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TennCare Pharmacy Advisory Committee (TPAC Meeting) May 10, 2007 Members in Attendance: David Beshara, RPh, Chief Pharmacy Officer (TennCare), Edward Capparelli, MD, Rufus Clifford, MD, Co-Chairman Alan Corley, DPh, Stanley Dowell, MD, Jeri Fitzpatrick, MD, Lynn Knott, PharmD, Wendy Long, MD, Chief Medical Officer (TennCare), Pat McCarthy, PA, Carol Minor, Chairman James Powers, MD, Sheila Spates, PharmD, Roger Zoorob, MD Non-Members Present from First Health: Tina Hawkins, PharmD, Nicole C. Woods, PharmD Guest Speaker: Joel Steelman, MD INTRODUCTIONS The meeting was called to order by Chairman Powers. He reminded listeners that all members had signed the Confidentiality/Conflict of Interest statement. The statement was read aloud, and Dr. Powers confirmed that no conflicts of interest had been identified. Then the members of the committee introduced themselves. MINUTES The minutes from the February 20, 2007 PAC meeting were reviewed. · The following misprints were pointed out: o On page 12, under the 2nd bullet point of the Discussion section - the generic drug not available in an 80 mg strength should be "pravastatin" not "lovastatin." o On page 21, the drug category should be "Potassium-Sparing Diuretics" instead of "Loop Diuretics." o On page 22, under the second bullet point of the Discussion section ­ the recommendation should read at least one other "potassium-sparing diuretic" instead of "loop diuretic." · Regarding the PAC's recommendation for ramipril on page 30, it was pointed out that the motion should have conveyed that the PAC accepted the proposed changes with the addition of "PostMI" to the first bullet point. The addition of an additional risk factor to the Diabetes bullet point was not part of the motion. · A motion was made to approve the minutes with the recommended changes. · The motion passed. TENNCARE UPDATE · Dr. Wendy Long stated that the 4/1/07 transition of ~370,000 TennCare enrollees in the middleTennessee region to the two new MCOs (AmeriChoice and Amerigroup) had been relatively smooth. A 90-day window was allowed for enrollees to continue to receive care from providers not in their new network in order to better facilitate the transition to the new plans. Dr. Long further stated that TennCare Select continued to be the statewide backup plan, as well as the plan for state custody and SSI children. o A question was posed as to whether non-state-custody TennCare Select patients would be transitioned to the two new MCOs. Dr. Long responded that this had occurred on 4/1/07. o A comment was made that the requirement for children in State custody to receive physicals at the Department of Health was contributing to problems for primary care physicians. This practice was interrupting patient care and resulting in many patients doubling up on physicals. Dr. Long responded that Dr. Jeanne Jordan, a new pediatrician with the State, would look into this issue. · Dr. Powers inquired about the status of the TennCare Joint Committee for Narcotic Management. David Beshara responded that information had been sent out to the Committee and the State was

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still awaiting their feedback. He added that there was a tentative target date of 7/1/07 to have the first phase implemented. The State was planning on having a phasic approach to implementing the new narcotic initiative, but the details were not yet available. o A question was posed as to whether the decisions from the Joint Committee for Narcotic Management would come before the PAC for their review. David Beshara responded that he did not think this was necessary, as the Joint Committee for Narcotic Management had been formed to deal with the creation of this initiative. o A question was posed as to whether the Joint Committee for Narcotic Management would reconvene before the 7/1 implementation date. David Beshara responded that the Joint Committee would reconvene, but probably not until after the implementation date. A comment was made expressing concern over the selection of Ventolin® HFA as the preferred HFA inhaler as of 5/15/07. Given the small size of the company, concern was voiced over the company not being able to keep up with the demand once Ventolin® HFA became the preferred HFA product. In addition, it was pointed out that Ventolin® HFA only has a 60-day shelf-life after it is opened. Concern was expressed over patients using this medication beyond the 60-day time frame and experiencing decreased efficacy. Furthermore, it was pointed out that there was the potential for increased utilization of short-acting inhalers due to the 60-day shelf-life of Ventolin® HFA. David Beshara responded that TennCare would look into these concerns, and if indeed there were issues with supply and shelf-life, the State would re-examine their choice of preferred agent. A comment was made that concern had been expressed by pulmonologists over there not being inhaled steroids (and long-acting beta-agonists) available on the Auto-Exemption list. It was added that family physicians were also requesting that a generic statin be made available on the Auto-Exemption list as well. A comment was made that Dr. Powers and David Beshara had presented to the TennCare Oversight committee and the PAC had been granted a 3-year extension.

GUEST SPEAKER ON ENDOCRINE AGENTS · Dr. Powers introduced Dr. Joel Steelman of the Pediatric Endocrinology department at Vanderbilt. · Growth Hormone (GH) Products: o Dr. Steelman stated that the main uses of GH products are: growth hormone deficiency (GHD), Turner syndrome, Prader-Willi syndrome, intra-uterine growth retardation / SGA, chronic renal insufficiency, and idiopathic short stature. o He stated that all GH products contain synthetically-produced human growth hormone. They are all essentially equivalent in efficacy. Factors considered in choosing a GH product are as follows: FDA-approved indications Patient and family needs Support services (nurses to train the family, etc.) Delivery devices Physician and nurse services, including benefits investigation, paperwork processing, and educational materials o Comments were provided on the proposed preferred and non-preferred GH products. Pros: multiple delivery devices and strong support services were available. Cons: There were no products with FDA-approved indications for Turner syndrome, chronic renal insufficiency, and idiopathic short stature. o Dr. Steelman further commented on the burden of switching patients, which involved regeneration of paperwork, retraining of patients, and concerns over back-logs in the process.

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Dr. Steelman recommended that TennCare continue to allow open prescribing of the GH agents. He added that if open prescribing was not acceptable to the State, he recommended that Nutropin® be added to the list of preferred products, given its indication for chronic renal insufficiency. Furthermore, he recommended that the State not mandate that patients be switched from a non-preferred product to a preferred product. o Dr. Steelman provided the following recommended changes to the proposed GH prior authorization criteria: For newborn infants, allow use of GH agents if the patient has hypoglycemia and EITHER a low GH level OR a low for age IGF-1/IGF binding protein-3 level (as opposed to hypoglycemia and a low GH). Qualify low IGF-1 levels with the phrase "based on age normal values for the patient" Change normalization of height velocity to "height velocity within the range of normal for the patient's age or bone age" Omit the statement that GH will not be approved if there is a decline in height velocity. Allow for use in idiopathic short stature (for patients with a height >2.25 SD below the mean in height for age and gender, AND non-delayed skeletal maturation) Questions/discussion regarding Dr. Steelman's comments on the GH Agents: o A question was posed as to how effective GH was in patients with idiopathic short stature (ISS). Dr. Steelman replied that he did not have experience with any ISS patients. He explained that ISS is a rare diagnosis, and often a diagnosis of last resort if no abnormality can be detected. o A question was posed as to whether the pen delivery devices were the primary way these shots were given. Dr. Steelman affirmed that the majority of patients used the pen devices in order to minimize the risk of misdosing associated with reconstitution of the vial. o A question was posed asking whether there truly was a difference among GH products, given that the various GH agents have the same generic entity yet differ in their FDAapproved indications. Dr. Steelman responded that chemically there is no difference between the GH products; however, the manufacturing process may be different. He pointed out that the company that manufactures Nutropin has spent time and money to establish dosing and safety of the product in chronic renal insufficiency. o A question was posed to David Beshara whether the reason for omitting Nutropin among the list of preferred GH products was strictly due to financial reasons. David Beshara responded that the GH agents were a new category with supplemental rebates. Expense was taken into account along with ensuring that there was a good distribution of devices, patient and provider services, etc. Dr. Steelman asked David Beshara whether there were any medico-legal issues with prescribing products off-label. David Beshara responded that within this category, since all the products contained the same drug and the drug itself has the FDA indication, the fact that a specific product may not have a particular approved indication should not pose a problem. Dr. Long agreed with this statement. Dr. Capparelli pointed out that generic drugs are not required to get re-approved for all of the brand product's indications. He added that 4 out of 10 GH agents seemed reasonable. IGF-1 Agents: o Dr. Steelman explained that IGF-1 is a product of GH with similar growth-promoting effects. He recommended for the State to include Increlex® among the preferred agents

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in this class, and further pointed out that it is currently the only agent in this category, as Iplex® has been removed from the market. · Other Endocrine Categories: o Dr. Steelman stated that he agreed with First Health's recommendations for the other endocrine classes being discussed at this meeting. o Regarding the use of LHRH agents in central precocious puberty, Dr. Steelman recommended the inclusion of Lupron Depot®. A question was asked as to how frequently this product is given at home by a caregiver. Dr. Steelman stated that he did have some caregivers trained to administer it. Dr. Woods stated that the new TennCare initiative requiring non-self-injectable medications to be billed on the medical side would allow for coverage of this drug on the pharmacy side in situations where the patient or caregiver had been trained to administer the injection. DRUG CLASS REVIEWS Endocrine: Growth Hormone Agents · Background Info/Recommendation: o The available growth hormone agents all contain the recombinant DNA-derived peptide hormone somatropin. Exogenous human growth hormone is used to treat: growth hormone deficiency, children small for gestational age (SGA), idiopathic short stature (ISS), chronic renal insufficiency, Prader-Willi syndrome, Turner syndrome, wasting associated with HIV/AIDS, and malabsorption due to short bowel syndrome. o No head-to-head comparative trials have been performed among the GH products. o In 2003, the American Association of Clinical Endocrinologists (AACE) published updated Medical Guidelines for Clinical Practice for Growth Hormone Use in Adults and Children. These guidelines recommend the following: For adults, GH therapy is indicated for adults with pituitary disease from known causes, including pituitary tumor, pituitary surgical damage, hypothalamic disease, irradiation, and trauma. In addition, the guidelines support the use of GH therapy in patients with childhood-onset GHD that is reconfirmed in adulthood by GH stimulation testing. The guidelines also recognize a benefit from supraphysiologic doses of GH in patients with wasting due to HIV/AIDS. For children, GH therapy is indicated for GHD (both idiopathic GHD and GHD due to pituitary conditions/trauma), Turner syndrome, chronic renal insufficiency, SGA or intrauterine growth retardation, and Prader-Willi syndrome. The 2003 AACE guidelines support the use of GH stimulation testing to confirm diagnoses of GHD, and recommend a cutoff value for GH stimulation tests of 5 mcg/L for adults and 10 mcg/L for children. While the available growth hormone products differ in their FDA-approved indications and recommended doses, all contain the same active ingredient and have been shown to exhibit similar efficacy and safety. Furthermore, clinical guidelines from the AACE and the Growth Hormone Research Society do not differentiate between the various GH products. Therefore, all agents in this class can be considered therapeutic alternatives to one another. Given the high cost of these medications and the potential for misuse, it is recommended that the growth hormone products all be subject to clinical criteria to ensure their appropriate use. · Discussion:

