary headache: cluster headache. In: Standards of carefor headache diagnosis and treatment. Chicago (IL): National Headache Foundation; 2004. p.59-72.4. Tfelt-Hansen P, Saxena PR, Dahlof C, et al: Ergotamine in the acute treatment of migraine; areview and European consensus. Brain 2000; 123:9-18.5. May A, Leone M, Afra J, Linde M, Sandor PS, Evers S, Goadsby PJ, EFNS Task Force. EFNSguidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias.Eur J Neurol 2006 Oct;13(10):1066-77.6. Boureau F, Kappos L, Schoenen J, et al: A clinical comparison of sumatriptan nasal spray anddihydroergotamine nasal spray in the acute treatment of migraine. Int J Clin Pract 2000;54:281-6.BACKGROUNDNEW: MIGRAINE COMBINATIONS• Many of the combination agents used for the treatment of migraine headaches areconsidered DESI agents and are not covered by Medicaid programs. The only agentsthat will be considered in this class are the combinations of ergotamine/caffeine andbutalbital combination products containing codeine. Butalbital may be combined withcaffeine, codeine and either aspirin (ASA) or acetaminophen (APAP).• These products work to treat migraine headaches by combining the mechanisms ofaction of various agents.o Butalbital has generalized CNS depressant effects and, in very high doses, hasperipheral effects.o Aspirin and APAP inhibit prostaglandins, thus producing analgesic and antiinflammatoryeffects. Aspirin also irreversibly inhibits platelet aggregation.o Ergotamine constricts peripheral and cranial blood vessels and depresses centralvasomotor centers.o Caffeine is thought to produce constriction of cerebral blood vessels andincrease absorption of ASA, APAP, butalbital and ergotamine.o Codeine binds to opiate receptors in the CNS resulting in inhibition of ascendingpain pathways and altering perception of and response to pain.• Butalbital combinations are indicated for the treatment of tension or muscle contractionheadache. Ergotamine combinations are approved for the treatment of migraineheadaches.• Butalbital combinations may most commonly cause CNS side effects such as confusion,drowsiness, dizziness, mental depression, nervousness or unusual excitement.Gastrointestinal upset, tachycardia and rash are also fairly common with these products.The most common adverse effects of the ergotamine combination are GI upset anddizziness.o The butalbital combination products are contraindicated in patients withangioedema, bleeding disorders, nasal polyps, prophyria or peptic ulcers.Ergotamine combination products are contraindicated in patients with peripheralvascular disease, coronary heart disease, hypertension, impaired hepatic orrenal function, severe pruritis, sepsis or pregnancy.o Butalbital combination products should be used with caution in children andpatients who are pregnant (Category C) or have renal or hepatic impairment.Codeine is a schedule III narcotic and may be habit forming. Ergotaminecombination products should be used with caution in patients with basilar orhemiplegic migraine. Caution should also be used if requiring a prolongedcourse of therapy with ergotamine products.Page 63 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• According to the US Headache Consortium’s 2000 guidelines and the National HeadacheFoundation’s 2004 guidelines for the treatment of headache, the use of butalbitalproducts should be limited and carefully monitored due to concerns about overuse,rebound headache, and withdrawal. According to the 2006 EFNS guidelines, ergotamineshould be used short term to prevent cluster headache when therapy with verapamil orsteroids is ineffective, contraindicated or not well tolerated. According to a Europeanconsensus on the use of ergotamine in the acute treatment of migraine, patients whoshould use ergotamine rather than a triptan include the following: patients established onergotamine with continuing satisfactory response, no contraindications to an ergot, andno signs of dose escalation; patients with very long attacks, lasting more than 48 hours;patients with frequent headache recurrence. For patients who need migraine-specifictherapy or who have failed analgesics and non-steroidal agents, a triptan is probably abetter choice for first-line migraine therapy.RECOMMENDATION:The agents within this class of medications treat migraine headaches by combining themechanisms of action of butalbital, caffeine, ASA, APAP, ergotamine and codeine.Ergotamine and butalbital combination products provide an alternative to triptans for those patientswhose headaches do not respond to a NSAID or for the treatment of cluster or vascular headache,and current treatment guidelines place these products as second or third line therapy in thetreatment of headache. Aspirin containing products should be avoided in those with renal disease,thrombotic disorders or concomnent use of drugs that inhibit platelet function. Acetaminophenproducts should be avoided in patients with liver disease or those treated with other hepatotoxicdrugs. Therefore, it is recommended that at least three generic migraine combination products beavailable for use in the management of headaches. It is also recommended that at least one ASAand APAP containing product be available for use in special patient populations.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDBUTALBITAL/APAP/CAFFEINE/CODEINE(Compares to Fioricet ® with codeine andPhrenilin with caffeine and codeine ® )BUTALBITAL COMPOUND/CODEINE(Compares to Fiorinal with Codeine ® )ERGOTAMINE/CAFFEINE tablets(Compares to Migergot ® )COMMITTEE VOTE:NEW: MIGRAINE COMBINATIONSNON-PREFERREDASCOMP ® WITH CODEINE(butalbital/ASA/caffeine/codeine)CAFERGOT ® (ergotamine/caffeine suppositories)FIORICET WITH CODEINE ®(butalbital/APAP/caffeine/codeine)FIORINAL WITH CODEINE ®(butalbital/ASA/caffeine/codeine)PHRENILIN WITH CAFFEINE AND CODEINE ®(butalbital/APAP/caffeine/codeine)MIGERGOT ® (ergotamine/caffeine)APPROVED DISAPPROVED APPROVED with MODIFICATIONPage 64 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2006. AccessedJune, 2006.2. Thompson MICROMEDEX on-line © 1974-2006. Accessed June, 2006.3. Silberstein SD for the US Headache Consortium. Practice parameter: Evidence-basedguidelines for migraine headache (an evidence-based review). Report of the Quality StandardsSubcommittee of the American Academy of Neurology. Neurology. 2000;55:754-63.4. May A, Leone M, Afra J, Linde M, Sandor PS, Evers S, Goadsby PJ, EFNS Task Force. EFNSguidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias.Eur J Neurol 2006 Oct;13(10):1066-77.5. Ruoff G, Urban G. Treatment of primary headache: episodic tension-type headache. In:Standards of care for headache diagnosis and treatment. Chicago (IL): National HeadacheFoundation; 2004. p. 53-8. http://www.guideline.gov/summary/summary.BACKGROUNDRE-REVIEW: DOPAMINE AGONISTS• The hallmark of Parkinson’s disease (PD) is degeneration of cells in the substantia nigrathat produce dopamine, a neurotransmitter responsible for the regulation of excitatoryand inhibitory outflow from the basal ganglia. Restless Legs syndrome (RLS) is the resultof dopamine and iron depletion.• Pramipexole and ropinirole work by directly stimulating the dopamine receptors in thecorpus striatum. Rotigotine stimulates dopamine receptors within the caudate-putamenin the brain.• Pramipexole, ropinirole, and rotigotine are approved for the treatment of signs andsymptoms of early-stage idiopathic PD. Pramipexole and ropinirole are both indicated forthe treatment of Restless Legs Syndrome (RLS).• Dopamine agonists are associated with neuropsychiatric, sedative and other side effectssuch as nausea, orthostatic hypotension, confusion, somnolence, hallucinations andimpulse disorders. The risks of hypotension and somnolence seem to be higher withropinirole than with pramipexole, while pramipexole appears to have a higher risk ofhallucinations.o There is growing evidence that dopamine agonists are associated with disordersof impulse control, including pathologic shopping, gambling and hypersexuality.Risk factors for this adverse effect include younger age at PD onset, highnovelty-seeking traits, medication-induced mania or hypomania, impairedplanning, and personal or family history of alcohol abuse.o These agents should be used with caution in patients with confusion, memory orcognitive impairment, or risk of hypotension. Ropinirole should be used withcaution in patients with hepatic or renal disease, and pramipexole dosagesshould be reduced in patients with CrCl

