November/December 2009, Vol 2, No 7

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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ NOVEMBER/DECEMBER 2009

VOLUME 2, NUMBER 7

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS EDITORIAL

Wellness and the Governing Dynamics of Healthcare Reform Robert E. Henry

COMMENTARIES

How the US Government Rations Healthcare Scott Gottlieb, MD

Doctors on Healthcare Reform Betsy McCaughey ™

BUSINESS

Health Plan Retention and Pharmacy Costs of Newly Diagnosed Patients with Chronic Kidney Disease in a Managed Care Population Maureen Kubacki, PharmD, MBA; Chureen Carter, PharmD, MS; Alan D.L. Herrera, PharmD; Jim Wang, PhD; Janice M. Lopez, PharmD; Catherine T. Piech, MBA

Stakeholder Perspective by Jeff Januska, PharmD REGULATORY

Quality Improvement Initiatives: The Missed Opportunity for Health Plans Sara Fernandez-Lopez, PhD; Barbara Lennert, RN, BSN, MAOM

Stakeholder Perspective Jeffrey A. Bourret, MS, RPh, FASHP CLINICAL

Economic Evaluation of Quality-of-Life Improvement with Second-Generation Antihistamines and Montelukast in Patients with Allergic Rhinitis Kim R. Saverno, RPh; Brian Seal, PhD; Michael J. Goodman, PhD; Kellie Meyer, PharmD

Stakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA DEPARTMENTS ◆ Industry Trends Management Tools for Molecular Diagnostic Testing ◆ Generic Drug Trends Increases in Drug Utilization and Patent Expirations: A Recipe for Growth of Generics’ Market Share, despite Stalling on Biosimilars

©2009 Engage Healthcare Communications, LLC www.AHDBonline.com

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CONTROL THE COST. MEASURE THE SAVINGS. For Anemic Cancer Patients on Myelosuppressive Chemotherapy…

Significantly Better Drug Cost Control With PROCRIT® Mean Cumulative ESA Cost per Treatment Episode (US$)

OUTPATIENT SETTING Significantly Lower Erythropoiesis-Stimulating Agent (ESA) Cost With PROCRIT®1 $10,000

$8000

$6000

$6089 $4000

29%

$43211

Cost reduction with PROCRIT®

$2000 P<.0001 P<.00 000 001 1 $0

Darbepoetin alfa n=6817

PROCRIT® n=4111

Retrospective cohort study of PharMetrics Patient-Centric database from >85 US healthcare plans during January 2006 to January 2008.1 • Patients received ≥2 doses of either PROCRIT® (n=4111) or darbepoetin alfa (n=6817) • Based on 2008 wholesale acquisition cost (WAC): PROCRIT®, $13.13/1000 Units; darbepoetin alfa, $4.722/mcg • Mean cumulative dose: PROCRIT®, 329,129 Units; darbepoetin alfa, 1289 mcg These findings are consistent with previous studies2-4 and provide an additional basis of comparison of ESA treatments for healthcare professionals, hospital systems, and policy decision makers.1 • This information is not intended to make comparative efficacy, safety, or dosing comparisons between these agents

Mean Cumulative ESA Cost per Inpatient Stay (US$)

INPATIENT SETTING Significantly Lower Mean ESA Cost per Hospitalization5

Retrospective analysis of records from the Premier Perspective Comparative Hospital database of >500 hospitals nationwide during January 2006 to March 2008.5

$2000

$1500

• Patients received ≥1 dose of either PROCRIT® (n=8854) or darbepoetin alfa (n=2709)

$1482 $1000

40%

$892 $500

Cost reduction with PROCRIT® P<.001

• Based on 2008 WAC: PROCRIT®, $13.77/1000 Units; darbepoetin alfa, $4.818/mcg • This information is not intended to make comparative efficacy, safety, or dosing comparisons between these agents

$0

Darbepoetin alfa n=2709

PROCRIT® n=8854

Outpatient Dose-Only Ratio1 ®

(units PROCRIT :mcg darbepoetin alfa)

Inpatient Dose-Only Ratio5 (units PROCRIT®:mcg darbepoetin alfa)

<350:1

211:1

infers lower cost for PROCRIT®, based on July 2009 WAC* †

255:1

* Based on Analysource pricing, July 22, 2009. † The weekly dose equivalent for this ratio is 40,000 U:114 mcg.

Calculation of breakeven ratio: • PROCRIT® = $14.44/1000 Units

• Darbepoetin alfa = $5.06/mcg

• How many Units of PROCRIT® for $5.06? (1000 Units x $5.06)/(14.44) = 350 Units

References: 1. Vekeman F, McKenzie RS, Bookhart BK, et al. Drug utilisation and cost considerations of erythropoiesis stimulating agents in oncology patients receiving chemotherapy: observations from a large managed-care database. J Med Econ. 2009;12(1):1-8. 2. Burton T, Larholt K, Apgar E, et al. Hematologic outcomes of FDA-approved fi xed initial erythropoiesis-stimulating agent (ESA) doses in cancer patients with chemotherapy-induced anemia (CIA): real world data from an observational study. Poster presented at: the 4th Annual Chicago Supportive Oncology Conference; October 15-18, 2008; Chicago, IL. 3. Harley C, Muser E, Rey GG, McKenzie RS, Piech CT, Borah B. Comparison of utilization patterns, resource use and treatment costs among cancer patients treated with epoetin alfa or darbepoetin alfa. Poster presented at: the 41st American Society of Health-System Pharmacy (ASHP) Midyear Clinical Meeting and Exhibition; December 3-7, 2006; Orange County, CA. 4. McLaughlin T, Mody SH, McKenzie RS. Real-world dosing of erythropoietic agents in a nationwide sample of patients with cancer receiving chemotherapy: results from a large retrospective, observational study. Poster presented at: the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 11th Annual International Meeting; May 20-24, 2006; Philadelphia, PA. 5. Vekeman F, Bailey RA, Lafeuille M-H, McKenzie RS, Herrera A, Lefebvre P. Comparison of Epoetin alfa and darbepoetin alfa dosing patterns and costs in cancer inpatients receiving chemotherapy. Poster presented at: International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 14th Annual International Meeting; May 16-20, 2009; Orlando, FL. HCEI for formulary committees or similar entities as per FDAMA section 114.