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A question was posed as to whether the current AACE guidelines include information about use in ISS. It was pointed out that the most recent guidelines do not include ISS. o A comment was made that since all products contain the same generic ingredient, the decision should be left up to First Health/TennCare to determine preferred agents in this class. o A question was posed as to whether current Growth Hormone users would be grandfathered. It was suggested that grandfathering for a definite amount of time may be appropriate for this class. Dr. Steelman was asked how difficult it would be to get all of his patients on a non-preferred GH product switched over to a preferred agent. Dr. Steelman responded that he had about 50-100 patients on TennCare and about 8 physicians in his clinic. A question was posed as to what a reasonable time frame would be to get GH patients switched over to a preferred agent. Dr. Steelman responded that 12 months would be reasonable. A comment was made that 6 months should be sufficient to allow for appointment "no-shows." o A motion was made to accept the proposed criteria, provided that First Health/TennCare look into adding Nutropin if cost-effective to do so. A 6-month grandfathering period was suggested. o The motion was approved. Proposed Clinical Criteria for Growth Hormone Agents: o For patients with a diagnosis of AIDS wasting or cachexia, Serostim® will be approved. o For patients with short bowel syndrome, Zorbtive® will be approved. o For patients less than 21 years old, therapy will be approved if any of the following criteria are met: Diagnosis of Turner's Syndrome; Diagnosis of Prader-Willi Syndrome; If the patient has evidence of hypothalamic-pituitary disease or structural lesions/trauma to the pituitary, including pituitary tumor, pituitary surgical damage, trauma, or cranial irradiation AND meets any one of the following: · Has failed at least one GH stimulation test (peak GH level <10 ng/mL) · Has at least one documented low IGF-1 level (below normal range for patient's age) · Has deficiencies in 3 or more pituitary axes If the patient has chronic renal insufficiency (serum creatinine < 30 mg/dl or creatinine clearance between 5 and 75 ml/min/1.73 m²); If the patient is a newborn infant and has evidence of hypoglycemia AND a low GH level (<20 ng/mL); If the patient has failed two GH stimulation tests (abnormal response is defined as peak growth hormone level less than 10 ng/ml), OR has failed one GH stimulation test and has a documented low IGF-1 level. · Continuation of growth hormone therapy will be approved only if normalization in height velocity is seen. · Therapy will not be approved once epiphyseal fusion occurs or if there is a decline in height velocity. · For recipients who have been on growth hormone prior to the start of this edit, the requirement for 2 stimulation tests will be waived. If the patient has a diagnosis of Small for Gestational Age (SGA) or Intrauterine Growth Retardation (IGR), is > 2 years old, and has a height at least 2 standard deviations below the population mean for the patient's age o

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NOTE: GH therapy will NOT be approved for idiopathic short stature. For patients > 21 years old, therapy will be approved if any of the following criteria are met: If the patient has evidence of hypothalamic-pituitary disease or structural lesions/trauma to the pituitary, including pituitary tumor, pituitary surgical damage, trauma, or cranial irradiation (this structural pituitary disease can be diagnosed either in childhood or adulthood) AND meets any one of the following: · Has failed at least one GH stimulation test · Has at least one documented low IGF-1 level · Has deficiencies in 3 or more pituitary axes NOTE: For recipients diagnosed in childhood with hypothalamic-pituitary disease or structural lesions/trauma to the pituitary who have a past history of GH use, no retesting is necessary. If the patient has failed two GH stimulation tests (abnormal response is defined as peak growth hormone level less than 5 ng/mL), OR has failed one GH stimulation test and has a documented low IGF-1 level. Criteria Discussion: o A question was asked as to why an individual would require GH in adulthood (after epiphyses close). Dr. Steelman responded that, while GH levels decline in adulthood, GH still has an impact on bone mass, lipids, and other metabolic functions. o Dr. Steelman recommended a change to the criteria for GHD pediatric patients from "normalization of height velocity" to "height velocity within normal range for patient's age or bone age." o Discussion took place around coverage of GH for ISS. Dr. Steelman recommended that GH be covered for patients >2.25 SD below the mean in height for age and gender who have non-delayed skeletal maturation and predicted height < 63 inches for boys and < 59 inches for girls. It was pointed out that clinical studies examining the impact of GH on children with ISS only showed an increase of 2-7 cm in final height, and failed to show any difference in social/emotional well-being. o A motion was made to accept the proposed criteria with the inclusion of Dr. Steelman's recommended wording regarding height velocity for pediatric GHD, and the provision that the State would consider including Nutropin® (if cost-effective to do so) given its additional indication for use in CRI. o The motion passed.

Endocrine: Insulin-Like Growth Factor-1 (IGF-1) Hormones · Background Info/Recommendation: o There are currently two insulin-like growth factor-1 (IGF-1) products available: Iplex® and Increlex®. The products are indicated for the treatment of growth failure in children with severe primary IGF-1 deficiency, or in children with growth hormone gene deletion who have developed neutralizing antibodies to GH. o IGF-1 binds to receptors in target tissues, resulting in statural growth, as well as stimulating metabolic pathways involved in the uptake of glucose, fatty acids, and amino acids to support growing tissues. o Common adverse events associated with IGF-1 agents include: hypoglycemia (31-42% incidence), hypertrophy of tonsils and/or adenoids, headache, dizziness, vomiting, arthralgia, injection site reactions, otitis media, and bone or limb pain. o No head-to-head comparative trials have been performed among the IGF-1 products. o Current guidelines do not address IGF-1 deficiency or the role of IGF-1 hormones.

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Both IGF-1 hormones have been shown to be safe and effective in the treatment of IGF-1 deficiency and in the treatment of patients with GH gene deletion who have developed neutralizing antibodies to GH. Therefore, these agents can be considered therapeutic alternatives to one another; however, in order to ensure appropriate use of these agents, it is recommended that they be subject to clinical criteria. Discussion o It was pointed out that Iplex® is no longer available. Given this information, it was suggested that the wording of the recommendation be changed to "Increlex® has been shown to be safe and effective in the treatment of IGF-1deficiency and in the treatment of patients with GH gene deletion who have developed neutralizing antibodies to GH. However, in order to ensure appropriate use of this agent, it is recommended that it be subject to clinical criteria." o A recommendation was made to move Increlex® to preferred, while keeping the clinical criteria in place. A question was asked as to whether TennCare would be able to collect rebates if Increlex® were listed as preferred on the PDL. David Beshara responded that this category was not contracted on. o A motion was made to accept the recommendation with the omission of Iplex® and the related wording changes described above. o The motion passed. Proposed Clinical Criteria for Increlex® o Will be approved for children (< 21 years old) with a diagnosis of either: Growth failure due to severe primary IGF-1 deficiency ­ Must have documentation of low IGF-1, OR Growth hormone gene deletion in a patient who has developed neutralizing antibodies to GH. IGF-1 hormones will not be approved for individuals with closed epiphyses. Criteria Discussion o A motion was made to approve the recommended criteria. o The motion passed.

Endocrine: Growth Hormone Releasing Hormone Agents · Background Info/Recommendation: o GHRH directly stimulates the pituitary gland to release GH. There is currently one growth hormone-releasing hormone (GHRH) agent available: sermorelin (Geref®). o Sermorelin is indicated for the treatment of idiopathic growth hormone deficiency in children with growth failure. It is also used as a diagnostic test for evaluating the ability of the pituitary to secrete GH. o Common adverse events associated with the use of sermorelin include: injection site reactions, headache, flushing, nausea, vomiting, dysphagia, dizziness, hyperactivity, somnolence, and urticaria. o There are few large randomized, controlled clinical trials examining the effects of sermorelin. One trial involving 60 patients with GHD randomized patients to treatment with sermorelin 30 mcg/kg/day, sermorelin 60 mcg/kg/day, or growth hormone 0.1 IU/kg/day. After 6 months, the study found that individuals experienced significantly more growth with GH than sermorelin (p<0.01). In addition, height velocity was higher for the GH-treated patients (14.6 cm/year compared to 9.2 to 9.3 cm/year with sermorelin). o Current guidelines do not address the role of GHRH agents in the treatment of GHD. Sermorelin has been shown to be safe and effective in the treatment of idiopathic GHD in children. However, given the greater effectiveness of GH agents in promoting growth,

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and the low utilization of this product, it is recommended that sermorelin be considered second-line therapy. Discussion o A question was posed as to whether TennCare had any utilization of this agent. Dr. Woods responded that there had been no utilization in first quarter of 2007. o A motion was made to accept the recommendation as proposed. o The motion passed.