CENTRAL NERVOUS SYSTEM AGENTS• When used early in PD, dopamine agonists delay the need for levodopa treatment and itsside effects. In general, monotherapy with dopamine agonists is effective for about oneyear or less in most patients; however, some patients may avoid combination therapy foras long as 3 years. Later in PD dopamine agonists allow for decreased levodopa dosesand increased on time. Dopamine agonists do not treat freezing, postural instability,autonomic dysfunction or dementia associated with PD nor do they prevent diseaseprogression.• The 2006 National Institute for Health and Clinical Excellence (NICE) guidelinesrecommend a dopamine agonist as a first line agent for the initial treatment of early PD,as well as adjunctive therapy for the treatment of more advanced PD. These agentsshould be titrated to effect and another agent in this class may be used if side effectsprevent titration.• The American Academy of Sleep Medicine suggests pramipexole and ropinirole asalternatives to carbidopa/levodopa in the treatment of RLS.RECOMMENDATION:Dopamine agonists act directly on postsynaptic dopamine receptors, do not require conversion toan active metabolite, and have a much longer half-life than levodopa. Dopamine agonists can beused as effective monotherapy in early disease or as adjunctive therapy to levodopa in moreadvanced states. Current treatment guidelines do not distinguish between the agents in this class;therefore, to allow for provider choice, it is recommended that at least 2 agents in this class beavailable. In addition, rotigotine should be available for patients with an inability to swallow a pill orfor those who are experiencing increased side effects at the beginning of dosing intervals orinadequate control of Parkinson’s symptoms at the end of dosing intervals.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONREREVIEW: DOPAMINE AGONISTSPREFERREDNON-PREFERREDMIRPAPEX ® QL (pramipexole)NEUPRO ® QL, ST (rotigotine)REQUIP ® (ropinirole)Quantity LimitsMirapex ® 1.5 mg tablets = 3/dayNeupro ® = 1/dayStep Therapy for NeuproRecipients requesting Neupro® should meet ONE of the following criteria:• Inability to swallow a pill; OR• Increased side effects at the beginning of dosing intervals with Requip® or Mirapex®; OR• Inadequate control of Parkinson’s symptoms at the end of dosing intervals with Requip® orMirapex®; OR• Intolerance or contraindication to both Requip® and Mirapex®.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPage 66 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Antiparkinson’s Agents Review. Sept 12, 2007.4. National Institute for Health and Clinical Excellence. Parkinson’s disease: nationalclinical guideline for diagnosis and management in primary and secondary care. 2006;http://www.nice.org.uk/CG0235. Rao SS, Hofmann LA, Shakil A. Parkinson’s disease: diagnosis and treatment. AmFam Physician. 2006 Dec 15;74(12):2046-54.6. Thomas A, Bonanni L, Di Iorio A. et al. End-of-dose deterioration in non ergolinicdopamine agonist monotherapy of Parkinson’s disease. J Neurol. 2006;253(12):1633-9.NEW: DOPAMINE PRECURSOR/DOPA DECARBOXYLASE INHIBITORSBACKGROUND• Carbidopa inhibits L-amino-acid-decarboxylase (L-ADD), the enzyme that breaks downlevodopa, and levodopa is the precursor to dopamine. Levodopa is always combinedwith carbidopa, because carbidopa prevents the conversion of levodopa to dopamine inthe periphery thereby lessening the peripheral adverse effects of dopamine whileincreasing the cerebral bioavailability of levodopa and subsequently dopamine.• Carbidopa/levodopa is FDA approved for the treatment of idiopathic PD, manganeseinduced Parkinsonism, postencephalitic Parkinsonism, and symptomatic Parkinsonismsecondary to nervous system injury by carbon monoxide intoxication.Carbidopa/levodopa is also used off label for the treatment of RLS.• The most frequently reported adverse effects with carbidopa/levodopa are adventitiousmovements (10-90%), anorexia (50%), GI upset with or without abdominal pain (80%),dry mouth, dysphasia, dysgeusia, sialorrhea, ataxia, increased hand tremor, headache,dizziness, numbness, weakness, confusion, insomnia, hallucinations, delusions, agitationand anxiety. Long term treatment with levodopa leads to the development of motorfluctuations, dyskinesias and neuropsychiatric complications. Nausea, vomiting andhypotension can be reduced by titrating the dose up slowly.o Carbidopa/levodopa is contraindicated in patients with undiagnosed skin lesionsor melanoma and narrow angle glaucoma.o Carbidopa/levodopa should be used with caution in patient with renal or hepaticimpairment, asthma, glaucoma, diabetes, peptic ulcer disease, endocrinedisorders, cardiovascular disease including arrhythmias, and underlyingdepression or psychosis. Abrupt discontinuation of carbidopa/levodopa maycause a neuroleptic malignant-like syndrome, particularly in patients receivingneuroleptics.o The combination of non-selective MAOIs and levodopa may lead to hypertensivecrisis; therefore, the use of these agents together is contraindicated.• A randomized, double-blind, parallel study involving 36 centers and 618 patients worldwide was conducted to compare the safety and efficacy of immediate releasecarbidopa/levodopa versus controlled release carbidopa/levodopa. Effects wererecorded at 3 month intervals for a total of 5 years. Motor fluctuation and dyskinesiaswere evaluated using a patient diary and a physician-recorded questionnaire. TheNottingham Health profile (NHP) was used to evaluate quality-of-life. No significantdifferences were seen between the two treatment groups in mean dose (426 mg IRversus 510 mg CR), motor fluctuations or dyskinesia (20.6% in IR versus 21.8% CR), orchanges in motor response by the questionnaire’s definition (16% in both groups).Page 67 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• Seven randomized, double-blind, placebo-controlled trials demonstrated the efficacy ofcarbidopa/levodopa in the treatment of RLS. These trials only included 6-41 patients pertrial, but it was enough evidence for the American Academy of Sleep Medicine to endorsecarbidopa/levodopa as a standard for the treatment of RLS.• The NICE guidelines and the American Academy of Family Physicians suggest thatcarbidopa/levodopa ± a catechol-O-methyltransferase (COMT) inhibitor should be addedwhen a dopamine agonist no longer provides adequate control of symptoms.Carbidopa/levodopa has been associated with decreased morbidity and mortality andmost all patients benefit from its use; however, carbidopa/levodopa is associated withmotor fluctuations such as wearing off, on-off phenomenon, dose failures, freezingepisodes and dyskinesias, particularly in those patients with newly diagnosed PD.Patients develop symptoms that do not respond to levodopa therapy such as freezingepisodes, autonomic dysfunction, falling and dementia as PD progresses. Therefore,carbidopa/levodopa should be added once the disease has progressed. The NICEGuidelines and The American Academy of Family Physicians name carbidopa/levodopaas the most effective agent for PD and the primary treatment for symptomatic patientsdue to its ability to control bradykinesia and rigidity associated with PD. They furtherstate that the sustained-release formulations have no added benefit over the immediaterelease formulation.