Please see Indication and Important Safety Information, including Boxed WARNINGS, on adjacent page.

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PROCRIT® Indication

Additional Important Safety Information

PROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT® increases mortality or decreases progression-free/recurrence-free survival are ongoing.

• PROCRIT® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.

• PROCRIT® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT® on progression-free and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).

• PROCRIT® is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).

• PROCRIT® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

• Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events (including myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis) when administered ESAs to target higher versus lower hemoglobin levels (13.5 vs.11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies; these risks also increased in controlled clinical trials of patients with cancer. A rate of hemoglobin rise of >1 g/dL over 2 weeks may contribute to these risks.

• PROCRIT® therapy should not be initiated at hemoglobin levels 10 g/dL. • The dose of PROCRIT® should be titrated for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for blood transfusion.

• When the hemoglobin reaches a level needed to avoid transfusion or, increases by more than 1 g/dL in a 2-week period, the PROCRIT® dose should be reduced by 25%. Withhold the dose of PROCRIT® if the hemoglobin exceeds a level needed to avoid transfusion. Restart dose at 25% below the previous dose when the hemoglobin approaches a level where transfusions may be required. Discontinue if after 8 weeks of therapy there is no response as measured by hemoglobin levels or if transfusions are still required.

• Monitor hemoglobin regularly during therapy, weekly until hemoglobin becomes stable.

• Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®; predominantly in patients with chronic renal failure receiving PROCRIT® by subcutaneous administration. PRCA has also been reported in patients receiving ESAs while undergoing treatment for hepatitis C with interferon and ribavirin. If any patient develops a sudden loss of response to PROCRIT®, accompanied by severe anemia and low reticulocyte count, and anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® and other erythropoietic proteins.

Contact ORTHO BIOTECH (1-888-2ASKOBI or 1-888-227-5624) to perform assays for binding and neutralizing antibodies. If erythropoietin antibody-mediated anemia is confirmed, PROCRIT® should be permanently discontinued and patients should not be switched to other erythropoietic proteins.

• The safety and efficacy of PROCRIT® therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (e.g., sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).

• In some female patients, menses have resumed following PROCRIT® therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.

• Prior to and regularly during PROCRIT® therapy monitor iron status; transferrin saturation should be 20% and ferritin should be 100 ng/mL. During therapy absolute or functional iron deficiency may develop and all patients will eventually require supplemental iron to adequately support erythropoiesis stimulated by PROCRIT®.

• Treatment of patients with grossly elevated serum erythropoietin levels (e.g., >200 mUnits/mL) is not recommended.

• During PROCRIT® therapy, blood pressure should be monitored carefully and aggressively managed, particularly in patients with an underlying history of hypertension or cardiovascular disease.

• Seizures in PROCRIT®-treated patients have been reported in the context of a significant increase in hemoglobin from baseline; increases in blood pressure were not always observed; and patients may have had other underlying central nervous system pathology.

• The most commonly reported side effects (>10%) for PROCRIT® in clinical trials were pyrexia, diarrhea, nausea, vomiting, edema, asthenia, fatigue, shortness of breath, paresthesia, and upper respiratory infection.

Important Safety Information WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).

• To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion.

• Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.

• ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.

• Discontinue following the completion of a chemotherapy course.

Perisurgery: PROCRIT® (Epoetin alfa) increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

Contraindications • PROCRIT® is contraindicated in patients with uncontrolled hypertension or with known hypersensitivity to albumin (human) or mammalian cell-derived products.

Please see Brief Summary of Prescribing Information, including Boxed WARNINGS, on adjacent page.

Manufactured by: Amgen Inc., Thousand Oaks, California 91320-1799 Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2009 10/09 08PCO9019 445782

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BRIEF SUMMARY OF PROCRIT® PRESCRIBING INFORMATION FOR THE TREATMENT OF ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY PROCRIT® (Epoetin alfa) FOR INJECTION FOR FULL PRESCRIBING INFORMATION FOR ALL INDICATIONS, REFER TO THE PHYSICIANS’ DESK REFERENCE® WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and INCREASED RISK OF TUMOR PROGRESSION OR RECURRENCE Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (see WARNINGS: Table 1).

• To decrease these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusion.

• Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.

• ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.

• Discontinue following the completion of a chemotherapy course.

Perisurgery: PROCRIT® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider deep venous thrombosis prophylaxis.

(See WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events, WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION in full Prescribing Information.)

INDICATIONS AND USAGE PROCRIT® is indicated for the treatment of anemia due to the effect of concomitantly administered chemotherapy based on studies that have shown a reduction in the need for RBC transfusions in patients with metastatic, non-myeloid malignancies receiving chemotherapy for a minimum of 2 months. Studies to determine whether PROCRIT® increases mortality or decreases progression-free/recurrence-free survival are ongoing.

• PROCRIT® is not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.

• PROCRIT® is not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure due to the absence of studies that adequately characterize the impact of PROCRIT® on progressionfree and overall survival (see WARNINGS: Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence).

• PROCRIT® is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding (see PRECAUTIONS: Lack or Loss of Response).

• PROCRIT® use has not been demonstrated in controlled clinical trials to improve symptoms of anemia, quality of life, fatigue, or patient well-being.

CONTRAINDICATIONS PROCRIT® is contraindicated in patients with: 1. Uncontrolled hypertension. 2. Known hypersensitivity to mammalian cell-derived products. 3. Known hypersensitivity to Albumin (Human).

WARNINGS Pediatrics Risk in Premature Infants The multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in premature infants which are sometimes fatal.