Endocrine: Agents for Acromegaly · Background Info/Recommendation: o Acromegaly is an uncommon disorder (3 to 4 cases per 1 million) characterized by hypersecretion of growth hormone. In more than 95% of cases, the source of GH hypersecretion is a pituitary somatotroph adenoma. First line treatment for acromegaly is surgery. For patients who are not candidates for surgery or who have had an incomplete response to surgery, pharmaceutical management is recommended. o The two main pharmaceutical agents used for the treatment of acromegaly are octreotide and pegvisomant. Octreotide is a somatostatin analogue, which reduces levels of GH and IGF-1. In addition, octreotide inhibits the release of serotonin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide. As a result, octreotide is approved for the treatment of carcinoid tumors and VIPomas. It is also used off-label for GI fistulas and relief of diarrhea associated with a variety of conditions including: AIDS, short bowel syndrome diabetes, pancreatic cholera syndrome, and chemotherapy/radiation. Pegvisomant is a GH receptor antagonist, which competes with endogenous GH for receptor binding. By blocking GH receptor dimerization and subsequent signaling, it also results in reduction of IGF-1. There are no long-term outcomes studies available for these drugs at this time. According to the 2004 American Association of Clinical Endocrinologists (AACE) Acromegaly Guidelines, surgical treatment is first line for virtually all patients with acromegaly. However, for those who are unwilling to undergo surgery or who are not candidates for surgery, somatostatin analogs (e.g., octreotide) are recommended as the drugs of choice. The AACE recommends that pegvisomant be reserved for individuals in whom treatment with a somatostatin analogue has proven ineffective. Octreotide and pegvisomant represent useful options for the treatment of acromegaly in recipients who are not candidates for surgery, or who fail to achieve a complete response from surgery. These agents have unique mechanisms of action and distinct side effect profiles. Furthermore, octreotide has additional uses in the treatment of carcinoid tumors, VIPomas, fistulas, and diarrhea. Therefore, these agents cannot be considered therapeutic alternatives. Current AACE guidelines for acromegaly recommend that octreotide be used as first-line pharmacologic therapy, with pegvisomant reserved for individuals who fail to respond to octreotide. Based on this information, pegvisomant should be considered second-line therapy behind octreotide. · Discussion: o A motion was made to accept the recommendations as proposed. o The motion passed. Endocrine: Disease Modifying Anti-Rheumatic Drugs (DMARDs) · Background Info/Recommendation:

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Disease modifying anti-rheumatic drugs (DMARDs) are agents that have been shown to improve symptoms, reduce or prevent joint damage, and preserve function in patients with rheumatoid arthritis. Based on current treatment guidelines, all patients with RA should be started on DMARDs within 3 months of their diagnosis. The available DMARDs vary in their effectiveness, safety, and onset of action. Methotrexate (MTX) ­the most commonly prescribed DMARD. Due to its favorable efficacy and toxicity profile, low cost, and established track record in the treatment of RA, MTX has become the standard against which new RA treatments are evaluated. Onset of action is usually 6 to 8 weeks. Leflunomide (Arava®) - alternative to methotrexate which displays similar efficacy. It is often used in combination with MTX to achieve a greater response than either agent alone. Onset of action is usually 6 to 8 weeks. Sulfasalazine ­effective DMARD for mild RA. Its favorable side effect profile makes it an attractive agent for use in early disease or in combination with other DMARDs. Onset of action 2 to 3 months. Hydroxychloroqine ­useful in mild RA or in combination with other DMARDs, but it does not slow radiologic progression to the extent other DMARDs do, and has a slow onset of action (2 to 4 months). Penicillamine ­rarely prescribed due to its slow onset of action (3 to 6 months) and toxic effects (leukopenia and autoimmune disorders). It is usually reserved for use in patients who have severe, active disease and who have failed to respond to an adequate trial of conventional therapy. Injectable gold (gold sodium thiomalate) ­effective DMARD; however, its difficult administration, long onset of action (3 to 6 months), and risk of toxicity (myelosuppression and proteinuria) result in this product being reserved for those who have failed conventional therapy. Oral gold (Ridaura®) ­ less effective than injectable gold; however it is better tolerated. For this reason, oral gold is typically used for early mild RA or in combination with other DMARDs. Onset of action is 4 to 6 months. There are several head-to-head trials that have examined the effects of DMARDs on RA progression/symptoms: Leflunomide vs. MTX - This study randomized 482 patients with RA to receive either leflunomide (20 mg daily), methotrexate (7.5 to 15 mg weekly), or placebo. Leflunomide and MTX displayed similar efficacy; however, leflunomide was associated with a higher incidence of liver enzyme elevations. MTX vs. oral gold ­ This study randomized 281 patients with RA to receive either low-dose oral MTX or auranofin. Patients receiving MTX exhibited earlier response and greater improvement compared to oral gold. In addition, auranofin was associated with more adverse events and withdrawals. Oral gold vs. injectable gold ­ This study randomized 122 patients with RA to receive either auranofin or injectable gold. No differences were observed in efficacy between the two groups; however, injectable gold was associated with higher rates of rash and pruritus, as well as higher withdrawal rates due to adverse reactions, than oral gold. Oral gold vs. penicillamine ­ This study looked at 90 patients with RA who were randomized to auranofin 6 mg/day or D-penicillamine 250 mg/day (increased to 750 mg/day). D-penicillamine was shown to be more effective than oral gold, but was also associated with more adverse events and withdrawals. Current guidelines from the American College of Rheumatology recommend that DMARDs be initiated within 3 months of diagnosis of RA. If the patient exhibits ongoing disease after 3 months of maximal therapy with the DMARD, the guidelines

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recommend that MTX be tried (either alone or in combination with the initial DMARD), if not used already. If the patient exhibits on-going disease after an adequate trial of MTX, the guidelines recommend addition of another DMARD or a biologic agent. The DMARDs are an important class of medications for the treatment of RA due to their ability to improve symptoms, reduce or prevent joint damage, and preserve function. However, the various DMARDs differ substantially in their efficacy, safety, and onset of action. Methotrexate has been proven to be effective, particularly in patients with severe disease. In addition, its relatively low toxicity allows for its long-term use (often beyond 3 years). Leflunomide exhibits similar efficacy to MTX, but is associated with higher rates of hepatotoxicity. However, it represents a valuable treatment option for those who cannot tolerate MTX or who experience an inadequate response to MTX. Sulfasalazine and hydroxychloroquine, although not as effective as MTX, have favorable safety profiles and represent reasonable options for individuals with mild disease. Penicillamine and the gold salts (both oral and injectable) can be considered inferior agents to the other DMARDs due to their toxicity and slow onset of action. Discussion: o A motion was made to accept the recommendations as presented. o A comment was made that the recommendation did not allow for gold therapy. It was pointed out that gold was less toxic than many of the other alternatives. o The motion was restated to accept the recommendation with the inclusion of oral gold as a preferred agent (along with methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine). o The motion was approved.

Endocrine: Immunomodulators · Background Info/Recommendation: o The available immunomodulators target two different types of chemical modulators in the body: cytokines (including tumor necrosis factor- (TNF-) and interleukin-1), and cell-adhesion molecules. By inhibiting these chemical modulators, the immunomodulators inhibit the inflammatory processes involved in several chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and Crohn's disease. o The immunomodulators vary in their FDA-approved indications: Rheumatoid arthritis: abetacept, adalimumab, anakinra, etanercept, infliximab Juvenile rheumatoid arthritis: etanercept Ankylosing spondylitis: adalimumab, etanercept, infliximab Plaque psoriasis: alefacept, efalizumab, etanercept, infliximab Psoriatic arthritis: adalimumab, etanercept, infliximab Crohn's disease: adalimumab, infliximab Ulcerative colitis: infliximab o Due to their mechanism of action, all immunomodulators are associated with an increase in the risk of infection (including serious and sometimes fatal infections). In addition, injection site reactions or infusion reactions are common. Infusion reactions tend to be more frequent with infliximab due to the fact that it is a chimeric monoclonal antibody (rather than a fully human monoclonal antibody). o Numerous studies have established the efficacy of the immunomodulators over placebo; however, no head to head studies are currently available. o Current guidelines from the American College of Rheumatology (2002) recommend that the immunomodulators be reserved for individuals with RA who have a suboptimal response to methotrexate (or other DMARD). In addition, a 2004 consensus statement

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from an expert panel of rheumatologists from 20 countries worldwide with expertise in the use of biological agents in the treatment of rheumatic disease echoed this recommendation. They stated that TNF blockers are recommended for the treatment of active RA, psoriatic arthritis, ankylosing spondylitis, and juvenile chronic arthritis after using another DMARD. o With regards to the use of immunomodulators in psoriatic arthritis, the 2006 NICE guidelines recommend etanercept for the treatment of severe active psoriatic arthritis in individuals who have not responded to at least two standard DMARDs. Infliximab is recommended for individuals who are intolerant of, or have contraindications to, treatment with etanercept, or who have trouble with self-administered injections. o With regards to the use of immunomodulators in psoriasis, the 2006 NICE guidelines recommend etanercept for the treatment of plaque psoriasis in individuals who have a Psoriasis Activity Severity Index (PASI) of 10 or more, and who have failed to respond to standard therapies, including cyclosporine, methotrexate, psoralen, and PUVA. These guidelines also state that efalizumab should be reserved for individuals failing to respond to treatment with (or intolerant of) etanercept. o According to the American Gastroenterological Association Institute position statement on inflammatory bowel disease, infliximab is recommended for treatment of moderately to severely active Crohn's disease or ulcerative colitis in patients who have not responded to adequate therapy with a corticosteroid or an immunosuppressant agent (azathioprine, 6-MP, or methotrexate). These guidelines also recommend use of infliximab in treatment of Crohn's disease with fistulas in patients who have not responded to treatment with antibiotics, surgical drainage, and/or immunosuppressive therapy. The available immunomodulators have been shown to be effective in the treatment of a variety of inflammatory disorders, including rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, ankylosing spondylitis, psoriasis, Crohn's disease, and ulcerative colitis. However, given the increased risk of infections and the high costs of these agents, it is recommended that they be subject to clinical criteria to ensure their appropriate use. · Since differences exist in the mechanism of action and safety profiles of the various immunomodulators, individuals should be approved only for agents that are FDAapproved for the requested diagnosis. (Note: off-label use can be granted if the physician provides sufficient documentation supporting the off-label use via the PA process.) · Based on the available clinical data, Kineret® appears to exhibit somewhat lower efficacy and higher toxicity compared to the other immunomodulators. Furthermore, it is dosed on a daily basis, which can lead to more injection site reactions and noncompliance. For these reasons, Kineret® can be considered an inferior agent within this class. · Among the TNF- inhibitors (Enbrel®, Humira®, and Remicade®), these agents have exhibited similar efficacy and safety in RA, psoriatic arthritis, and ankylosing spondylitis, and can thus be considered therapeutic alternatives to one another for these indications. In addition, the data suggests that these agents display better efficacy and tolerability than Kineret® and can be considered superior agents within the class. Since Remicade® is not able to be self-administered, it is recommended that at least Enbrel® or Humira® be made available. Discussion: o A comment was made that the new approach to RA is to treat the patient hard and early. o A motion was made to accept the recommendations as proposed. o The motion passed. Proposed Criteria for the Immunomodulators:

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For a diagnosis of Plaque Psoriasis: Enbrel® or Raptiva® will be approved for patients meeting the following criteria: Diagnosis of chronic, moderate to severe plaque psoriasis Treatment failure with at least 2 topical treatments (corticosteroids, calcipotriene, coal tar, tazarotene, anthralin) and at least one oral treatment (Soriatane®, methotrexate, cyclosporine), unless contraindicated Length of authorization: Initial PA of 6 months, and yearly thereafter if medication is well tolerated. For continuation of therapy after the initial PA, a 50% reduction of total Psoriasis Area Severity Index (PASI) score must be achieved. o For a diagnosis of Rheumatoid Arthritis: Enbrel®, Humira®, or Kineret® will be approved for patients meeting the following criteria: Patient must have failed or been intolerant to therapy with glucocorticoids (unless absolutely contraindicated by severe brittle diabetes, severe osteoporosis, etc.) AND methotrexate (unless there is a documented absolute contraindication such as alcohol abuse, cirrhosis, chronic liver disease). For recipients who have a contraindication to methotrexate, another DMARD must be tried and failed. o For a diagnosis of Ankylosing Spondylitis: Enbrel®, Remicade®, Humira® will be approved for patients meeting the following criteria: Patient must have failed an adequate trial of two NSAIDs (unless contraindicated). o For a diagnosis of Psoriatic Arthritis: Enbrel® or Humira® will be approved for patients meeting the following criteria: Patient must have failed an adequate trial of methotrexate (unless contraindicated) o For a diagnosis of Juvenile Rheumatoid Arthritis (JRA): Enbrel® will be approved. For JRA patients that have persistent arthritis into adulthood, the patient must meet the same criteria as the Rheumatoid Arthritis criteria listed above. o For a diagnosis of Crohn's Disease: Humira® will be approved. Criteria Discussion o Clarification was requested as to whether an individual would need to try and fail a preferred agent prior to being able to obtain a non-preferred agent. Dr. Woods responded that this was the intent (preferred agents first). A suggestion was made to specify in the RA criteria that Enbrel® and Humira® would be first line over Kineret® (given that Kineret® is less effective and more toxic than other immunomodulators). o A suggestion was made to remove Remicade® from the Ankylosing Spondylitis criteria since it is given via an IV infusion (non-self-injectable). o A motion was made to accept the criteria with the recommended changes. o The motion passed. o

Endocrine: Anabolic Steroids · Background Info/Recommendation: o Anabolic steroids are synthetic derivatives of testosterone which exert actions similar to those of male sex hormones. All agents are classified as C-III controlled substances. There are 3 anabolic steroids available: nandrolone, oxandrolone, and oxymetholone. o The FDA-approved indications for the available anabolic steroids are as follows: Nandrolone decanoate - management of anemia of renal insufficiency Oxandrolone - relief of bone pain accompanying osteoporosis, offset protein catabolism associated with prolonged administration of corticosteroids, promote weight gain after weight loss following extensive surgery, chronic infection, or

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· ·

severe trauma (and in some patients who, without definite pathophysiologic reasons, fail to gain/maintain weight). Oxymetholone - treatment of anemias caused by deficient red blood cell production o The anabolic steroids are also used for many off-label uses, including HIV/AIDS wasting (for nandrolone and oxymetholone), alcoholic liver disease, short stature associated with Turner syndrome, constitutional delay of growth and puberty, Duchenne and Becker muscular dystrophy, breast cancer, and enhancement of athletic performance. o The anabolic steroids are associated with many adverse effects. Among the most common are: acne, hirsuitism, gynecomastia, changes in libido, weight gain, deepening of the voice, decreased glucose tolerance, menstrual irregularities (women), oligospermia/impotence (men), premature epiphyseal closure (children), insomnia, and retention of electrolytes/edema. In addition, use of anabolic steroids has been associated with the development of hepatocellular neoplasms, peliosis hepatitis, and blood lipid changes (increased LDL/decreased HDL). o There are no head to head trials comparing the various anabolic steroids at this time. o Few treatment guidelines address the appropriate use of anabolic steroids. The Mayo Clinic treatment guidelines for HIV-wasting include anabolic steroids as a treatment option to improve muscle strength and body composition. The available anabolic steroids differ in their approved indications and clinical utility; therefore, they cannot be considered therapeutic alternatives to one another. Due to the serious adverse events associated with the use of anabolic steroids, as well as their potential for misuse/abuse, it is recommended that all agents in this class be subject to clinical criteria in order to ensure that they are being used appropriately, and that the patient is being properly monitored. Discussion: o A motion was made to approve the recommendation as proposed. o The motion passed. Clinical Criteria for the Anabolic Steroids o Requests for Anadrol® (oxymetholone) will be approved for patients meeting all of the following criteria: The recipient has a diagnosis of one of the following: · Anemias caused by deficient red blood cell production · Acquired or congenital aplastic anemia · Myelofibrosis · Hypoplastic anemias The recipient does not have severe hepatic dysfunction. The recipient does not have prostate cancer or breast cancer (if male), or breast cancer with hypercalcemia (if female). Note: Anadrol® will not be approved for use in enhancing athletic performance. o Requests for Oxandrin® or oxandrolone will be approved for patients meeting all of the following criteria: The recipient is using the drug for one of the following indications: · To promote weight gain after weight loss following extensive surgery, chronic infection (including HIV/AIDS wasting), or severe trauma including extensive burns · To offset protein catabolism associated with prolonged administration of corticosteroids · To relieve bone pain associated with osteoporosis The recipient does not have hypercalcemia.

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·

The recipient does not have prostate cancer or breast cancer (if male), or breast cancer with hypercalcemia (if female). Note: Oxandrin® and oxymetholone will not be approved for use in enhancing athletic performance. Criteria Discussion: o A comment was made that even though there is risk of abuse of these agents, they can be extremely useful for select patients. o A suggestion was made to omit the bullet point allowing use of anabolic steroids in patients with bone pain associated with osteoporosis. A comment was made that estrogens are not used in osteoporosis anymore due to concerns over clots, so anabolic steroids may be beneficial in certain patients. o A motion was made to accept the recommendation as proposed. o The motion passed (1 opposed).

Endocrine: Androgens · Background Info/Recommendation: o There are 3 different androgens available: testosterone, methyltestosterone, and fluoxymesterone. All are indicated for the treatment of hypogonadism and delayed puberty in males, and for the treatment of metastatic breast cancer in females. o The androgens stimulate receptors in organs and tissues to promote growth and development of the male sex organs and to maintain secondary sex characteristics in androgen-deficient males. o The major difference between the available androgens is the route of administration, dosage forms, and adverse effects (related to route of administration). Methyltestosterone and fluoxymesterone are given orally, and as a result, are associated with higher rates of hepatic toxicity than the testosterone products. Testosterone is rapidly inactivated by first-pass metabolism, and therefore, cannot be administered orally. Instead it is available as an intramuscular suspension, subcutaneous implant, transdermal patch, topical gel, or buccal system. Studies have shown similar efficacy between the various dosage forms of testosterone (although side effects may differ). o Common side effects associated with androgens include gynecomastia, acne, hirsuitism, male pattern baldness, changes in libido, headache, dizziness, alterations in liver function, and amenorrhea in women. In addition, injection site reactions are common with the injectable formulations, and dermatologic reactions are common with the gel and patch formulations. o There are no head-to-head comparative trials between the various androgens. o Current clinical literature recommends against using methyltestosterone or fluoxymesterone due to the greater potential for hepatotoxicity with these products. The 2002 AACE Guidelines for the Treatment of Hypogonadism in Adult Male Patients recommend testosterone therapy for patients with hypogonadism. No preferred method of delivery is listed. The available testosterone products have been shown to exhibit similar efficacy and safety in the treatment of hypogonadism and delayed puberty in males, and can thus be considered therapeutic alternatives to one another. In order to allow for patient and prescriber choice, it is recommended that at least one buccal and at least one transdermal testosterone product be available on the PDL. Methyltestosterone and fluoxymesterone are associated with greater hepatotoxicity than the testosterone products, and current guidelines for the treatment of hypogonadism recommend against using these products. Therefore, methyltestosterone and fluoxymesterone can be considered inferior agents within this category.

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Discussion: o A motion was made to accept the recommendation as presented. o The motion was accepted.

Endocrine: Luteinizing Hormone-Releasing Hormones · Background Info/Recommendation: o This class consists of two agents: nafarelin acetate (Synarel®) and leuprolide acetate (Lupron®). Both Synarel® and Lupron® are potent gonadotropin-releasing hormone (GnRH) agonists. When therapy is first initiated, these agents stimulate the release of the pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH); however repeated dosing results in an inhibitory effect on the release of gonadotropins from the pituitary. o Synarel® and Lupron® are both used for the management of endometriosis, including pain relief and reduction of endometriotic lesions, and for the treatment of central precocious puberty. Lupron® is also indicated for palliative treatment of advanced prostatic cancer and preoperative hematologic improvement of patients with anemia caused by uterine leiomyomata (given along with iron therapy). o There are no long-term outcomes studies with Synarel® or Lupron®. o Based on guidelines from the American College of Obstetricians and Gynecologists (ACOG) regarding medical management of endometriosis, treatment with a gonadotropin-releasing hormone (GnRH) agonist for at least 3 months or with danazol for at least 6 months is recommended for pain relief in most patients. No recommendation is made as to which GnRH is preferred. No treatment guidelines could be found regarding central precocious puberty. Current literature on the treatment of endometriosis and central precocious puberty recommends use of a GnRH agonist, but does not specify an agent of choice. Lupron® and Synarel® have different routes of administration and side effect profiles, and Lupron® has additional FDA-approved indications. In order to provide for patient and prescriber choice, it is recommended that both agents be made available. · Discussion: o A question was posed as to whether these agents are self-administered. It was pointed out that they can be self-administered or the IM injection can be given by a caregiver. o A motion was made to accept the recommendation as proposed. o The motion was approved. Cardiovascular: Lipotropics ­ High Potency Statins · Background Info/Recommendation: o The high potency statins are the most effective class of drugs for lowering LDL cholesterol concentrations, and all agents in this class produce dose-dependent LDL lowering. There are numerous studies available which have found the use of statins to be associated with reduced morbidity and mortality, including reduced incidence of cardiovascular events. o The statins competitively inhibit HMG-CoA reductase, the enzyme responsible for catalyzing the rate-limiting step in cholesterol biosynthesis. Inhibition of cholesterol biosynthesis results in lower cholesterol levels in the liver, increases synthesis of LDLreceptors, and thus, increases uptake of LDL from the bloodstream. In addition, statins decrease production of VLDL particles, a precursor for LDL. o The high potency statins have been found to produce the following effects on lipids: Drug Change in Change in Total Change in Change in

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atorvastatin (Lipitor ) rosuvastatin (Crestor®) simvastatin (Zocor®) simvastatin/ezetimibe (Vytorin®) o