• The American Academy of Sleep (AASM) medicine recommends the use ofcarbidopa/levodopa as standard therapy that is effective in the treatment of RLS alongwith pramipexole and ropinirole.RECOMMENDATION:Carbidopa/levodopa is an effective treatment for Parkinson’s disease (PD) and Restless Legssyndrome (RLS). Current guidelines place this agent as a first line therapy when dopamineagonists are no longer controlling symptoms of PD. In addition, current guidelines recognizecarbidopa/levodopa as a standard of care for the treatment of RLS. These guidelines alsoconclude that controlled release products have no benefit over immediate release formulations. Itis recommended that at least one immediate release carbidopa/levodopa product be available foruse in patients with PD and RLS.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: DOPAMINE PRECURSOR/DOPA DECARBOXYLASE INHIBITORSPREFERREDNON-PREFERREDCARBIDOPA/LEVODOPA (Compares to PARCOPA ® (carbidopa/levodopa/Sinemet ® , Sinemet CR ® , Parcopa ® ) SINEMET ® (carbidopa/levodopa)SINEMET CR ® (carbidopa/levodopa)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Antiparkinson’s Agents Review. Sept 12, 2007.4. National Institute for Health and Clinical Excellence. Parkinson’s disease: nationalclinical guideline for diagnosis and management in primary and secondary care. 2006;http://www.nice.org.uk/CG0235. Littner MR, Kushida C, Anderson WM, et al. Practice parameters for the dopaminergictreatment of restless legs syndrome and periodic limb movement disorder. Sleep.2004;27:557-9.6. Koller WC, Hutton JT, Tolosa E, et al. Immediate-release and controlled-releasecarbidopa/levodopa in PD: a 5-year randomized multicenter study. Carbidopa/LevodopaStudy Group. Neurology. 1999;53:1012-9.Page 68 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSNEW: CATECHOL-O-METHYLTRANSFERASE INHIBITORSBACKGROUND• Catechol-O-methyltransferase (COMT), along with the amino acid decarboxylase, is oneof the two main enzymes responsible for the metabolism of levodopa, dopamine, andother catecholamines.• Entacapone and tolcapone selectively and reversibly inhibit COMT, an enzymeresponsible for catalyzing levodopa resulting in increased plasma levels of levodopa.• The COMT inhibitors are FDA approved for the symptomatic relief of advancedParkinson’s disease (PD) in conjunction with carbidopa/levodopa therapy. These agentsare not indicated for monotherapy.• COMT inhibitors commonly are associated with diarrhea (explosive in up to 10% ofpatients), dyskinesia, hallucinations, orthostatic complications, nausea, and somnolence.The incidences of all of these reactions were higher in the tolcapone treated patientscompared to placebo than with entacapone compared to placebo. Tolcapone was alsoassociated with anorexia.o Tolcapone’s prescribing information contains a black box warning about threefatal cases of acute liver failure. The actual incidence of hepatocellular injuryappears to be 10-100 times higher with this agent. Patients must sign aninformed consent before starting therapy with tolcapone, and prescribers areencouraged to discontinue the drug if no efficacy is seen within 3 weeks of theinitiation of therapy.o Tolcapone is contraindicated in patients with hepatic disease; however, bothentacapone and tolcapone should be used with caution in patients with hepaticdysfunction. Tolcapone is also contraindicated in patients with non-traumaticrhabdomyolysis or hyperpyrexia/confusion related to medication.o Entacapone has been associated with rhabdomyolysis, exacerbation ofpreexisting dyskinesia and a complex resembling neuroleptic malignantsyndrome. The safety of tolcapone has not been established in patients with acreatanine clearance less than 25 mL/min, and it has been associated withrhabdomyolysis as well.o MAO and COMT are the 2 major enzyme systems involved in catecholaminemetabolism; therefore, non-selective MAO inhibitors (eg, phenelzine,tranylcypromine) would result in inhibition of the majority of the pathwaysresponsible for normal catecholamine metabolism and the combination ofCOMTs and MAOIs should be avoided. COMT inhibitors may be takenconcomitantly with a selective MAO-B inhibitor (eg, selegiline).• No head to head trials have been conducted comparing the two available COMTinhibitors. However, studies have shown that both agents are superior to placebo. TheLasting effect in Adjunct therapy with Rasagiline Given Once daily (LARGO) wasconducted using 687 patients who were randomized in a double blind fashion to receiveentacapone, rasagiline, or placebo for 18 weeks. There was a total daily off timedecrease of 21% with both active treatments compared to 7% with placebo. Entacaponeand rasagiline significantly improved Unified Parkinson Disease Rating Scale Activities ofDaily Living (UPDRA ADL) and UPDRA motor compared to placebo. There was nodifference in the incidence of dyskinesia between the groups.Page 69 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• COMT inhibitors are used in addition to levodopa to reduce the wearing off of levodopatherapy which may result in motor complications. COMT inhibitors allow for reduceddoses of levodopa, and many experts recommended the addition of a COMT with theinitiation of levodopa therapy to reduce the risk of developing motor complications. TheQuality Standards Subcommittee of the American Academy of Neurology recommendsthat tolcapone only be used in PD patients taking carbidopa/levodopa who areexperiencing symptom fluctuations and are not candidates for other adjunctive therapy.Monitoring of liver function testes (LFTs) are recommended at base line, every 2-4 weeksfor the first 6 months, then periodically thereafter. The American Academy of Neurologyrecommends that entacapone be offered to patients with PD with motor fluctuations toreduce off time. Tolcapone is considered as an alternative along side pramipexole andropinirole.RECOMMENDATION:The catechol-O-methyltransferase (COMT) inhibitors increase plasma levels of levodopa resultingin relief from the end-of-dose wearing off phenomenon seen. These agents also reduce the risk ofmotor compilations if used from the onset of levodopa and have been shown to improve motor andADL scores in stable levodopa responders. Tolcapone has a higher incidence of adverse effectsand might cause significant hepatocellular injury leading it to be second line therapy behindentacapone. Therefore, it is recommended that entacapone be available for use in patients withPD and that tolcapone be reserved for those patients who have tried and failed entacaponetherapy.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: CATECHOL-O-METHYLTRANSFERASE INHIBITORSPREFERREDNON-PREFERREDCOMTAN ® (entacapone)TASMAR ® (tolcapone)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Antiparkinson’s Agents Review. Sept 12, 2007.4. National Institute for Health and Clinical Excellence. Parkinson’s disease: nationalclinical guideline for diagnosis and management in primary and secondary care. 2006;http://www.nice.org.uk/CG0235. Rao SS, Hofmann LA, Shakil A. Parkinson’s disease: diagnosis and treatment. AmFam Physician. 2006 Dec 15;74(12):2046-54.6. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patientswith Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjuncttherapy with Rasagiline Given Once daily, study): a randomized, double-blind, parallelgrouptrial. Lancet. 2005;365:947-54.BACKGROUNDNEW: ANTIPARKINSON’S AGENTS: ANTICHOLINERGICS• Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized bytremor, bradykinesia and rigidity. PD is thought to be caused by a degeneration ofdopamine-containing neurons in the substantia nigra leading to the formation of Lewybodies.Page 70 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• The anticholinergic drugs, benztropine, biperiden, procyclidine and trihexyphenidyl, areused to treat PD because they inhibit the reuptake and storage of dopamine causing aprolongation of the actions of dopamine.• The anticholinergic drugs are approved for the treatment of PD and to treat drug-inducedextrapyramidal symptoms; however, benztropine is not approved for the treatment oftardive dyskinesia.• The most common adverse effects of the anticholinergics are CNS effects such asmemory impairment, acute confusion, hallucinations, sedation and dysphoria. Peripheralside effects include: dry mouth, blurred vision, constipation, nausea, urinary retention,impaired sweating and tachycardia.oAnticholinergics are contraindicated in patients with glaucoma, benign prostatichypertrophy and dementia.o These agents should be used with caution in elderly patients as these agentsmay cause confusion and hallucinations. Procyclidine and trihexyphenidylshould be used with caution in patients with hepatic disease. Trihexyphenidylshould also be used with caution in patients with renal disease.• A randomized, double-blind crossover study was conducted in which 29 patients withmild to moderate PD stabilized on levodopa/carbidopa were given benztropine orplacebo. Statistically significant improvements were seen in rigidity, finger tapping speedand activities of daily living during the benztropine phase. No significant adverse effectswere seen.• According to the 2006 National Collaborating Center for Chronic Conditions (NICE) andthe American Academy of Family Physicians, anticholinergics are typically used inpatients