Adults Increased Mortality, Serious Cardiovascular and Thromboembolic Events Patients with chronic renal failure experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Patients with chronic renal failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients. PROCRIT® and other ESAs increased the risks for death and serious cardiovascular events in controlled clinical trials of patients with cancer. These events included myocardial infarction, stroke, congestive heart failure, and hemodialysis vascular access thrombosis. A rate of hemoglobin rise of > 1 g/dL over 2 weeks may contribute to these risks.

In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rHuEPO) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03).

Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to PROCRIT® treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%. Increased mortality was observed in 634 patients randomized to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs. 2.3%), vascular access thromboses (39% vs. 29%), and all other thrombotic events (22% vs. 18%) were also higher in the group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents.

In a randomized controlled study (referred to as Cancer Study 1 - the ‘BEST’ study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). The study was terminated prematurely when interim results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

A systematic review of 57 randomized controlled trials (including Cancer Studies 1 and 5 - the ‘BEST’ and ‘ENHANCE’ studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08 (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients.

An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/Vascular Events in full Prescribing Information). In a randomized controlled study (referred to as the ‘SPINE’ study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT,

determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Deep venous thrombosis prophylaxis should be strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION in full Prescribing Information).

Increased mortality was also observed in a randomized placebo-controlled study of PROCRIT® in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to PROCRIT® versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events. ESAs are not approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery.

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence Erythropoiesis-stimulating agents resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 1). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Cancer Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Cancer Study 1) or lymphoid malignancy (Cancer Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Cancer Studies 7 and 8).

Table 1: Randomized, Controlled Trials with Decreased Survival and/or Decreased Locoregional Control Adverse Achieved Outcome for Hemoglobin Hemoglobin Primary ESA-containing Study / Tumor / (n) Target (Median Q1,Q3) Endpoint Arm Chemotherapy Cancer Study 1 Metastatic breast 12-14 g/dL 12.9 g/dL 12-month overall Decreased 12-month cancer (n=939) 12.2, 13.3 g/dL survival survival Cancer Study 2 Lymphoid 13-15 g/dL (M) 11.0 g/dL Proportion of Decreased overall malignancy (n=344) 13-14 g/dL (F) 9.8, 12.1 g/dL patients achieving survival a hemoglobin response Cancer Study 3 Early breast 12.5-13 g/dL 13.1 g/dL Relapse-free and Decreased 3 yr. cancer (n=733) 12.5, 13.7 g/dL overall survival relapse-free and overall survival Cancer Study 4 Cervical Cancer 12-14 g/dL 12.7 g/dL Progression-free Decreased 3 yr. (n=114) 12.1, 13.3 g/dL and overall survival progression-free and locoregional and overall survival control and locoregional control Radiotherapy Alone Cancer Study 5 Head and neck 15 g/dL (M) Not available Locoregional Decreased 5-year cancer (n=351) 14 g/dL (F) progression-free locoregional survival progression-free survival Decreased overall survival Cancer Study 6 Head and neck 14-15.5 g/dL Not available Locoregional Decreased cancer (n=522) disease control locoregional disease control No Chemotherapy or Radiotherapy Cancer Study 7 Non-small cell 12-14 g/dL Not available Quality of life Decreased overall lung cancer (n=70) survival Cancer Study 8 Non-myeloid 12-13 g/dL 10.6 g/dL RBC transfusions Decreased overall malignancy (n=989) 9.4, 11.8 g/dL survival Decreased overall survival: Cancer Study 1 (the ‘BEST’ study) was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the Epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).

Cancer Study 7 was a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with Epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).

Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.

Decreased progression-free survival and overall survival: Cancer Study 3 (the ‘PREPARE’ study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment.

After a median follow-up of approximately 3 years, the survival rate (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) were lower in the darbepoetin alfatreated arm compared to the control arm.

Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive Epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in Epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in Epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the Epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91).

Overall survival at 3 years was lower in the Epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42).

Cancer Study 5 (the ‘ENHANCE’ study) was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with a median of 406 days Epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving Epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).

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PROCRIT ® (Epoetin alfa) FOR INJECTION Decreased locoregional control: Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).

Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT®. This has been reported predominantly in patients with CRF receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs while undergoing treatment for hepatitis C with interferon and ribavirin. Any patient who develops a sudden loss of response to PROCRIT®, accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: Lack or Loss of Response). If anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT® and other ESAs. Contact ORTHO BIOTECH at 1 888 2ASK OBI (1-888-227-5624) to perform assays for binding and neutralizing antibodies. PROCRIT® should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other ESAs as antibodies may cross-react (see ADVERSE REACTIONS: Immunogenicity).

Albumin (Human) PROCRIT® contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

PRECAUTIONS The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rashes were occasionally observed concurrently with PROCRIT® therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS in full Prescribing Information for more information regarding allergic reactions).

The safety and efficacy of PROCRIT® therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders).

In some female patients, menses have resumed following PROCRIT® therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated.

Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated with PROCRIT®.

However, PROCRIT® has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT® should be used with caution in patients with known porphyria.

In preclinical studies in dogs and rats, but not in monkeys, PROCRIT® therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with PROCRIT® for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with PROCRIT®.

Cancer patients should have hemoglobin measured once a week until hemoglobin has been stabilized, and measured periodically thereafter.

Lack or Loss of Response: If the patient fails to respond or to maintain a response to doses within the recommended dosing range, the following etiologies should be considered and evaluated: 1. Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION); 2. Underlying infectious, inflammatory, or malignant processes; 3. Occult blood loss; 4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders); 5. Vitamin deficiencies: Folic acid or vitamin B12; 6. Hemolysis; 7. Aluminum intoxication; 8. Osteitis fibrosa cystica; 9. Pure Red Cell Aplasia (PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: Pure Red Cell Aplasia).

Iron Evaluation: During PROCRIT® therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/mL. Prior to and during PROCRIT® therapy, the patient’s iron status, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by PROCRIT®.