®

LDL -25% to -60% -35% to -60% -20% to -50% -35% to -60%

Cholesterol -25% to -45% -30% to -45% -20% to -40% -30% to -45%

HDL +0.1% to + 9% + 8% to +14% + 3% to +16% + 6% to +12%

Triglycerides -17% to -37% -10% to -35% -9% to -34% -23% to -35%

·

Numerous comparative trials have examined the impact of statins on cardiovascular outcomes. Both atorvastatin and simvastatin have been shown to significantly improve all-cause and cardiovascular mortality in large, double-blinded, placebo-controlled trials. No large outcomes trials are available for rosuvastatin and simvastatin/ezetimibe; however, similar lipid-lowering effects compared to atorvastatin would suggest that they would provide similar cardiovascular benefits. o According to the ATP-III guidelines, statins should be considered first line drugs when LDL-lowering drugs are indicated to achieve LDL treatment goals. Among the high potency statins, all agents in this class result in similar effects on lipids when dosed in equivalent doses. Simvastatin appears to produce lower maximum reductions in LDL and total cholesterol compared to atorvastatin, rosuvastatin and simvastatin/ezetimibe; however, it is a reasonable option for individuals requiring less than a 50% reduction in LDL from baseline. Atorvastatin, rosuvastatin, or simvastatin/ezetimibe should be available to individuals requiring more than a 45% reduction in LDL. Discussion: o A comment was made that a high potency statin (not including simvastatin) should be available as a preferred, unrestricted agent on the PDL. o A recommendation was made to have simvastatin added to the short list (AutoExemption list). It was expressed that this would help to keep simvastatin utilization up. o It was pointed out that an LDL goal < 70 would be almost impossible to achieve without a high potency statin. Simvastatin as the sole preferred agent would not be clinically acceptable. o A written comment was read from Dr. Baker (the cardiologist on the PAC) stating that he was upset with the recommendation, felt his time could be better used elsewhere, and saw his future involvement with the committee as "tenuous at best." o Concern was expressed over the PA process for high potency statins being tedious to prescribers. In addition, it was suggested that patients in rural areas may have trouble getting their medications if they are required to wait on a PA approval. o A question was posed as to whether it would be acceptable to the Committee to have simvastatin and Crestor available as preferred agents (without any PA). The Committee stated that they would need to have at least one high potency statin, so Crestor plus simvastatin would be acceptable; however, it was pointed out that Crestor has less outcomes data than some of the other statins. o David Beshara mentioned that TennCare gets out-marketed by the pharmaceutical companies, and there are patients who require < 45% reduction in LDL who jump right to a branded high potency statin product. o A motion was made to accept the recommendation, but require no step therapy on Crestor. Dr. Woods asked if the motion could be reworded to request that at least one of the 3 high potency statins (rosuvastatin, atorvastatin, or simvastatin/ezetimibe) be available unrestricted as a preferred agent on the PDL The Committee agreed to this request.

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·

·

o The motion was approved. Proposed Clinical Criteria: o High potency statins (Crestor®, Vytorin®, and Lipitor®) will be approved only for recipients who meet one of the following criteria: Have tried and failed to achieve goal lipid levels following an adequate trial of simvastatin Require greater than a 45% reduction in LDL from baseline Have a contraindication or intolerance to simvastatin NOTE: All recipients currently receiving Crestor® 20 mg or 40 mg, Lipitor® 40 mg or 80 mg, or Vytorin® 10/40 mg or 10/80 mg will be allowed to remain on their current therapy (via indefinite grandfathering). Criteria Discussion: o It was pointed out that if the Committee's recommendation was accepted, there would not be a need for step therapy criteria for the high potency statins. However, the criteria would be discussed in case the State decided to implement it. o A suggestion was made to specify that contraindication or intolerance to simvastatin would be an appropriate reason to approve Vytorin®. o A comment was made commending First Health for including information about grandfathering in the criteria. o A question was posed as to whether it would be useful to include Crestor® 10 mg among the products to be grandfathered. The Committee pointed out that they considered Crestor® 10 mg high potency, so it should be included among the agents to be grandfathered. o A motion was made to approve the criteria with the recommended changes. o The motion passed.

Cardiovascular Agents: Statin/CCB Combinations · Background Info/Recommendation: o Caduet® (atorvastatin/amlodipine) is intended for use in patients for whom treatment with both amlodipine and atorvastatin is deemed appropriate. Amlodipine is indicated for the treatment of hypertension, treatment of chronic stable or vasospastic angina, and to reduce hospitalization in patients without heart failure who have recently angiographically documented CAD. Lipitor is indicated for the treatment of patients with hyperlipidemia. o The statins competitively inhibit HMG-CoA reductase, the enzyme responsible for catalyzing the rate-limiting step in cholesterol biosynthesis. Inhibition of cholesterol biosynthesis results in lower cholesterol levels in the liver, increases synthesis of LDLreceptors, and thus, increases uptake of LDL from the bloodstream. Amlodipine inhibits calcium ions from entering cells, resulting in decreased mechanical contraction of cardiac and smooth muscle, dilation of the arteries, a decrease in peripheral resistance, decreased blood pressure, and decreased afterload. o Caduet® has been shown to result in lipid changes comparable to those seen with Lipitor® (atorvastatin): 25 - 60% reduction in LDL, 0.1 - 9% increase in HDL, and 17-37% decrease in triglycerides. In addition, Caduet® has been shown to lower blood pressure comparable to Norvasc® (amlodipine): reduction in systolic blood pressure ~17-25 mm Hg, reduction in diastolic blood pressure ~10-17 mm Hg. o No long-term outcomes studies have been performed with Caduet® at this time. o According to the ATP-III guidelines, statins should be considered first line drugs when LDL-lowering drugs are indicated to achieve LDL treatment goals. According to the JNC-VII guidelines for hypertension, CCBs are first line therapy (in combination with

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· ·

·

ACE inhibitors or beta-blockers) for high-risk CHD patients and diabetic patients. For patients who do not have high risk CHD or diabetes, CCBs are appropriate add-on therapy if blood pressure is not controlled on a thiazide diuretic or other recommended first line agent. Caduet® produces lipid lowering effects similar to those seen with the other high potency statins. In addition, Caduet® produces blood pressure lowering effects comparable to those seen with amlodipine. However, given the product's high cost and the challenges associated with titrating individuals to the proper dose of atorvastatin and amlodipine on the fixed dose combination product, it is recommended that Caduet® be subject to clinical criteria. Discussion: o A motion was made to accept the recommendation as proposed. o The motion was approved. Proposed Clinical Criteria for Caduet®: o Caduet® will only be authorized for recipients who: Are receiving amlodipine therapy, AND Have tried and failed, or have a contraindication or intolerance to, simvastatin plus one other high potency statin Criteria Discussion: o A suggestion was made to change the wording of the criteria so that it requires trial and failure of 2 preferred agents, rather than simvastatin plus one other preferred statin. o A motion was made to accept the criteria as presented, and if Lipitor® is preferred on the PDL, revisit this criteria. o The motion passed.

Cardiovascular Agents: Lipotropics ­ Cholesterol Absorption Inhibitors · Background Info/Recommendation: o There is currently one cholesterol absorption product available, Zetia® (ezetimibe). This product inhibits absorption of both dietary cholesterol and cholesterol in the bile. As a result, this product results in reductions in LDL, total cholesterol, and triglycerides, and elevates HDL. It can be used alone or in combination with other lipid lowering medications. When used with statins or other cholesterol lowering agents, Zetia® has been found to exhibit a synergistic effect. o Zetia® inhibits cholesterol absorption along the brush border of the small intestine, reducing delivery of intestinal cholesterol to the liver. This results in decreased cholesterol stores, increased cholesterol uptake from the blood, and ultimately, reductions in LDL, total cholesterol, triglycerides, and apolipoprotein B, as well as slight increases in HDL. o Use of Zetia® has been found to result in the following lipid changes: Drug Regimen Zetia® monotherapy Addition of Zetia® to ongoing statin therapy Addition of Zetia® to ongoing bile acid sequestrant therapy Change in LDL -18% -25% -19% Change in Total Cholesterol -12% to -13% -17% -18% Change in HDL +1% +3% 0% Change in Triglycerides -8% -14% -14%

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·

·

·

No long-term outcomes studies on the impact of Zetia® (ezetimibe) on cardiovascular morbidity and/or mortality are available at this time. o Zetia® (ezetimibe) was not available at the time the ATP-III guidelines were published. However, the 2004 NCEP update to the ATP-III guidelines lists ezetimibe as reasonable add-on therapy for those not achieving lipid goals on statin therapy alone, or for those who wish to achieve their lipid goals with a lower dose of statin. Zetia® (ezetimibe) is less effective than the available statins, producing only a small reduction in LDL (<20%) and triglycerides (<10%). For this reason, the use of Zetia® as monotherapy should be reserved for individuals who cannot tolerate or have a contraindication to a statin. However, Zetia® should be available for individuals requiring it in combination with other lipid lowering therapies, such as statins, bile acid sequestrants, fibrates, and niacin. Discussion: o A comment was made voicing agreement with having Zetia® subject to step therapy criteria, but suggesting that Zetia® be moved to the preferred side of the PDL. Concern was voiced over physicians and pharmacists not seeking the PA for Zetia® if it were listed on the non-preferred side of the PDL. o A motion was made to accept the recommendation with the movement of Zetia® to preferred on the PDL. o The motion was approved. Step Therapy Criteria for Zetia®: o For requests for Zetia® use as monotherapy (without any other lipid lowering medications), recipients must have tried and failed, been intolerant to, or have a contraindication to a statin. o Use of Zetia® in combination with a statin, bile acid sequestrant, fibrate, or niacin will be approved. Criteria Discussion: o A question was asked as to whether the criteria would involve an automatic look-back. Dr. Woods stated that a look-back could be done. o A question was posed as to whether there would be a dose requirement for previous statin use. Discussion took place around this issue - some individuals wanting to know that patients had tried higher doses of a statin before adding Zetia®, whereas others were concerned about patients with intolerance to higher doses of statins and requiring Zetia® use with a lower dose of statin. o A motion was made to accept the criteria as proposed. o The motion was approved. o