CENTRAL NERVOUS SYSTEM AGENTSReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Provider Synergies. Antiparkinson’s Agents Review. Sept 12, 2007.4. National Institute for Health and Clinical Excellence. Parkinson’s disease: nationalclinical guideline for diagnosis and management in primary and secondary care. 2006;http://www.nice.org.uk/CG0235. Rao SS, Hofmann LA, Shakil A. Parkinson’s disease: diagnosis and treatment. AmFam Physician. 2006 Dec 15;74(12):2046-54.6. Tourtellotte WW, Potvin AR, Sundulko K. et al. Parkinson’s disease: Cogentin withSinemet, a better response. Prog Neuropsychopharmacol Biol Psychiatry. 1982;6:51-5.BACKGROUNDNEW: MONOAMINE OXIDASE B INHIBITORS• Rasagiline and selegiline are highly selective monoamine oxidase type B (MAO-B)inhibitors used for Parkinson’s disease (PD). There is also a patch formulation ofselegiline, which is used for depression.• The MAO-Bs exert their physiological effects by irreversibly inhibiting monoamineoxidase type B activity, blocking dopamine breakdown, increasing dopaminergic activityand interfering with dopamine reuptake at the synapse.• Both agents are approved for adjunctive therapy to levodopa in advanced PD.Rasagiline is also approved for use as monotherapy in early PD. Emsam ® , thetransdermal formulation of selegiline, is FDA approved for the treatment of majordepressive disorder.• The most common adverse effects include confusion, dizziness, diskinesia, orthostaticcomplications and nausea. Selegiline seems to cause a greater incidence of confusion,dizziness and dyskinesia than rasagiline. However, rasagiline seems to cause moreorthostatic complications. In addition, application site reactions may be seen with thetransdermal patch formulation of selegiline (24% incidence).o MAO-Bs are contraindicated in patients with pheochromocytoma and those whoare undergoing general anesthesia. MAO-Bs should never be used inconjunction with other MAOIs.o Rasagiline should be adjusted to 0.5 mg daily in patients with mild hepaticimpairment, and it should be avoided in patients with moderate or severe hepaticdisease. Selegiline should also be used with caution in patients with hepaticimpairment. The MAO-Bs should be used with caution in renal disease as well.o The concurrent use of meperidine, methadone, propoxyphene, tramadol, andsympathomimetic amines should be avoided due to the risks of hypertensivereactions. The simultaneous use of MAO-Bs along with SSRIs and TCAs is notrecommended. MAO-Bs do not cause a reaction after consumption of tyraminerichfoods; therefore, they are safer than the nonselective MAOIs.o Selegiline undergoes extensive first-pass metabolism in the liver resulting in 5metabolites, including pharmacologically active l-amphetamine and l-methamphetamine which can increase the risk for confusion, specifically in elderpatients with underlying cognitive dysfunction. Because orally disintegratingselegiline tablets avoid the first pass effect, clinical efficacy can be achieved atlower doses resulting in lower concentrations of amphetamine metabolites.Page 72 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• No head-to-head trials have been completed comparing the MAO-Bs to each other.o A pivotal trial compared rasagiline monotherapy (1 mg or 2 mg) to placebo inearly PD. After 6 months of treatment, a mean adjusted change in UnifiedParkinsons Disease Rating Scale (UPDRS) score of -4.2 in the 1 mg rasagilinegroup and -3.56 in the 2 mg rasagiline group were observed, compared toplacebo. These changes were quantitatively similar to those seen with levodopatherapy. Patients who had received placebo were then switched over torasagiline therapy. After an additional 6 months of therapy, patients receivingrasagiline for all 12 months had less functional decline than patients with thedelayed start, indicating potential neuroprotective effects.• The 2006 NICE guidelines recommend MAO-Bs as a symptomatic treatment for earlyPD; however, they also identify MAO-Bs as the least effective (behind levodopa anddopamine agonist) in symptomatic treatment of PD. The MAO-Bs have been shown toimprove motor performance slightly and delay the development of disability requiring theaddition of levodopa. Therefore, MAO-Bs are effective as adjunctive therapy to allowlower doses and longer dosing intervals of levodopa resulting in increased “on-time”percentages in advanced PD.• The American Academy of Neurology along with the NICE guidelines report that there isno convincing, clinical evidence of neuroprotective benefit of selegiline. Current dataseems to indicate that rasagiline may offer a neuroprotective effect, although long-termstudies are still ongoing.• For the treatment of depression, MAOIs are useful for patients who are refractory toTCAs or intolerant to the anticholinergic effects of TCAs. The 2004 NICE guidelines andthe American Psychiatric Association recommend that MAOIs be used for depressiononly in patients whose depression has failed to respond to other antidepressants.RECOMMENDATION:The monoamine oxidase type B (MAO-B) inhibitors have been shown to improve motorperformance and delay the development of disability requiring the addition of levodopa in patientswith Parkinson’s disease (PD). Because, these agents selectively inhibit monoamine oxidase typeB, the safety of theses agents is not as much of a concern as with the nonselective agents.Current treatment guidelines recommend their use as second line therapy for the symptomatictreatment of PD, or as a first line agent in adjunctive therapy to allow lower dosages and longerdosing intervals of levodopa. In order to allow for patient and prescriber choice, it is recommendedthat at least two MAO-B inhibitors be available for the treatment of PD. In addition, disintegratingtablets must be available for those with difficulties swallowing or for patients in whom the adversereactions secondary to the active metabolites, l-amphetamine and l-methamphetamine, are aconcern. It is also recommended that transdermal selegiline be available for use in patients withrefractory major depressive disorder, who have failed to respond to other availableantidepressants.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: MONOAMINE OXIDASE B INHIBITORSPREFERREDNON-PREFERREDSELEGILINE (Compares to Eldepryl ® ) ELDEPRYL (selegiline)AZILECT ® (rasagiline)EMSAM ® ST, QL (selegiline)ZELAPAR ® (selegiline disintegratingtablets)COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPage 73 of 85November 8, 2007 Tennessee PAC