Drug Interaction: No evidence of interaction of PROCRIT® with other drugs was observed in the course of clinical trials.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenic potential of PROCRIT® has not been evaluated. PROCRIT® does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In female rats treated IV with PROCRIT®, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg.

Pregnancy Category C: PROCRIT® has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT® should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.

In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. PROCRIT® has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation).

Nursing Mothers: Postnatal observations of the live offspring (F1 generation) of female rats treated with PROCRIT® during gestation and lactation revealed no effect of PROCRIT® at doses of up to 500 Units/kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were no PROCRIT®-related effects on the F2 generation fetuses.

It is not known whether PROCRIT® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT® is administered to a nursing woman.

Pediatric Use: See WARNINGS: Pediatrics Pediatric Cancer Patients on Chemotherapy: The safety and effectiveness of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study (see CLINICAL EXPERIENCE, Weekly (QW) Dosing, Pediatric Patients in full Prescribing Information).

Geriatric Use: Insufficient numbers of patients age 65 or older were enrolled in clinical studies of PROCRIT® for the treatment of anemia associated with pre-dialysis chronic renal failure, cancer chemotherapy, and Zidovudine-treatment of HIV infection to determine whether they respond differently from younger subjects.

Information for Patients Patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic events, and increased risk of tumor progression or recurrence (see WARNINGS). In those situations in which the physician determines that a patient or their caregiver can safely and effectively administer PROCRIT® at home, instruction as to the proper dosage and administration should be provided. Patients should be instructed to read the PROCRIT® Medication Guide and Patient Instructions for Use and should be informed that the Medication Guide is not a disclosure of all possible side effects. Patients should be informed of the possible side effects of PROCRIT® and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. If home use is prescribed for a patient, the patient should be thoroughly instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, or drug product. A puncture-resistant container should be

available for the disposal of used syringes and needles, and guidance provided on disposal of the full container.

Hypertension: Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with PROCRIT®. Nevertheless, blood pressure in patients treated with PROCRIT® should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease.

Seizures: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with PROCRIT® TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with PROCRIT® also had underlying CNS pathology which may have been related to seizure activity.

In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 1.2% (n = 2/168) of safetyevaluable patients treated with PROCRIT® and 1% (n = 1/165) of placebo-treated patients had seizures.

Seizures in the patients treated with weekly PROCRIT® occurred in the context of a significant increase in hemoglobin from baseline values however significant increases in blood pressure were not seen. These patients may have had other CNS pathology.

Thrombotic Events: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT® TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonary embolism, cerebrovascular accident), (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events).

In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT®, 6.0% (n = 10/168) of safetyevaluable patients treated with PROCRIT® and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients had clinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic event including pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thrombotic microangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence of clinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobin measurements in this study.

The safety and efficacy of PROCRIT® were evaluated in a randomized, double-blind, placebo-controlled, multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhood malignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignancies and of anti-neoplastic treatments employed), a determination of the effect of PROCRIT® on the incidence of thrombotic events could not be performed. In the PROCRIT® arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%.

ADVERSE REACTIONS Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving PROCRIT® (see WARNINGS: Pure Red Cell Aplasia) during post-marketing experience.

There has been no systematic assessment of immune responses, i.e., the incidence of either binding or neutralizing antibodies to PROCRIT®, in controlled clinical trials.

Where reported, the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products within this class (erythropoietic proteins) may be misleading.

Adverse Experiences Reported in Clinical Trials In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with PROCRIT® or placebo-treated patients were as indicated below: Percent of Patients Reporting Event

Event Pyrexia Diarrhea Nausea Vomiting Edema Asthenia Fatigue Shortness of Breath Parasthesia Upper Respiratory Infection Dizziness Trunk Pain * Statistically significant

Patients Treated With PROCRIT® (n = 63) 29% 21%* 17%* 17% 17%* 13% 13% 13% 11% 11% 5% 3%*

Placebo-treated Patients (n = 68) 19% 7% 32% 15% 1% 16% 15% 9% 6% 4% 12% 16%

Although some statistically significant differences between patients being treated with PROCRIT® and placebotreated patients were noted, the overall safety profile of PROCRIT® appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to PROCRIT®) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of PROCRIT® was consistent with the progression of advanced cancer.

Three hundred thirty-three (333) cancer patients enrolled in a placebo-controlled double-blind trial utilizing Weekly dosing with PROCRIT® for up to 4 months were evaluable for adverse events. The incidence of adverse events was similar in both the treatment and placebo arms.

OVERDOSAGE The expected manifestations of PROCRIT® overdosage include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including any of the cardiovascular events described in WARNINGS and listed in ADVERSE REACTIONS in full Prescribing Information. Patients receiving an overdosage of PROCRIT® should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the effects due to PROCRIT® overdosage, reintroduction of PROCRIT® therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dL per 14 days). In patients with an excessive hematopoietic response, reduce the PROCRIT® dose in accordance with the recommendations described in DOSAGE AND ADMINISTRATION in full Prescribing Information.

Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 Distributed by: Ortho Biotech Products, L.P. Raritan, New Jersey 08869-0670 Revised 04/2009 © OBPLP 2000 10112803BC

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EDITORIAL BOARD

CLINICAL EDITOR

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA

Nirav R. Shah, MD, MPH Assistant Professor of Medicine NYU School of Medicine, NYC Senior Investigator, Geisinger Health System, Danville, PA

GOVERNMENT EDITOR

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC

HEALTH INFORMATION TECHNOLOGY

ACTUARY

HEALTH OUTCOMES RESEARCH

David Williams Milliman Health Consultant Windsor, CT CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Chair, Board of Directors, NCCN Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY RESEARCH

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York ENDOCRINOLOGY RESEARCH

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA Gordon M. Cummins, MS Director, IntegriChain

Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

MANAGED CARE & GOVERNMENT AFFAIRS

Alex Hathaway, MD, MPH, FACPM Senior Medical Policy Advisor Government Programs GlaxoSmithKline, Philadelphia, PA