Cardiovascular Agents: Antihypertensives ­ Direct Renin Inhibitors · Background Info/Recommendations: o Tekturna® (aliskiren) is a new antihypertensive agent that, similarly to the ACE inhibitors and ARBs, targets the renin-angiotensin system. It serves as a direct renin inhibitor, preventing renin from cleaving angiotensinogen to angiotensin 1, and thus, inhibiting the subsequent conversion of angiotensin I to angiotensin II, a powerful vasoconstrictor. o Aliskiren is indicated for the treatment of hypertension, either alone or in combination with other antihypertensive agents. o Based on clinical trials, the usual (placebo-subtracted) range in blood pressure reduction observed with aliskiren monotherapy is as follows: 150 mg tablet: 4.8 to 9.3 mm Hg reduction in systolic blood pressure, and 2 to 5.4 mm Hg reduction in diastolic blood pressure

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o

300 mg tablet: 8.3 to 10.9 mm Hg reduction in systolic blood pressure, and 3.3 to 6.2 mm Hg reduction in diastolic blood pressure Comparative trials have been conducted with aliskiren and the following agents: Hydrochlorothiazide (HCTZ) - 2,776 patients were randomized to aliskiren (75, 150, or 300 mg), hydrochlorothiazide (6.25, 12.5, or 25 mg), or a combination of the two medications. Placebo-subtracted reductions in blood pressure are listed in the following table. HCTZ 0 mg -1.9/1.8 4.8/2 8.3/3.3 HCTZ 6.25 mg 3.5/2.1 6.8/3.8 7.8/3.4 -HCTZ 12.5 mg 6.4/3.2 8.2/4.2 10.1/5 12.3/7 HCTZ 25 mg 6.8/2.4 9.8/4.5 12/5.7 13.7/7.3

Aliskiren 0 mg Aliskiren 75 mg Aliskiren 150 mg Aliskiren 300 mg

Valsartan - 1,797 patients were randomized to either aliskiren (150 mg or 300 mg), valsartan (160 mg or 320 mg), or a combination of the two medications. Placebo-subtracted reductions in blood pressure are listed in the following table. Valsartan 0 mg -5.4/2.7 8.4/4.9 Valsartan 160 mg 5.6/3.9 10.0/5.7 -Valsartan 320 mg 8.2/5.6 -12.6/8.1

Aliskiren 0 mg Aliskiren 150 mg Aliskiren 300 mg

o

Current hypertension guidelines (JNC-VII) do not include the direct renin inhibitor class. o Tekturna® exhibits similar blood pressure reduction to the ARBs (as evidenced by the comparative trial vs. valsartan). As with the ARBs, this product may be useful for individuals who experience intolerance to an ACE inhibitor. Given the lack of long-term outcomes studies for Tekturna® compared to the large number of positive long-term outcomes studies for the ACE inhibitors and the ARBs, it is recommended that Tekturna® be reserved for cases where patients fail or are intolerant to an ACE inhibitor and/or ARB.

·

·

·

Discussion: o A comment was made that while there may be a potential benefit of this product over ACEs/ARBs, there are not sufficient studies available yet. A suggestion was made to table the decision on this agent for 6 months. o David Beshara pointed out that for the TennCare program, drugs that are non-preferred must have some sort of rationale for how a patient can obtain that drug. o A motion was made to accept the proposed recommendations, and bring this class back in 6 months for re-review. o The motion was approved. Proposed Clinical Criteria for Tekturna®: o Tekturna® will be approved for the treatment of hypertension in individuals who have failed to achieve their goal blood pressure on an adequate trial of an angiotensin-receptor blocker (ARB). o Tekturna® will also be approved for individuals with an intolerance to both ACE inhibitors and ARBs. Criteria Discussion:

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o o

A motion was made to accept the proposed criteria. The motion was approved.

Cardiovascular Agents: Oral Anticoagulants · Background Info/Recommendation: O Anticoagulants are used to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or embolization after MI. They are also used for the prophylaxis or treatment of venous thrombosis, pulmonary embolism, atrial fibrillation, or cardiac valve replacement. o Warfarin sodium is an anticoagulant that exerts its effect by blocking the regeneration of vitamin K(1) epoxide, thus inhibiting synthesis of vitamin K-dependent clotting factors which include factors 2, 7, 9 and 10, and the anticoagulant proteins C and S. o Hematologic adverse reactions are the major concern for anticoagulants, where fatal or nonfatal hemorrhage from any issue or organ may occur. Necrosis of skin and other tissues can appear within a few days at the start of therapy. Hepatitis, jaundice, and an elevation of liver enzymes may also occur. o There are several studies that have examined the anticoagulant agents: In 5 prospective randomized controlled clinical trials (AFASAK, SPAF, BAATAF, CAFA, and SPINAF) involving 3,711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke. The risk reduction ranged from 60% to 86%. The incidence of major bleeding in these trials ranged from 0.6% to 2.7%. Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2 to 4.5) or low INR (1.4 to 3). There was a significant reduction in minor bleeds at the low INR. WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1,214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. (But note that a lower INR was achieved and increased bleeding was associated with INRs above 4.) The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. All study endpoints, including decreased mortality, recurrent MI, and cerebrovascular events favored the warfarin study group. o Warfarin is often the oral anticoagulant used for outpatient treatment and prophylaxis of venous thrombosis and pulmonary embolism, treatment of patients with heart disease and embolization, prophylaxis of thrombosis in patients following myocardial infarction and prophylaxis of thrombosis in patients with congenital deficiency of antithrombin III, protein C or protein S. o Oral anticoagulants are used to prevent thrombotic events including MI, stroke and TIA. Warfarin is effective in preventing recurrent vascular events among patients with vascular disease. It is recommended that warfarin sodium products be available as preferred agents on the PDL. · Discussion: o A comment was made that it appeared that Jantoven® was significantly less costly than generic warfarin. A question was posed as to whether it would be appropriate to go with Jantoven® as the sole preferred agent in this category. o Dr. Hawkins replied that Jantoven® is the least utilized of the available warfarin products. Concern was voiced over the need to monitor a large number of patients if Jantoven were the sole preferred agent.

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o

o

A motion was made to accept the recommendation as proposed, with the provision that the State would consider placing Jantoven® the sole preferred agent if it were deemed cost-effective to do so. The motion was approved.

Cardiovascular Agents: Injectable Anticoagulants · Background Info/Recommendation: o There are two main types of injectable anticoagulants that are commonly used on an outpatient basis: low molecular weight heparins (LMWHs) and Selective Factor-Xa Inhibitors. o The approved indications are slightly different for each drug in this class. The FDAapproved indications are as follows: FDA-approved Indication Prophylaxis Hip Replacement Knee Replacement Hip Fracture Surgery Abdominal Surgery Immoble patients at risk for VTE Ischemic complications in ACS (Acute Coronary Syndrome) Ischemic complications in patients with unstable angina or non-Q-wave MI, when given with ASA VTE Treatment, when given with warfarin X X X X X X X X X X X X dalteparin (Fragmin®) enoxaparin (Lovenox®) tinzaparin (Innohep®) fondaparinux (Arixtra®)

X

X

X

X

o

o

o

o

Although not FDA-approved for this indication, fondaparinux does not cause Heparin Induced Thrombocytopenia (HIT) and may be used as a bridge to warfarin or as a means to provide VTE prophylaxis in patients with a history of HIT (recent or subacute). LMWHs work by binding to and potentiating the action of antithrombin III (AT-III), and thus inhibiting the action of Factor Xa. Fondaparinux works by selectively binding to and inhibiting ATIII, resulting in the neutralization of factor Xa. Because the LMWHs and fondaparinux target Factor Xa rather than thrombin, they do not require monitoring of partial thromboplastin time (PTT) as unfractionated heparin does. Hematological adverse reactions are the major concern for this group of drugs. Serious side effects associated with these agents include major bleeding, thrombocytopenia, elevations of AST/ALT, and injection site reactions. Several trials have examined the impact of LMWHs in both prophylaxis use and outpatient use. Below is a summary of the clinical trials.

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DRUG

dalteparin

Treatment: Recurrent VTE (%) Total Hip Total Knee Hip Fracture Replacement Replacement Surgery 4 - 30 -30 0-9

Prophylaxis: Development of post-operative DVT (%)

enoxaparin

6 - 38

19 - 37

19.1

3.3 - 4.1

fondaparinux tinzaparin

1.7 - 5.6 21 - 31

12.5 45

8.3 --

3.9 0-4.2

·

A meta-analysis of LMWH versus unfractionated heparins found that all agents were able to reduce mortality rates after acute DVT with similar safety and efficacy. O Studies in orthopedic surgery (hip fracture, hip replacement, and knee replacement) have found fondaparinux to be more effective than LMWHs at reducing the incidence of postoperative venous thromboembolism (VTE), although this benefit was accompanied by an increased risk of bleeding. For DVT prophylaxis, similar rates of thrombotic events and similar bleeding rates were seen between fondaparinux and the LMWHs. O The American College of Chest Physicians (ACCP) recommends the use of LMWHs or fondaparinux in prophylaxis and treatment of VTE. Although the various products differ in their FDA-approved indications, the ACCP makes no distinction between products for orthopedic surgery prophylaxis or treatment of VTE. Low molecular weight heparins (LMWHs) and selective factor-Xa inhibitors are effective agents at reducing the risk of venous thromboembolism. Based on the available clinical literature and treatment guidelines, these injectable anticoagulants all produce similar anticoagulant effects, display similar safety/tolerability, and have similar clinical utility; therefore, all agents in this class can be considered therapeutic alternatives to one another. Due to tinzaparin's limited FDA-approved indications, it can be considered inferior to the other products in this class. Given the extensive FDA-approved indications for enoxaparin and the role of fondaparinux in the treatment of patients with a history of HIT, these products can be considered superior among the agents in this class. Discussion: o A suggestion was made to incorporate a statement into the recommendation requiring that all FDA-approved indications be included among the preferred agents on the PDL. o A motion was made to accept the recommendation with the suggested change. o The motion was approved. O

Cardiovascular Agents: Antihypertensives ­ Peripherally-Acting Anti-Adrenergics · Background Info/Recommendations: o There are two main categories of products within the peripherally-acting anti-adrenergic class: alpha-adrenergic receptor blockers (doxazosin, prazosin, and terazosin) and postganglionic adrenergic blockers (reserpine). While the agents in this class are effective at