Quantity LimitsEmsam ® 1 patch/dayCENTRAL NERVOUS SYSTEM AGENTSStep Therapy for Emsam ®The recipient will need to have tried and failed, or been intolerant to, at least two antidepressantsof different mechanisms from any two of the following classes:• SSRIs• SNRIs• New generation antidepressants (i.e. bupropion, mirtazapine)• TCAs• Another MAOICOMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007 ProviderSynergies. Antiparkinson’s Agents Review. Sept 12, 2007.3. National Institute for Health and Clinical Excellence. Parkinson’s disease: nationalclinical guideline for diagnosis and management in primary and secondary care. 2006;http://www.nice.org.uk/CG023.4. National Institute for Health and Clinical Excellence. Depression: Management ofdepression in primary and secondary care. 2004; http://www.nice.org.uk/CG0235. The American Psychiatric Association.http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. Accessed August, 2007.6. Littner MR, Kushida C, Anderson WM, et al. Practice parameters for the dopaminergictreatment of restless legs syndrome and periodic limb movement disorder. Sleep.2004;27:557-9.7. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline inearly Parkinson disease. Arch Neurol. 2004 Apr;61(4):561-6.NEW: DOPAMINE PRECURSOR / DOPA DECARBOXYLASE INHIBITOR /COMT INHIBITORBACKGROUND• Parkinson’s disease (PD) is characterized by low plasma levels of dopamine. Severalagents can be used to increase dopamine and therefore treat the symptoms of PD. Oneagent, levodopa/carbidopa/entacapone (Stalevo TM ), combines three of the availablemechanisms for increasing dopamine in a single agent. Levodopa is the immediateprecursor to dopamine, carbidopa inhibits the decarboxylation of levodopa andentacapone inhibits catechol-O-methyltransferase from converting levodopa to 3-Omethyldopa;therefore, all these agents work together to increase plasma levodopa levelsand treat the signs and symptoms of PD.• Stalevo TM is indicated for the symptomatic treatment of idiopathic PD.• The most common adverse effects observed with the use of Stalevo TM are dyskinesia, GIupset, confusion, dizziness, somnolence, hallucinations (4%), discolored urine (10%) andfatigue. Rare but severe adverse effects seen in those who use Stalevo TM includeorthostatic hypotension (1%), severe diarrhea (1.3%) or psychotic disorders.Page 74 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSoStalevo TM is contraindicated in patients with narrow angle glaucoma and historyof melanoma or undiagnosed skin lesions.o Abrupt discontinuation or dose reduction of carbidopa/levodopa may result in aneuroleptic malignant-like syndrome, particularly in patients receivingneuroleptics; therefore, gradual tapering of the Stalevo dose is indicated.Stalevo should also be used with caution in patients with asthma, biliaryobstruction, endocrine, hepatic, cardiac or pulmonary disease and history ofpeptic ulcer disease.o The concurrent use of Stalevo and non-selective MAOIs is contraindicated due tothe potential for severe orthostatic hypotension. MAOIs should be discontinued14 days prior to the initiation of Stalevo.• No head to head trials comparing Stalevo TM to the combination of carbidopa/levodopaand entacapone taken individually exist; therefore, most believe that the fixed-doseproduct should be used mainly for convenience to the patient. Although clinical studieswith the fixed combination of these agents are lacking, this formulation appearsbioequivalent to the individual agents used for concomitant therapy. Separateadministration of levodopa/carbidopa and entacapone may be required to achieveoptimal clinical benefit and in special situations (eg, liver disease).• The 2006 NICE guidelines and the American Academy of Family Physicians suggest thatcarbidopa/levodopa ± a catechol-O-methyltransferase (COMT) inhibitor be added when adopamine agonist no longer provides adequate control of symptoms.Carbidopa/levodopa has been associated with decreased morbidity and mortality andmost all patients benefit from its use; however, carbidopa/levodopa is associated withmotor fluctuations such as wearing off, on-off phenomenon, dose failures and freezing.COMT inhibitors are used in addition to levodopa to reduce the wearing off of levodopatherapy which may result in motor complications. COMT inhibitors allow for reduceddoses of levodopa, and many experts recommended the addition of a COMT with theinitiation of levodopa therapy to reduce the risk of developing motor complications.RECOMMENDATION:Stalevo TM combines the mechanisms of action of two separate drugs in order to increase serumdopamine levels and effectively treat Parkinson’s disease (PD). The addition of entacapone tolevodopa/carbidopa may prolong "on" time and improve Unified Parkinson's Disease Rating Scale(UPDRS) scores in some parkinsonian patients with fluctuating disease. Current treatmentguidelines endorse the use of these agents when a dopamine agonist is no longer providingadequate control of the symptoms of PD; however, no distinction is made between thecombination product and the individual components. Therefore, the combination product(Stalevo TM ) and the individual components (levodopa/carbidopa plus entacapone) can beconsidered therapeutic alternatives to one another.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: DOPAMINE PRECURSOR/DOPA DECARBOXYLASE INHIBITOR/COMT INHIBITORPREFERREDNON-PREFERREDSTALEVO TMN/A(levodopa/carbidopa/entacapone)COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPage 75 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSReferences1. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.2. Stalevo [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation;March 2007.3. National Institute for Health and Clinical Excellence. Parkinson’s disease: nationalclinical guideline for diagnosis and management in primary and secondary care. 2006;http://www.nice.org.uk/CG0234. Rao SS, Hofmann LA, Shakil A. Parkinson’s disease: diagnosis and treatment. AmFam Physician. 2006 Dec 15;74(12):2046-54.BACKGROUNDNEW: ANTIANXIETY AGENTS• Everyone experiences a certain amount of nervousness and apprehension, anxiety,when faced with stress; however, this response is usually reasonable and fleeting.Anxiety is diagnosed in those who experience anxiety-like symptoms and possess fearsthat are frequently abnormal, irrational, and severely impair normal daily functioning.Anxiety may induce secondary symptoms such as palpitations, tachycardia, chest pains,shortness of breath, or hyperventilation, and it may be idiopathic, drug-induced, orassociated with a psychiatric disease. The Diagnostic and Statistical Manual of MentalDisorders (DSM-IV) classifies anxiety disorders into several categories including:generalized anxiety disorder, panic disorder, agoraphobia without a history of panicdisorder, phobic disorders, obsessive-compulsive disorder, post-traumatic stressdisorder, and acute stress disorder.• The agents in this class include buspirone and meprobamate. It is unknown how theseagents work to reduce anxiety. We know that buspirone exhibits high affinity forserotonin receptors, moderate affinity for brain dopamine receptors, no significant affinityfor benzodiazepine receptors and no effect on GABA binding. It is thought thatmeprobamate acts at multiple sites in the central nervous system including the thalamusand limbic systems.• Both agents in this class are FDA-approved for the treatment of anxiety disorder or theshort term relief of the symptoms of anxiety.• The antianxiety drugs most commonly cause central nervous system depression.o Buspirone, specifically, is most commonly associated with asthenia (2%),anger/hostility (2%), blurred vision (2%), confusion (2%), dizziness (9%),excitement (2%), headache (3%), numbness (2%), nausea (3%), andnervousness (2%). Rare but severe adverse effects include cerebrovascularaccident, congestive heart failure, or myocardial infarction.o Meprobamate has been most commonly associated with asthenia, ataxia,dizziness, ECG and EEG abnormalities, euphoria, GI upset, headache,paresthesia, skin rashes (sometimes life threatening), slurred speech,somnolence, and vertigo. Rare but severe adverse effects includeagranulocytosis, aplastic anemia, hypotension and leukopenia.o Meprobamate is contraindicated in patients with acute intermittent porphyria.o Buspirone and meprobamate should be used with caution in patients with severehepatic or renal disease. Buspirone is pregnancy category B; however,meprobamate is category D. Buspirone will not prevent withdrawal symptoms inpatients who are dependent on sedative hypnotics or anxiolytics drugs. Abruptdiscontinuation of meprobamate after prolonged or excessive use shouldavoided. Meprobamate may be habit forming (schedule IV) and may impairmental or physical abilities to perform potentially hazardous tasks such asoperating heavy machinery. Meprobamate should also be used very cautiouslyin patients with seizure disorder as it may actually precipitate seizures.Page 76 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSNEW: MONOAMINE OXIDASE INHIBITORSBACKGROUND• There are a variety of neurotransmitters including norepinephrine, serotonin anddopamine that can become imbalanced to precipitate or cause depressive disorders.Monoamine oxidase is a complex enzyme system, widely distributed throughout thebody, which is responsible for the metabolic decomposition of biogenic amines (e.g.,norepinephrine, epinephrine, dopamine, and serotonin).