MANAGED MARKETS

J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago

Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL Jeffrey A. Bourret, MS, RPh, FASHP Senior Director, Customer Marketing & Innovation, US Specialty Customers Pfizer Specialty Business Unit Collegeville, PA

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA PERSONALIZED MEDICINE

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation

F. Randy Vogenberg, RPh, PhD Chief Strategy Officer Employer-based Pharmaceutical Strategies Senior Scholar, Department of Health Policy, Thomas Jefferson University

Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

EPIDEMIOLOGY RESEARCH

PHARMACY BENEFIT DESIGN

AMERICAN HEALTH & DRUG BENEFITS

REIMBURSEMENT POLICY

Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account Amgen, Thousand Oaks, CA Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Co., Philadelphia, PA RESEARCH & DEVELOPMENT

Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, HarvardMIT Division of Health Sciences and Technology, Cambridge, MA SPECIALTY PHARMACY

PHARMACOECONOMICS

266

POLICY & PUBLIC HEALTH

Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City

PATIENT ADVOCACY

Joshua N. Liberman, PhD Vice President, Strategic Research CVS Caremark, Hunt Valley, MD

Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA

Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL

Paul Anthony Polansky, BSPharm, MBA Executive VP and Chief Pharmacy Officer Sanovia Corp., Philadelphia, PA

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute

Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim Ridgefield, CT

Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE

Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

William J. Cardarelli, PharmD Director of Pharmacy Atrius Health Harvard Vanguard Medical Associates

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

November/December 2009

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

VOL. 2

NO. 7

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JOIN AHDB PEER REVIEW American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other experts in benefit design who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal.

You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewers’ names will be published in AHDB at the end of the year.

Reviewers should have at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted for publication in AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to): • Administration/Management • Benefit design • Disease management/state (eg, asthma, infectious diseases, pain management, schizophrenia) • Drug therapy (including biologics, generics) • Drug utilization • Employer benefits • Finance/economics • Health information technology • Health policy/reform • Patient education/initiatives/quality-of-life issues • Pharmacoeconomics: cost-benefit analysis, cost-effectiveness • Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits • Reimbursement: Medicare/Medicaid, health insurance, prior authorization • Research: methods, study design, data collection/analysis

To become a peer reviewer, please complete the form below and fax to: 732-992-1881 or e-mail to editorial@ahdbonline.com Reviewer Information _______________________________________________________________________________________ First Name Last Name Credentials _______________________________________________________________________________________ Title Company _______________________________________________________________________________________ Address _______________________________________________________________________________________ E-mail Phone

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NOVEMBER/DECEMBER 2009

VOLUME 2, NUMBER 7

™

™

TABLE OF CONTENTS EDITORIAL

274 Wellness and the Governing Dynamics of Healthcare Reform Robert E. Henry COMMENTARY

277 How the US Government Rations Healthcare Scott Gottlieb, MD

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889

279 Doctors on Healthcare Reform Betsy McCaughey

Associate Editor Lara J. Reiman 732-992-1892

BUSINESS

283 Health Plan Retention and Pharmacy Costs of Newly Diagnosed Patients with Chronic Kidney Disease in a Managed Care Population Maureen Kubacki, PharmD, MBA; Chureen Carter, PharmD, MS; Alan D.L. Herrera, PharmD; Jim Wang, PhD; Janice M. Lopez, PharmD; Catherine T. Piech, MBA 290 Stakeholder Perspective by Jeff Januska, PharmD

Senior Production Manager Lynn Hamilton Business Manager Blanche Marchitto Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

REGULATORY

297 Quality Improvement Initiatives: The Missed Opportunity for Health Plans Sara Fernandez-Lopez, PhD; Barbara Lennert, RN, BSN, MAOM 304 Stakeholder Perspective by Jeffrey A. Bourret, MS, RPh, FASHP

Continued on page 270

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Benefit designs are greatly affected by clinical, business, and policy conditions.

This publication provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory

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Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1892 F: 732-992-1881

VOL. 2

NO. 7

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VOL. 2 Š2009, NO.Boehringer 6 Copyright Ingelheim Pharmaceuticals, Inc. All rights reserved.

September/October(11/09) 2009

www.AHDBonline.comDI69732269

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NOVEMBER/DECEMBER 2009

VOLUME 2, NUMBER 7

™

TABLE OF CONTENTS

™

(Continued)

CLINICAL

309 Economic Evaluation of Quality-of-Life Improvement with Second-Generation Antihistamines and Montelukast in Patients with Allergic Rhinitis Kim R. Saverno, RPh; Brian Seal, PhD; Michael J. Goodman, PhD; Kellie Meyer, PharmD 316 Stakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA DEPARTMENTS

291 INDUSTRY TRENDS Management Tools for Molecular Diagnostic Testing: Financial and Clinical Implications Douglas Moeller, MD 293 GENERIC DRUG TRENDS Increases in Drug Utilization and Patent Expirations: A Recipe for Growth of Generics’ Market Share, despite Stalling on Biosimilars Dalia Buffery, MA, ABD 318 ExECUTIvE SUMMARIES

American Health & Drug Benefits, ISSN 19422962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

Copyright © 2009 by Engage Healthcare Communications, LLC. All rights reserved.

American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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KAPIDEX WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

KAPIDEX is the first and only PPI with a Dual Delayed Release™ (DDR) formulation, which provides a second release of drug Mean plasma concentration (in healthy subjects; day 5; ng/mL)1 1200 1000 800 600 400

KAPIDEX K KA A 60 mg 200

KA KA KAPIDEX 30 mg

0 0

6

12

18

24

Time (h)

• KAPIDEX 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41 • KAPIDEX 60 mg provided consistently high erosive esophagitis healing rates at week 81 • KAPIDEX offers a safety and tolerability profile similar to lansoprazole1 • KAPIDEX can be taken without regard to food1 KAPIDEX should be swallowed whole. Alternatively, capsules can be opened, sprinkled on 1 tablespoon of applesauce, and swallowed immediately. While KAPIDEX can be taken without regard to food, some patients may benefit from administering the dose prior to a meal if post-meal symptoms do not resolve under post-fed conditions.