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reducing blood pressure, they are usually reserved for second- or third-line therapy due to the relatively high incidence of side effects, including orthostatic hypotension. Alphablockers may be reasonable first line therapy in select patients with concurrent benign prostatic hyperplasia (BPH). Reserpine may also be used in the treatment of certain psychiatric disorders (mainly agitated psychotic states in patients unable to tolerate phenothiazines or those who also require concomitant antihypertensive treatment), as well as in the treatment of thyrotoxicosis (off-label) in patients who are resistant to propranolol. Doxazosin, prazosin, and terazosin selectively block the alpha1-adrenergic receptors, resulting in decreased smooth muscle tone and systemic vascular resistance, and therefore, a reduction in blood pressure. Reserpine depletes catecholamine stores in the vesicles of sympathetic neurons, resulting in depression of sympathetic nerve function, and thus, a reduction in blood pressure and heart rate. Alpha-adrenergic blockers are commonly associated with orthostatic hypotension. Common adverse events seen with reserpine include orthostatic hypotension, dizziness, nasal congestion, lethargy, and psychiatric depression. In addition, reserpine has been linked to cardiac dysrhythmia, gastrointestinal hemorrhage, and thrombocytopenia. A report from the ALLHAT study examined differences in cardiovascular outcomes in adults >55 years old with hypertension and glucose disorders between treatment with chlorthalidone versus doxazosin. This analysis found no differences in all-cause mortality or incidence of MI among the two treatment groups. However, there was a difference in cardiovascular disease favoring use of chlorthalidone. In addition, a metaanalysis examining outcomes among the various anti-hypertensive medications found that low-dose diuretics reduced risks of CHF (RR 0.51) and cardiovascular events (RR 0.84) significantly more than alpha-blockers. According to the JNC-7 guidelines for hypertension, the peripherally-acting antiadrenergics are not recommended as first-line or compelling therapy; however, they represent a class of medications that do have utility as add-on therapy in individuals not meeting their goals on first-line agents. Alpha-blockers may be useful in individuals with BPH or other urinary outflow obstruction. o The peripherally-acting anti-adrenergics represent a group of medications mainly used as add-on therapy in individuals not responding adequately to other antihypertensive medications. The alpha-blockers represent a reasonable first-line treatment option in individuals with BPH or urinary outflow obstruction who do not have a "compelling indication" for another first line treatment (compelling indications set forth in the JNC-7 guidelines for hypertension). All alphablockers produce similar reductions in blood pressure and have similar tolerability; therefore, they can be considered therapeutic alternatives to one another. In order to ensure patient and prescriber choice, it is recommended that at least 2 alpha-blockers be made available. Reserpine should be reserved for patients not responding to other anti-hypertensive treatments, as it has the potential risk for serious side effects. Due to these safety concerns, reserpine can be considered an inferior agent within this category.

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Discussion o A request was made to specify that at least 3 generic agents be available among the preferred agents on the PDL. o A suggestion was made to include Cardura XR® among the non-preferred agents in this class (it had been omitted from this category). o A motion was made to approve the recommendation with the suggested changes. o The motion passed.

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Cardiovascular Agents: Antihypertensives ­ Ganglionic Blockers · Background Info/Recommendations: o There is currently only one ganglionic blocker available in the U.S.: Inversine® (mecamylamine). This agent is indicated for treatment of moderately severe to severe essential hypertension and/or treatment of uncomplicated cases of malignant hypertension. o Mecamylamine inhibits acetylcholine at the autonomic ganglia, resulting in a reduction in blood pressure in both hypertensive and normotensive individuals. o Mecamylamine is contraindicated in patients with mild to moderate, or labile hypertension, as well as in individuals with coronary insufficiency or recent MI. Mecamylamine is also contraindicated in patients with uremia or renal insufficiency manifested by an elevated BUN, patient receiving antibiotics and sulfonamides, patients with glaucoma, and patients with organic pyloric stenosis. Concomitant use with other antihypertensives requires a reduction in the dose of mecamylamine and/or the other agents in order to avoid excessive hypotension. Common adverse events associated with the use of mecamylamine include: orthostatic hypotension, dizziness, constipation, nausea, vomiting, xerostomia, sedation, and fatigue. Rare but serious adverse events associated with mecamylamine use include tremor, choreiform movements, mental aberrations, and convulsions (usually associated with large doses). o There are no large scale outcomes studies available for mecamylamine. o The JNC-7 guidelines for hypertension do not recommend mecamylamine as either first or second-line therapy for essential hypertension. According to JNC-7, most patients with blood pressures > 160/100 mm Hg (Stage 2 hypertension) should be started on dual therapy, usually involving a thiazide diuretic, ACE inhibitor or ARB, beta-blocker, or calcium channel blocker. o Inversine® (mecamylamide) should be reserved only for patients with severe essential hypertension or malignant hypertension who fail to respond to alternative antihypertensive therapies, such as thiazide diuretics, beta-blockers, ACE inhibitors/ARBs, and calcium channel blockers. Due to the numerous contraindications, drug interactions, and serious adverse events associated with the use of mecamylamide, this agent should be subject to clinical criteria ensuring that alternative therapies have been tried first. · Discussion: o A motion was made to accept the recommendations as proposed. o The motion was accepted. · Proposed Clinical Criteria for Inversine®: o Inversine® (mecamylamine) may be approved for individuals with moderately severe to severe essential hypertension and/or malignant hypertension who have tried and failed agents in at least two of the following anti-hypertensive medication categories: Thiazide diuretics ACE inhibitors or ARBs Beta-blockers Calcium channel blockers · Criteria Discussion: o A motion was made to accept the proposed criteria as presented. o The motion passed. Cardiovascular Agents: Antihypertensives ­ Agents for Pheochromocytoma · Background Info/Recommendations:

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Pheochromocytoma is a rare catecholamine-secreting tumor that causes excessive catecholamine secretion and is associated with hypertension, tachycardia, palpitations, headache, sweating, flushing, and anxiety. The treatment of choice is surgical resection of the tumor. Careful treatment with alpha- and beta-blockers is required preoperatively to control blood pressure and prevent intraoperative hypertensive crises. In those for whom surgery is contraindicated, alpha-blockers or tyrosine-kinase inhibitors can be used to reduce catecholamine levels long-term. o Phenoxybenzamine (Dibenzyline®) is the preferred alpha-blocker in preparation for surgery in patients with pheochromocytoma . o Metyrosine (Demser®) inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. Metyrosine is indicated for preoperative preparation of patients for surgery, management of patients when surgery is contraindicated, and chronic treatment of patients with malignant pheochromocytoma. It is usually reserved for patients who are refractory to phenoxybenzamine therapy, or as an adjunct to phenoxybenzamine therapy. o Phenoxybenzamine has been associated with postural hypotension, tachycardia, nasal congestion, meiosis, GI irritation, drowsiness, and fatigue. The incidence of hypotension and tachycardia is greater when administered with another alpha- or beta-blocker. Metyrosine is associated with sedation in almost all patients, although this tends to wane after 2-3 days. Metyrosine is also associated with extrapyramidal symptoms (EPS) in ~10% of patients, diarrhea in ~10% of patients, anxiety and psychiatric disturbances, galactorrhea, nasal congestion, N/V, and dry mouth. o There are no large outcomes studies available for the pheochromocytoma agents. o According to the American Association of Clinical Endocrinologists 2006 Hypertension Guidelines definitive treatment by surgical excision of the tumor cures hypertension in about 75% of pheochromocytoma cases. Preoperative control as well as management of any residual disease (particularly with malignant involvement) is best accomplished with a-adrenergic blocking agents and addition, as needed, of BBs or CCBs (or both). o While surgery is usually the treatment of choice for pheochromocytoma, phenoxybenzamine and metyrosine have a role in the preoperative preparation of patients for surgery, management of patients for whom surgery is contraindicated, and chronic treatment of patients with malignant pheochromocytoma. Based on current hypertension guidelines from the AACE, phenoxybenzamine is considered an agent of choice for preoperative management of pheochromocytoma or control of residual disease. Metyrosine is not mentioned in the AACE hypertension guidelines. In addition, it is associated with serious side effects (EPS, sedation, anxiety/psychiatric disturbances. Therefore, phenoxybenzamine should be made available for individuals with pheochromocytoma, while metyrosine should be reserved for patients not responding to phenoxybenzamine or for use as an adjunct to phenoxybenzamine therapy. Discussion: o Due to the toxicity associated with these agents, a suggestion was made to place clinical criteria around them to ensure that they are being used for pheochromocytoma. It was pointed out that there were only 4 claims per quarter for these drugs (suggesting they are not being misused), and criteria would inhibit prescribers from being able to easily access these meds. o A motion was made to accept the recommendation as presented. o The motion passed. o

Cardiovascular Agents: Antihypertensives ­ Peripheral Vasodilators and Combinations

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Background Info/Recommendations: o The peripheral vasodilator class consists of hydralazine and minoxidil. Hydralazine is indicated for the treatment of essential hypertension (either alone or as adjunct therapy). Minoxidil is indicated only for treatment of severe hypertension that is symptomatic or associated with target organ damage and is not manageable with maximum therapeutic doses of diuretic plus 2 other antihypertensives. o Hydralazine and minoxidil produce a direct vasodilating effect on the peripheral blood vessels, resulting in a reduction in blood pressure. o The most common adverse events associated with hydralazine are headache, anorexia, nausea, vomiting, diarrhea, palpitations, tachycardia, hypotension, edema, and nasal congestion. In addition to these, hydralazine use has also been linked to blood dyscrasias, lymphadenopathy, splenomegaly, SLE-like symptoms, peripheral neuritis, angina attacks, and MI. For minoxidil, the most common adverse events include elongation/thickening/enhanced pigmentation of hair (80% incidence), changes in the direction and magnitude of T waves (60% incidence), tachycardia, angina attacks, nausea/vomiting, edema, and pericardial effusion, occasionally with tamponade (3% incidence). Other rare side effects associated with minoxidil use include thrombocytopenia, leukopenia, rashes including bullous eruptions and Stevens-Johnson syndrome, and breast tenderness. o There are limited large-scale outcomes trials for the peripheral vasodilators. The Vasodilator Heart Failure Trial (V-HeFT) II showed that patients with mild to moderate HF who received enalapril for an average of 2.5 years experienced a significant decrease of 28% (P=0.016) in the risk of death at 2 years compared to patients on the combination hydralazine and isosorbide dinitrate (HYD/ISDN) (ARR 5.41%; NNT=18.5). o The ACC/AHA guidelines for CHF recommend the addition of a combination of hydralazine and a nitrate for patients with reduced LVEF who are already taking an ACE inhibitor and beta-blocker for symptomatic HF and who have persistent symptoms. o The peripheral vasodilators should be reserved for patients not achieving optimal blood pressure control on first- and second-line antihypertensive agents (ACE inhibitors, beta-blockers, etc.). Based on the ACC/AHA guidelines for CHF, hydralazine (in combination with a nitrate) is recommended as add-on therapy in patients with reduced LVEF who are already taking an ACE inhibitor and betablocker and continue to have persistent HF symptoms. For this reason, at least one hydralazine formulation should be made available. Minoxidil, however, is associated with more severe side effects than hydralazine and must be administered under close physician supervision, usually with concomitant betablocker and diuretic use to prevent tachycardia, increased myocardial workload, and fluid accumulation. Minoxidil is typically recommended only in situations of severe symptomatic hypertension that is not manageable with maximum therapeutic doses of a diuretic plus 2 other antihypertensives. For this reason, minoxidil is considered inferior within this class and is recommended to be subject to clinical criteria. Discussion o A comment was made that hydralazine is one of the few anti-hypertensive agents that can be used in pregnant women. o A motion was made to accept the recommendation as proposed. o The motion was approved. Proposed Clinical Criteria for Minoxidil: o Minoxidil tablets will be approved only for patients meeting all of the following: Diagnosis of severe hypertension (symptomatic or associated with target organ damage)

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Have tried and failed to achieve adequate blood pressure control on a diuretic PLUS at least 2 of the following (unless contraindication or intolerance to): · ACE inhibitor /ARB · Beta-blocker · Calcium channel blocker Does NOT have a diagnosis of pheochromocytoma (as minoxidil may stimulate secretions of catecholamines from the tumor) Note: Minoxidil will not be approved for alopecia Criteria Discussion: o A motion was made to accept the criteria as presented. o The motion was approved.