• Monoamine oxidase inhibitors (MAOIs) inhibit the enzyme system that is responsible fordecomposition of neurotransmitters such as norepinephrine, serotonin and dopamine,causing an increase in their concentrations.• The nonselective MAOIs, isocarboxazid, phenelzine and tranylcypromine, are FDAapproved for the treatment of patients with atypical depression, exogenous or neurotic.• Common adverse reactions of the nonselective MAOIs include: orthostatic or posturalhypotension, tachycardia, palpitations, hyperreflexia, mania or hypomania, sleepdisturbances, confusion, memory impairment, GI upset, and elevated serumtransaminases. Less common, but severe adverse reactions include: disorders of thehematopoietic structure and seizures.o All of the MAOIs carry the same black box warning, “Antidepressants increasedthe risk of suicidal thinking and behavior (suicidality) in short-term studies inchildren and adolescents with major depressive disorder (MDD) and otherpsychiatric disorders. Anyone considering the use of MAOIs or any otherantidepressant in a child or adolescent must balance this risk with the clinicalneed. Closely observe patients who are started on therapy for clinical worsening,suicidality, or unusual changes in behavior. Advise families and caregivers of theneed for close observation and communication with the prescriber. MAOIs arenot approved for use in children.”o MAOIs are contraindicated in patients with pheochromocytoma, cardiovasculardisease including CHF, liver disease or abnormal LFTs, severe renal impairment,confirmed or suspected cerebrovascular disorders, hypertension and history ofheadaches. These agents are also contraindicated in patients who consumecaffeine or foods containing large amounts of tyramine such as cheese.o Cautious downward titration and discontinuation of MAOIs will prevent withdrawalsymptoms including nausea, vomiting, malaise, vivid nightmares with agitation,frank psychosis, and convulsions. The MAOIs each have specific patientpopulations in which caution should be used.• Isocarboxazid, phenelzine and tranylcypromine should be usedcautiously in patients with epilepsy and hyperthyroidism.• Diabetic, schizophrenic or epileptic patients should use phenelzine withcaution.• Tranylcypromine should be used cautiously in patients with angina,diabetes, and renal impairment.• Phenelzine and tranylcypromine are pregnancy category B, butisocarboxazid is pregnancy category C.• Tranylcypromine and isocarboxazid may cause hyperthyroidism andaggravate coexisting symptoms in depression such as anxiety andagitation. There have been reports of drug dependency in patients usingdoses of tranylcypromine and isocarboxazid in significant excess of thetherapeutic range. Some of these patients had a history of previoussubstance abuse.o The drug to drug interactions with MAOIs are numerous; however, only a handfulof these drug interactions are actually contraindications:Page 78 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• MAOIs compared to TCAso• MAOIs should be discontinued at least 10 days prior to elective surgery,because local anesthesia containing sympathomimetic vasoconstrictorscombined with MAOIs can cause significant hypotensive effects.• Do not administer MAOIs together with or immediately following otherantidepressants. This combination may cause serious, sometimes fatal,reactions such as hyperthermia, rigidity, myoclonus, autonomicinstability, and mental status changes which can progress to delirium andcoma.• Allow 14 days between discontinuation of MAOIs and initiation ofbupropion, because the concurrent use is contraindicated.• Hypertensive crises, severe convulsive seizures, coma, or circulatorycollapse may occur in patients receiving MAOIs and carbamazepine.• The coadministration of MAOIs and dextromethorphan may causehyperpyrexia, abnormal muscle movement, psychosis, bizarre behavior,hypotension, coma, and death.• Several cases of elevated blood pressure have been associated withisocarboxazid in combination with buspirone. Allow at least 10 daysbetween discontinuation of isocarboxazid and institution of buspirone.A study of 131 outpatients given phenelzine 45 to 75 mg/day, amitriptyline 75 to187.5 mg/day, or placebo was conducted. Results show that amitriptyline andphenelzine were equally effective in treating patients with depression or mixedanxietydepression. The two agents showed similar maximal effects at 6 weeks.Phenelzine demonstrated anti-anxiety effects, whereas amitriptyline was superiorto phenelzine in patients with anergia and impaired work and interests.o Patients were randomized to double-blind treatment with tranylcypromine 30-60mg/day (n=37), nortriptyline 75-150 mg/day (n=40), or placebo (n=45). Evaluationof depression was accomplished with the Hamilton Depression Scale, the NewPhysicians' Rating Scale (NPRL) and the Zung Self-Rating Depression Scale(completed by the patient). No significant differences in patient outcome betweenthe 2 active drugs emerged on any of these scales. The type of side effectsdiffered between the 2 active medications, with tranylcypromine being associatedwith dizziness (65%), insomnia (54%), and overexcitement (24%), whilenortriptyline was associated with a greater incidence of anticholinergic effectssuch as dry mouth, constipation, blurred vision, and confusion. Blood pressurewas consistently lowered by tranylcypromine and raised by nortriptyline.• Traditionally, the MAOIs have been avoided because of potentially severe drug-drug anddrug-food interactions. The TCAs are considered first-line for phobias and anxietydisorders in patients with stable personalities; however, some data suggest MAOIs maybe superior. MAOIs are useful for patients who are refractory to TCAs or intolerant to theanticholinergic effects of TCAs. The 2004 NICE guidelines recommend the use ofphenelzine in patients whose depression has failed to respond to other antidepressantsand who are prepared to tolerate the side effects and dietary restrictions associated withits use. The American Psychiatric Association advocates the use of a TCA or MAOI assecond line therapy for Post Traumatic Stress Disorder, and they suggest that MAOIs beused for depression only in patients whose depression has failed to respond to otherantidepressants.Page 79 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSRECOMMENDATION:MAOIs are considered second or third line therapy in the treatment of depression and posttraumatic stress disorder. The various MAOIs seem to be equal in efficacy; however,tranylcypromine and isocarboxazid may aggravate coexisting symptoms of depression, can causehyperthyroidism, and have the potential to cause addiction if given in large doses; therefore,phenelzine can be considered a superior agent within this category. Because MAOIs are notconsidered first line agents, and given their extensive side effect profile, safety concerns, and drugto drug interactions, it is recommended that all agents in this class be subject to step therapyrequiring the trial of other antidepressants as first line therapy.