Conclusions of comparative efficacy cannot be drawn from this information.

Indications KAPIDEX is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Important Safety Information KAPIDEX is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with KAPIDEX use. Symptomatic response with KAPIDEX does not preclude the presence of gastric malignancy. Most commonly reported treatment-emergent adverse reactions (≥2%): diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).

Do not co-administer atazanavir with KAPIDEX because atazanavir systemic concentrations may be substantially decreased. KAPIDEX may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).

Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time.

Increases in INR and prothrombin time may lead to abnormal bleeding, which can lead to serious consequences.

Please see adjacent brief summary of prescribing information for KAPIDEX.

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BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION KAPIDEXâ&#x201E;¢ (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE KAPIDEX is indicated for: s THE HEALING OF ALL GRADES OF EROSIVE ESOPHAGITIS %% FOR UP TO WEEKS

s MAINTAINING HEALING OF %% FOR UP TO MONTHS AND s THE TREATMENT OF HEARTBURN ASSOCIATED WITH NON EROSIVE GASTROESOPHAGEAL REmUX DISEASE '%2$ FOR WEEKS CONTRAINDICATIONS +!0)$%8 IS CONTRAINDICATED IN PATIENTS WITH KNOWN HYPERSENSITIVITY TO ANY COMPONENT OF THE FORMULATION (YPERSENSITIVITY AND ANAPHYLAXIS HAVE BEEN REPORTED WITH +!0)$%8 USE [see Adverse Reactions] WARNINGS AND PRECAUTIONS Gastric Malignancy 3YMPTOMATIC RESPONSE WITH +!0)$%8 DOES NOT PRECLUDE THE PRESENCE OF GASTRIC MALIGNANCY ADVERSE REACTIONS Clinical Trials Experience 4HE SAFETY OF +!0)$%8 WAS EVALUATED IN PATIENTS IN CONTROLLED AND UNCONTROLLED CLINICAL STUDIES INCLUDING PATIENTS TREATED FOR AT LEAST MONTHS AND PATIENTS TREATED FOR ONE YEAR 0ATIENTS RANGED IN AGE FROM TO YEARS MEDIAN AGE YEARS WITH FEMALE #AUCASIAN

"LACK !SIAN AND OTHER RACES 3IX RANDOMIZED CONTROLLED CLINICAL TRIALS WERE CONDUCTED FOR THE TREATMENT OF %% MAINTENANCE OF HEALED %% AND SYMPTOMATIC '%2$ WHICH INCLUDED PATIENTS ON PLACEBO PATIENTS ON +!0)$%8 MG PATIENTS ON +!0)$%8 MG AND PATIENTS ON LANSOPRAZOLE MG ONCE DAILY

DRUG REACTION ASTHENIA CHEST PAIN CHILLS FEELING ABNORMAL INmAMMATION

MUCOSAL INmAMMATION NODULE PAIN PYREXIA Hepatobiliary Disorders: BILIARY COLIC CHOLELITHIASIS HEPATOMEGALY Immune System Disorders: HYPERSENSI TIVITY Infections and Infestations: CANDIDA INFECTIONS INmUENZA NASOPHAR YNGITIS ORAL HERPES PHARYNGITIS SINUSITIS VIRAL INFECTION VULVO VAGINAL INFECTION Injury, Poisoning and Procedural Complications: FALLS FRACTURES

JOINT SPRAINS OVERDOSE PROCEDURAL PAIN SUNBURN Laboratory Investigations: !,0 INCREASED !,4 INCREASED !34 INCREASED BILIRUBIN DECREASED INCREASED

BLOOD CREATININE INCREASED BLOOD GASTRIN INCREASED BLOOD GLUCOSE INCREASED

BLOOD POTASSIUM INCREASED LIVER FUNCTION TEST ABNORMAL PLATELET COUNT DECREASED TOTAL PROTEIN INCREASED WEIGHT INCREASE Metabolism and Nutrition Disorders: APPETITE CHANGES HYPERCALCEMIA HYPOKALEMIA Musculoskeletal and Connective Tissue Disorders: ARTHRALGIA ARTHRITIS MUSCLE CRAMPS

MUSCULOSKELETAL PAIN MYALGIA Nervous System Disorders: ALTERED TASTE

CONVULSION DIZZINESS HEADACHES MIGRAINE MEMORY IMPAIRMENT PARES THESIA PSYCHOMOTOR HYPERACTIVITY TREMOR TRIGEMINAL NEURALGIA Psychiatric Disorders: ABNORMAL DREAMS ANXIETY DEPRESSION INSOMNIA LIBIDO CHANGES Renal and Urinary Disorders: DYSURIA MICTURITION URGENCY Reproductive System and Breast Disorders: DYSMENORRHEA DYSPAREUNIA MENORRHAGIA

MENSTRUAL DISORDER; Respiratory, Thoracic and Mediastinal Disorders: ASPI RA TION ASTHMA BRONCHITIS COUGH DYSPNOEA HICCUPS HYPERVENTILATION

RESPIRATORY TRACT CONGESTION SORE THROAT Skin and Subcutaneous Tissue Disorders: ACNE DERMATITIS ERYTHEMA PRURITIS RASH SKIN LESION URTICARIA Vascular Disorders: DEEP VEIN THROMBOSIS HOT mUSH HYPERTENSION

!DDITIONAL ADVERSE REACTIONS THAT WERE REPORTED IN A LONG TERM UNCONTROLLED STUDY AND WERE CONSIDERED RELATED TO +!0)$%8 BY THE TREATING PHYSICIAN INCLUDED ANAPHYLAXIS AUDITORY HALLUCINATION " CELL LYMPHOMA CENTRAL OBESITY CHOLECYSTITIS ACUTE DECREASED HEMOGLOBIN DEHYDRATION DIABETES MELLITUS DYSPHONIA EPISTAXIS FOLLICULITIS GASTROINTESTINAL PAIN GOUT HERPES !S CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS ADVERSE RE ZOSTER HYPERGLYCEMIA HYPERLIPIDEMIA HYPOTHYROIDISM INCREASED NEUTROPHILS

ACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COM -#(# DECREASE NEUTROPENIA ORAL SOFT TISSUE DISORDER RECTAL TENESMUS

PARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REmECT THE RESTLESS LEGS SYNDROME SOMNOLENCE THROMBOCYTHEMIA TONSILLITIS RATES OBSERVED IN PRACTICE /THER ADVERSE REACTIONS NOT OBSERVED WITH +!0)$%8 BUT OCCURRING WITH -OST #OMMONLY 2EPORTED !DVERSE 2EACTIONS THE RACEMATE LANSOPRAZOLE CAN BE FOUND IN THE LANSOPRAZOLE PACKAGE INSERT

4HE MOST COMMON ADVERSE REACTIONS r THAT OCCURRED AT A HIGHER !$6%23% 2%!#4)/.3 SECTION INCIDENCE FOR +!0)$%8 THAN PLACEBO IN THE CONTROLLED STUDIES ARE PRESENTED DRUG INTERACTIONS IN 4ABLE Drugs with pH-Dependent Absorption Pharmacokinetics Table 2: Incidence of Treatment-Emergent Adverse +!0)$%8 CAUSES INHIBITION OF GASTRIC ACID SECRETION +!0)$%8 IS LIKELY TO Reactions in Controlled Studies SUBSTANTIALLY DECREASE THE SYSTEMIC CONCENTRATIONS OF THE ()6 PROTEASE Placebo KAPIDEX KAPIDEX KAPIDEX Lansoprazole INHIBITOR ATAZANAVIR WHICH IS DEPENDENT UPON THE PRESENCE OF GASTRIC ACID FOR ABSORPTION AND MAY RESULT IN A LOSS OF THERAPEUTIC EFFECT OF ATAZANAVIR AND 30 mg 60 mg Total 30 mg THE DEVELOPMENT OF ()6 RESISTANCE 4HEREFORE +!0)$%8 SHOULD NOT BE (N=896) (N=455) (N=2218) (N=2621) (N=1363) Adverse Reaction % % % % % CO ADMINISTERED WITH ATAZANAVIR $IARRHEA

!BDOMINAL 0AIN

.AUSEA

5PPER 2ESPIRATORY Tract Infection

6OMITING

&LATULENCE

)T IS THEORETICALLY POSSIBLE THAT +!0)$%8 MAY INTERFERE WITH THE ABSORPTION OF OTHER DRUGS WHERE GASTRIC P( IS AN IMPORTANT DETERMINANT OF ORAL BIOAVAILABILITY E G AMPICILLIN ESTERS DIGOXIN IRON SALTS KETOCONAZOLE Warfarin #O ADMINISTRATION OF +!0)$%8 MG AND WARFARIN MG DID NOT AFFECT THE PHARMACOKINETICS OF WARFARIN OR ).2 (OWEVER THERE HAVE BEEN REPORTS OF INCREASED ).2 AND PROTHROMBIN TIME IN PATIENTS RECEIVING 00)S AND WARFARIN CONCOMITANTLY )NCREASES IN ).2 AND PROTHROMBIN TIME MAY LEAD TO ABNORMAL BLEEDING AND EVEN DEATH 0ATIENTS TREATED WITH +!0)$%8 AND WARFARIN CONCOMITANTLY MAY NEED TO BE MONITORED FOR INCREASES IN ).2 AND PROTHROMBIN TIME

!DVERSE 2EACTIONS 2ESULTING IN $ISCONTINUATION )N CONTROLLED CLINICAL STUDIES THE MOST COMMON ADVERSE REACTION LEADING TO USE IN SPECIFIC POPULATIONS DISCONTINUATION FROM +!0)$%8 THERAPY WAS DIARRHEA Pregnancy /THER !DVERSE 2EACTIONS /THER ADVERSE REACTIONS THAT WERE REPORTED IN CONTROLLED STUDIES AT AN Teratogenic Effects 0REGNANCY #ATEGORY " 4HERE ARE NO ADEQUATE AND WELL CONTROLLED STUDIES INCIDENCE OF LESS THAN ARE LISTED BELOW BY BODY SYSTEM Blood and Lymphatic System Disorders: ANEMIA LYMPHADENOPATHY Cardiac WITH DEXLANSOPRAZOLE IN PREGNANT WOMEN 4HERE WERE NO ADVERSE FETAL EFFECTS Disorders: ANGINA ARRHYTHMIA BRADYCARDIA CHEST PAIN EDEMA MYOCARDIAL IN ANIMAL REPRODUCTION STUDIES OF DEXLANSOPRAZOLE IN RABBITS "ECAUSE ANIMAL INFARCTION PALPITATION TACHYCARDIA Ear and Labyrinth Disorders: EAR PAIN REPRODUCTION STUDIES ARE NOT ALWAYS PREDICTIVE OF HUMAN RESPONSE +!0)$%8 TINNITUS VERTIGO Endocrine Disorders: GOITER Eye Disorders: EYE IRRITATION SHOULD BE USED DURING PREGNANCY ONLY IF CLEARLY NEEDED EYE SWELLING Gastrointestinal Disorders: ABDOMINAL DISCOMFORT ABDOMINAL ! REPRODUCTION STUDY CONDUCTED IN RABBITS AT ORAL DEXLANSOPRAZOLE DOSES UP TENDERNESS ABNORMAL FECES ANAL DISCOMFORT "ARRETT S ESOPHAGUS BEZOAR TO MG PER KG PER DAY APPROXIMATELY FOLD THE MAXIMUM RECOMMENDED BOWEL SOUNDS ABNORMAL BREATH ODOR COLITIS MICROSCOPIC COLONIC POLYP HUMAN DEXLANSOPRAZOLE DOSE ; MG= BASED ON BODY SURFACE AREA ;"3!= CONSTIPATION DRY MOUTH DUODENITIS DYSPEPSIA DYSPHAGIA ENTERITIS ERUC REVEALED NO EVIDENCE OF HARM TO THE FETUS DUE TO DEXLANSOPRAZOLE )N ADDITION