Cardiovascular Agents: Nitrates · Background Info/Recommendations: o All agents in this class are indicated for the treatment and/or prevention of angina pectoris. Sublingual isosorbide dinitrate, sublingual nitroglycerin, nitroglycerin lingual spray, and amyl nitrite can be used to relieve acute symptoms of angina pectoris. The sublingual and spray formulations of nitroglycerin have an onset of action of 1-3 minutes, while sublingual isosorbide dinitrate takes up to 10 minutes for effect. Sustained-release nitroglycerin, transdermal nitroglycerin, topical nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate can be used to prevent angina symptoms in patients with coronary artery disease. These products all require up to 45-60 minutes for onset of action. The extended-release formulations of isosorbide dinitrate and isosorbide mononitrate have longer durations of action and thus reduce the number of doses required per day compared to the immediate-release formulations. o The nitrates form free radical nitric oxide in the body, which produces smooth muscle vasodilation, decreasing both preload and afterload. o The most common adverse events associated with the nitrates are hypotension, headache, tachycardia, and dizziness. The topical formulations can also cause dermatitis/rash. o The ACC/AHA Guidelines for Chronic Stable Angina and Asymptomatic Suspected or Known Coronary Artery Disease recommend that sublingual nitroglycerin or nitroglycerin spray be used for the immediate relief of symptoms of angina. To help prevent MI or death in patients with chronic stable angina, combination therapy with a beta-blocker, aspirin (or clopidogrel), a statin, and an ACE inhibitor (in pts with CAD, diabetes, and/or LV systolic dysfunction) should be used; however long-acting nitrates (or calcium channel blockers) are recommended when beta-blockers are contraindicated or unsuccessful. o The ACC/AHA Guidelines for CHF recommend the addition of a combination of hydralazine and a nitrate for patients with reduced LVEF who are already taking an ACE inhibitor and beta-blocker for symptomatic HF and who have persistent symptoms. o Nitrates are an important class of medications for the treatment and prevention of angina pectoris, as well as for the management of CHF patients. It is recommended that the PDL include nitrate products with a quick onset of action for the treatment of acute angina, as well as nitrate products with a more sustained onset of action for the prevention of angina symptoms. For the treatment of acute angina:

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The nitroglycerin sublingual tablets and lingual spray formulations exhibit similar onset of action and similar efficacy at relieving acute angina symptoms; therefore, they can be considered therapeutic alternatives to one another. The spray formulation may offer an advantage over the sublingual tablets for individuals with manual dexterity problems, and should thus be available (either as a preferred agent on the PDL or via prior authorization) to individuals with manual dexterity problems. · The sublingual isosorbide dinitrate formulation has a longer onset of action than the sublingual or lingual nitroglycerin formulations. Amyl nitrate has a shorter duration of action than nitroglycerin and is flammable. Therefore, sublingual isosorbide dinitrate and amyl nitrate can be considered inferior agents in the treatment of acute angina. For the prevention of angina symptoms: · Sustained-release nitroglycerin tablets, transdermal nitroglycerin, topical nitroglycerin, oral isosorbide dinitrate, and oral isosorbide mononitrate appear to exhibit similar efficacy and safety; therefore, they can be considered therapeutic alternatives to one another. However, in order to ensure adequate patient and prescriber choice, it is recommended that at least one oral isosorbide dinitrate product, at least one oral isosorbide mononitrate product, and at least one non-oral nitroglycerin formulation (either transdermal or topical) be available as preferred agents on the PDL. Discussion: o A comment was made that a sublingual nitroglycerin formulation and a nitroglycerin lingual spray formulation should be available as preferred agents on the PDL. It was added that the nitrolingual spray had 200 sprays and was stable at room temperature for up to 2 years. It was expressed that the superior stability of this product would serve to counteract the additional cost. o A motion was made to accept the recommendations with the provision that both a sublingual nitroglycerin formulation and a nitroglycerin lingual spray formulation be made available as preferred agents on the PDL. The recommendation also involved doing away with any clinical criteria for the lingual spray formulations of nitroglycerin. o The motion passed. Proposed Clinical Criteria for Nitroglycerin Lingual Spray: o Nitroglycerin lingual spray formulations will be approved for individuals with manual dexterity problems for whom manipulation/administration of sublingual nitroglycerin tablets would be difficult. Criteria Discussion: o Given the discussion and recommendation above, the Committee disapproved of the proposed criteria, and voted to move at least one lingual nitroglycerin spray to the preferred side of the PDL.

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Cardiovascular Agents: Vasodilator/Nitrate Combinations · Background Info/Recommendations: o BiDil® (hydralazine / isosorbide dinitrate) is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status. o The approval of BiDil® was based in part on the results of the African-American Heart Failure Trial (A-HeFT). The study involved 1,050 self-identified black patients with severe heart failure who had already been treated with a loop diuretic, an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, and a beta blocker.

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Patients on BiDil® experienced a 43% reduction in death and a 39% decrease in hospitalization for heart failure compared to placebo, and a decrease of their symptoms of heart failure. o The current ACC/AHA guidelines for CHF recommend the addition of a combination of hydralazine and a nitrate for patients with reduced LVEF who are already taking an ACE inhibitor and beta-blocker for symptomatic HF and who have persistent symptoms. o No reference to BiDil® is made in the guidelines; however, it is stated that "the addition of isosorbide dinitrate and hydralazine to a standard medical regimen for HF, including ACE inhibitors and beta-blockers, is reasonable and can be effective in blacks with NYHA functional class III or IV HF." o Currently, the benefit of BiDil® in non-African-American populations has not been studied. Based on the current ACC/AHA guidelines for CHF, the combination of hydralazine and isosorbide dinitrate represents a reasonable choice for individuals with reduced LVEF who are already taking an ACE inhibitor and beta-blocker for symptomatic HF and who have persistent symptoms. However, data is lacking to support the additional clinical benefit for the fixed combination BiDil® over the two agents individually; therefore it is recommended that BiDil® be subject to clinical criteria. Discussion: o Dr. Dowell mentioned that the most recent AHA guidelines recommended a "fixed dose combination" of hydralazine and isosorbide dinitrate. Dr. Dowell replied that he would forward the updated guidelines to Dr. Woods. o A motion was made to reword the recommendation to require the BiDil® be listed as a preferred agent on the PDL, but subject to clinical criteria. o The motion was approved. (Dr. Dowell abstained from voting.) Proposed Clinical Criteria for BiDil®: o BiDil® will be approved for patients who meet all of the following criteria: Diagnosis of heart failure Currently on standard therapy for heart failure (loop diuretic, ACE inhibitor/ARB, and beta-blocker) Has failed to achieve an adequate response on concomitant therapy with the individual components isosorbide dinitrate and hydralazine. Criteria Discussion: o A comment was made that the proposed criteria should limit approvals of BiDil® to selfidentified black patients, as this was the population in which this medication was studied and found to be effective. o A motion was made to accept the proposed criteria with the specification that the drug would only be approved for heart failure in black patients and the removal of the 3rd bullet point (requiring trial and failure of the individual components). o A question was posed to the Committee if their recommendation would change if the updated AHA guidelines did not mention the "fixed dose" combination. The response from the Committee was that the recommendation would not change. o David Beshara stated that he would have to run this by the legal team. o The motion was approved.

REVIEW OF FEBRUARY PAC MEETING DECISIONS First Health reviewed TennCare's decisions from the February 20, 2007 PAC meeting. In the interest of time, decisions were presented only for those classes in which the committee had not accepted First Health's recommendations as is. The classes where TennCare's decisions differed from the recommendations of the Committee are as follows:

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Oral Antifungals used for Onychomycosis o The PAC had suggested to change the wording of "diagnosis" to "treatment" and to remove the first bullet point requiring a positive lab culture. o TennCare accepted the wording change, but decided to change the first bullet point to require: "There is a positive diagnostic microbiological or histological test (including KOH preparation, periodic acid Schiff (PAS) stain, or lab culture)." ACE inhibitors o PAC recommended that Altace® be preferred on the PDL. o TennCare opted to keep Altace® non-preferred, but subject to clinical criteria allowing for its use in patients expected to benefit from Altace® over other ACE inhibitors based on the existing clinical literature (i.e., patients with CAD, diabetes, etc.).

PHARMACEUTICAL MANUFACTURER REPRESENTATIVES FOR PUBLIC TESTIMONY May 10, 2007 TPAC Testimony Bill Guest Speaker Organization Bobby S. Arelli, MD AstraZeneca Donald Roberson, PharmD sanofi-aventis Nerissa Kreher, MD EMD Serono Susan Wood, PhD Boehringer Ingelheim Ray Lancaster, PharmD Novartis Barry Tucker, PharmD Amgen Suneel Kudaravalli, PharmD GlaxoSmithKline Rick Szymialis, RPh Eli Lilly Donald Williams, PharmD ScheringPlough MEETING ADJOURNED

Discussion Crestor® Lovenox® Saizen® Aggrenox® Tekturna® Enbrel® Arixtra® Humatrope® Zetia®

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