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: MONAMINE OXIDASE INHIBITORSPREFERREDNON-PREFERREDNARDIL ® ST, QL (phenelzine)MARPLAN ® ST, QL (isocarboxazid)PARNATE ® ST, QL (tranylcypromine)TRANYLCYPROMINE ST, QL (compares toParnate ® )Quantity LimitsNardil ® 6 tabs/dayMarplan ® 6 tabs/dayParnate ® 6 tabs/dayTranylcypromine 6 tabs/dayStep TherapyMAOIs will be approved if one of the following criteria is met:1. A patient has a diagnosis of major depression and has been refractory or intolerant to anadequate trial (Defined as: 3 weeks at the maximum tolerated dose within therecommended therapeutic range) of at least one SSRI, SNRI, and TCA, OR2. A patient has a diagnosis of Post Traumatic Stress Disorder and has been refractory orintolerant to an adequate trial (Defined as: 3 weeks at the maximum tolerated dose withinthe recommended therapeutic range) of at least one SSRI and TCA.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007. Accessed August,2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed August, 2007.3. National Institute for Health and Clinical Excellence. Depression: Management of depression inprimary and secondary care. 2004; http://www.nice.org.uk/CG0234. The American Psychiatric Association. http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm.Accessed August, 2007.5. Paykel ES, Rowan PR, & Parker RR: Effects of phenelzine and amitriptyline on depression.Psychopharmacol Bull 1981; 17:104-105.6. White K & Simpson G: The combined use of MAOIs and tricyclics. J Clin Psychiatry 1984; 45:67-69.Page 80 of 85November 8, 2007 Tennessee PAC

BACKGROUNDCENTRAL NERVOUS SYSTEM AGENTSNEW: MOOD STABILIZERS• The mood stabilizers include lithium and select anticonvulsants. This review will consistof lithium only, as the anticonvulsants will be reviewed in a separate category.• While the exact mechanism is unknown, lithium seems to exert its physiological effectsby altering sodium transport in nerve and muscle cells resulting in metabolism ofcatecholamines.• Lithium is FDA-approved for the acute treatment of manic episodes associated withbipolar disorder and as maintenance therapy to reduce the frequency and intensity ofmanic episodes which may occur.• Adverse reactions include: tremor, polydipsia, polyuria, weight gain, GI discomfort andreversible T-wave depression on ECG.o Lithium carries a black box warning stating, “Lithium toxicity is closely related toserum lithium levels, and can occur at doses close to therapeutic levels. Facilitiesfor prompt and accurate serum lithium determinations should be available beforeinitiating therapy.”o Lithium is contraindicated in patients with cardiovascular or renal disease, severedehydration or sodium depletion. Serum lithium levels are closely related tolithium toxicity; therefore, patients should be warned to look for signs andsymptoms of lithium toxicity, including diarrhea, vomiting, tremor, mild ataxia,drowsiness, or muscle weakness.o There are multiple drug-drug interactions involving lithium including:• Encephalopathic syndrome if given concurrently with haloperidol.• Increased chances of neurotoxicity if given with calcium channelblockers, carbamazepine, metronidazole or SSRIs.• Increased lithium levels if given with diuretics, ACE inhibitors or NSAIDs.• Decreased lithium levels if given concurrently with acetazolaminde, urea,xanthine or alkalinizing agents.• Lithium has been compared to carbamazepine for the treatment of bipolar disorder.o In a randomized double blind study involving treatment-naive bipolar patients,lithium (targeted to blood levels of 0.6-1 mmol/liter) was superior tocarbamazepine (target blood levels of 6-10 mg/liter) for preventing recurrence ofmanic or major depressive episodes. During the 2 year study period 27% oflithium and 42% of carbamazepine patients experienced relapse.o An open, randomized, controlled clinical trial was conducted in which patientswere treated with an average of 26.8 mmol per day of lithium (n=86) or anaverage of 635 mg per day of carbamazepine (n=85) for 2.5 years.Rehospitalization rates were similar for both treatment groups, more patientsdemonstrated a good clinical response (low inter-episodic morbidity withoutrehospitalization or drop-out) during lithium (40%) than during carbamazepinetreatment (24%).• In a double-blinded study lamotrigine (n=59) and lithium (n=46) were compared toplacebo (n=70) as the sole agent for maintenance therapy of bipolar I for 18 months.Lamotrigine doses ranged from 100 to 400 mg daily. Lithium was titrated to serum levelsof 0.8 to 1.1 mEq/L. The median time to intervention due to a mood episode was 141days in the lamotrigine arm compared to 292 days in the lithium arm and 85 days in theplacebo arm. Twenty lamotrigine patients, 8 lithium patients and 28 placebo patientsdeveloped mania. Eight lamotrigine patients, 10 lithium patients and 21 placebo patientsdeveloped depression. Development of mania and development of depression were notstatistically different between lamotrigine and lithium; however, patients in the lithium armwere more likely to discontinue therapy early due to adverse events.Page 81 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• The 2002 American Psychiatric Association considers the first-line pharmacologicaltreatment for more severe manic or mixed episodes of bipolar disorder to be either:lithium plus an antipsychotic or valproate plus an antipsychotic. The recommendation forless ill patients is monotherapy with lithium, valproate, or an antipsychotic such asolanzapine. Lithium or lamotrigine are also considered first-line therapy for the treatmentof depressive episodes associated with bipolar disorder. The initial treatment for patientswho experience rapid cycling should include lithium or valproate; however, many patientswill require combination therapy. The American Psychiatric Association also states thatlithium and valproate are the medications with the best empirical evidence to supporttheir use for chronic maintenance therapy in patients with bipolar disorder.RECOMMENDATION:Lithium is recommended as a first line pharmacological agent for the treatment of severe manicor mixed episodes associated with bipolar disorder, as well as for bipolar depressive episodes,rapid cycling and maintenance therapy. Given this important role in the management of bipolar,lithium should be available.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPREFERREDLITHIUM CARBONATE (compares toEskalith ® )LITHIUM CARBONATE SA (Eskalith ® CR,Lithobid) ®LITHIUM CITRATE, solutionNEW: MOOD STABILIZERSNON-PREFERREDESKALITH ® (lithium carbonate)ESKALITH ® CR (lithium carbonate SA)LITHOBID ® (lithium carbonate SA)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Practice guideline for the treatment of patients with bipolar disorder (revision). Am JPsychiatry 2002 Apr;159(4 Suppl):1-50.4. McClellan J, Kowatch R, Findling RL, Work Group on Quality Issues. Practice parameterfor the assessment and treatment of children and adolescents with bipolar disorder. J AmAcad Child Adolesc Psychiatry 2007 Jan;46(1):107-25.5. Bowden C, Calabrese J, Sachs G, et al: A placebo-controlled 18-month trial oflamotrigine and lithium maintenance treatment in recently manic or hypomanic patientswith bipolar I disorder. Arch Gen Psychiatry 2003; 60:392-4006. Hartong E, Moleman P, Hoogduin C, et al: Prophylactic efficacy of lithium versuscarbamazepine in treatment-naive bipolar patients. J Clin Psychiatry 2003; 64(2):144-151.Page 82 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSBACKGROUNDNEW: CHOLINERGIC MUSCLE STIMULANTS• Myasthenia gravis is a disease characterized by episodic muscle weakness caused byloss or dysfunction of acetylcholine receptors. The cholinergic muscle stimulants used totreat Myasthenia gravis include: ambenonium, neostigmine and pyridostigmine.• All agents in this category are all indicated for the symptomatic treatment of myastheniagravis.• Ambenonium, neostigmine, and pyridostigmine exert their physiological activity byinhibiting the destruction of acetylcholine by cholinesterase and facilitating thetransmission of impulses across the myoneural junction.o Neostigmine may be useful for long-term oral therapy; however, pyridostigmine isgenerally considered to be the drug of choice for oral administration because ofits longer duration of action and lower incidence of adverse effects..o Ambenonium has a longer duration of action than the other anticholinesteraseinhibitors (AChIs), resulting in a greater residual effect upon awakening than withother agents. Ambenonium also causes fewer gastrointestinal and othermuscarinic side effects than other anticholinesterase agents, and it may be usedfor those patients who have displayed intolerance to the bromide component ofneostigmine and pyridostigmine.• Common adverse effects of ambenonium are arrhythmias, seizures, dysarthia/dysphonia,increased salivation and GI secretions and GI upset. Neostigmine and pyridostigminecan cause GI upset, muscle twitching and increased salivationo Pyridostigmine carries a black box warning which urges that this drug be,“administered by adequately trained individuals familiar with its actions,characteristics, and hazards.”o All AChIs are contraindicated in patients with mechanical intestinal and urinaryobstruction. Neostigmine and pyridostigmine are contraindicated in patients withperitonitis and patients with hypersensitivity reactions to bromides.o Use these agents with caution in patients with bronchial asthma, epilepsy,bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism, cardiacarrhythmias or peptic ulcer. Cardiac and respiratory arrests have occurred rarelywith AChIs.• Currently there are no head to head trials between the cholinergic muscle stimulants.The Guidelines for The Treatment of Autoimmune Neuromuscular TransmissionDisorders and the National Institute of Neurological Disorders and Stroke both advocatethe use of an acetylcholinesterase inhibitor as first line therapy for the treatment ofmyasthenia gravis. The guidelines mention neostigmine and pyridostigmine as examplesof acetylcholinesterase inhibitors, but do not recommend an agent of choice.RECOMMENDATION:Cholinergic Muscle Stimulants are used to treat the muscle weakness associated with Myastheniagravis. Based on the current treatment guidelines, pyridostigmine is usually the agent of choice forthe treatment of Myasthenia gravis due to its better tolerability and longer duration of action thanneostigmine. Given this information, it is recommended that at least pyridostigmine be availablefor use in patients with myasthenia gravis.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONPage 83 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTSPREFERREDMESTINON ® syrup, 180 mg ER tablets(pyridostigmine)PYRIDOSTIGMINE 60 mg tablets(compares to Mestinon ® )NEW: CHOLINERGIC MUSCLE STIMULANTSNON-PREFERREDMESTINON ® 60 mg tabletsMYTELASE ® caplets (ambenonium)NEOSTIGMINE (compares to Prostigmin ® )PROSTIGMIN ® (neostigmine)References1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2006.Accessed June, 2006.2. Thompson MICROMEDEX on-line © 1974-2006. Accessed June, 2006.3. National Institute of Neurological Disorders and Stroke.http://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm4. Skeie GO, Apostolski S, Evoli A, Gilhus NE, Hart IK, Harms L, Hilton-Jones D, Melms A,Verschuuren J, Horge HW. Guidelines for the treatment of autoimmune neuromusculartransmission disorders. Eur J Neurol 2006 Jul;13(7):691-9.http://www.guideline.gov/summary/summary.aspx?doc_id=10464&nbr=005487&string=myasthenia+AND+gravisBACKGROUNDNEW: AGENTS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS)• Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's Disease, is aprogressive, fatal, neurodegenerative disease caused by the degeneration of the nervecells in the central nervous system that control voluntary muscle movement. This disordercauses muscle weakness and atrophy throughout the body as both the upper and lowermotor neurons degenerate and die, ceasing to send messages to muscles.• Riluzole works by inhibiting glutamate release, inactivating voltage-dependent sodiumchannels and interfering with intracellular events that follow transmitter binding atexcitatory amino acid receptors. This results in decreased stimulation of excitatory aminoacid receptors on the postsynaptic cell preventing neuronal death.• Riluzole is FDA-Approved for the treatment of ALS. This agent dose not cure ALS, but itslows the progression.• Common and severe adverse reactions include arthralgia, cardiac arrest,tachyarrhythmias, hypertension, dizziness, liver and renal impairment, GI upset,hypertonia, neutropenia, respiratory distress and rhinitis.o Approximately 14% of the individuals with ALS who received riluzole inpremarketing clinical trials discontinued treatment because of an adverseexperience, most commonly nausea, abdominal pain, constipation, and ALTelevations.o Riluzole should be used cautiously in patients with renal and hepatic impairment.Riluzole is metabolized by CYP1A2; therefore caution should be used in womenas CYP1A2 activity is reduced. Clearance of riluzole is reduced in Japanesepatients by as much as 50% possibly due to a lower capacity for metabolism.Cigarette smoking is known to induce CYP1A2; therefore, patients who smokemay metabolize riluzole faster.• A meta analysis of 4 trials examining tracheotomy-free survival of 974 riluzole (100 mgdaily) treated patients and 503 placebo patients found a 9% gain in the probability ofsurviving one year with riluzole. There was a small beneficial effect on both bulbar andlimb function, but not on muscle strength. Elevated ALTs were more frequent in theriluzole group.Page 84 of 85November 8, 2007 Tennessee PAC

CENTRAL NERVOUS SYSTEM AGENTS• An observational study including 73 patients given riluzole and 53 control patients whohad been diagnosed with ALS between 1998-1999. This study found riluzole therapyincreased survival rates at 12 months by approximately 10% and prolonged survival by 6months. This increase in survival was only seen in patients with bulbar-onset ALS. Inpatients aged >70 riluzole was associated with an 8 month longer median survival timeand a reduction in mortality of 27% at 12 months regardless of the site of symptom onset.Riluzole did not seem to effect survival past 24 months among younger patients, but hada positive effect on survival at 24 months and through the entire follow-up period inelderly patients.• According to treatment guidelines, all patients with ALS should be offered treatment withriluzole(class IA) as soon as a diagnosis is made. Riluzole should also be considered inprogressive spinal muscular atrophy (PMA) and primary lateral sclerosis (PLS) patientswho have a first degree relative with ALS.RECOMMENDATION:The exact patient population and the appropriate duration of therapy is still debatable for riluzole;however, riluzole is the only drug indicated for the treatment of ALS and the only drug proven inclinical trials to prolong ALS survival. It is recommended that riluzole be available for use in ALSpatients.COMMITTEE VOTE:APPROVED DISAPPROVED APPROVED with MODIFICATIONNEW: AGENTS FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS)PREFERREDNON-PREFERREDRILUTEK ® (riluzole)N/AReferences1. Facts and Comparisons on-line. Version 4.0; Wolters Kluwer Health, Inc.; 2007.Accessed September, 2007.2. Thompson MICROMEDEX on-line © 1974-2007. Accessed September, 2007.3. Andersen PM, Borasio GD, Dengler R, Hardiman O, Kollewe K, Leigh PN, Pradat PF,Silani V, Tomik B, EFNS Task Force on Diagnosis and Management of AmyotrophicLateral. EFNS task force on management of amyotrophic lateral sclerosis: guidelines fordiagnosing and clinical care of patients and relatives. Eur J Neurol 2005 Dec;12(12):921-38.4. Traynor BJ, Alexander M. An outcome study of riluzole in amyotrophic lateral sclerosis -a population based study in Ireland, 1996-2000. J Neurology 2003 Apr 250(4):473-9.5. Zoccolella S. Beghi E, Palagano G. et al. Riluzole and amyotrophic lateral sclerosissurvival: a population-based study in southern Italy. Eup J Nephr. Mar 2007;14(3):262-8.Page 85 of 85November 8, 2007 Tennessee PAC