TATION ESOPHAGITIS GASTRIC POLYP GASTRITIS GASTROENTERITIS GASTRO INTESTINAL REPRODUCTION STUDIES PERFORMED IN PREGNANT RATS WITH ORAL LANSOPRAZOLE AT DISORDERS GASTROINTESTINAL HYPERMOTILITY DISORDERS '%2$ ') ULCERS AND DOSES UP TO MG PER KG PER DAY TIMES THE RECOMMENDED HUMAN DOSE PERFORATION HEMATEMESIS HEMATOCHEZIA HEMORRHOIDS IMPAIRED GASTRIC BASED ON "3! AND IN PREGNANT RABBITS AT ORAL LANSOPRAZOLE DOSES UP TO MG EMPTYING IRRITABLE BOWEL SYNDROME MUCUS STOOLS NAUSEA AND VOMITING PER KG PER DAY TIMES THE RECOMMENDED HUMAN DOSE BASED ON "3! REVEALED ORAL MUCOSAL BLISTERING PAINFUL DEFECATION PROCTITIS PARESTHESIA ORAL RECTAL NO EVIDENCE OF IMPAIRED FERTILITY OR HARM TO THE FETUS DUE TO LANSOPRAZOLE HEMORRHAGE General Disorders and Administration Site Conditions: ADVERSE

TOC_EditBoard:Cover 12/11/09 5:19 PM Page 273

Nursing Mothers )T IS NOT KNOWN WHETHER DEXLANSOPRAZOLE IS EXCRETED IN HUMAN MILK (OWEVER

LANSOPRAZOLE AND ITS METABOLITES ARE PRESENT IN RAT MILK FOLLOWING THE ADMINI S TRATION OF LANSOPRAZOLE !S MANY DRUGS ARE EXCRETED IN HUMAN MILK AND BECAUSE OF THE POTENTIAL FOR TUMORIGENICITY SHOWN FOR LANSOPRAZOLE IN RAT CARCINOGENICITY STUDIES [see Carcinogenesis, Mutagenesis, Impairment of Fertility] A DECISION SHOULD BE MADE WHETHER TO DISCONTINUE NURSING OR TO DISCONTINUE THE DRUG

TAKING INTO ACCOUNT THE IMPORTANCE OF THE DRUG TO THE MOTHER

WERE TREATED ORALLY WITH LANSOPRAZOLE AT DOSES OF TO MG PER KG PER DAY

ABOUT TO TIMES THE EXPOSURE ON A BODY SURFACE MG M BASIS OF A KG PERSON OF AVERAGE HEIGHT M "3! GIVEN THE RECOMMENDED HUMAN DOSE OF LANSOPRAZOLE MG PER DAY

OVERDOSAGE 4HERE HAVE BEEN NO REPORTS OF SIGNIlCANT OVERDOSE OF +!0)$%8 -ULTIPLE DOSES OF +!0)$%8 MG AND A SINGLE DOSE OF +!0)$%8 MG DID NOT RESULT IN DEATH OR OTHER SEVERE ADVERSE EVENTS $EXLANSOPRAZOLE IS NOT EXPECTED TO BE REMOVED FROM THE CIRCULATION BY HEMODIALYSIS )F AN OVERDOSE OCCURS TREATMENT SHOULD BE SYMPTOMATIC AND SUPPORTIVE

4HE POTENTIAL EFFECTS OF DEXLANSOPRAZOLE ON FERTILITY AND REPRODUCTIVE PERFORMANCE WERE ASSESSED USING LANSOPRAZOLE STUDIES ,ANSOPRAZOLE AT ORAL DOSES UP TO MG PER KG PER DAY TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3! WAS FOUND TO HAVE NO EFFECT ON FERTILITY AND REPRODUCTIVE PERFORMANCE OF MALE AND FEMALE RATS PATIENT COUNSELING INFORMATION

CLINICAL PHARMACOLOGY

[see FDA-Approved Patient Labeling in the full prescribing information]

Pharmacodynamics !NTISECRETORY !CTIVITY 4HE EFFECTS OF +!0)$%8 MG N OR LANSOPRAZOLE MG N ONCE DAILY FOR lVE DAYS ON HOUR INTRAGASTRIC P( WERE ASSESSED IN HEALTHY SUBJECTS IN A MULTIPLE DOSE CROSSOVER STUDY

Information for Patients 4O ENSURE THE SAFE AND EFFECTIVE USE OF +!0)$%8 THIS INFORMATION AND INSTRUCTIONS PROVIDED IN THE &$! APPROVED PATIENT LABELING SHOULD BE DISCUSSED WITH THE PATIENT )NFORM PATIENTS OF THE FOLLOWING

,ANSOPRAZOLE PRODUCED DOSE RELATED GASTRIC %#, CELL HYPERPLASIA AND %#, CELL CARCINOIDS IN BOTH MALE AND FEMALE RATS [see Clinical Pharmacology].

)N RATS LANSOPRAZOLE ALSO INCREASED THE INCIDENCE OF INTESTINAL METAPLASIA OF THE GASTRIC EPITHELIUM IN BOTH SEXES )N MALE RATS LANSOPRAZOLE PRODUCED A Pediatric Use 3AFETY AND EFFECTIVENESS OF +!0)$%8 IN PEDIATRIC PATIENTS LESS THAN YEARS DOSE RELATED INCREASE OF TESTICULAR INTERSTITIAL CELL ADENOMAS 4HE INCIDENCE OF THESE ADENOMAS IN RATS RECEIVING DOSES OF TO MG PER KG PER DAY TO OF AGE HAVE NOT BEEN ESTABLISHED TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3!

Geriatric Use EXCEEDED THE LOW BACKGROUND INCIDENCE RANGE TO FOR THIS STRAIN )N CLINICAL STUDIES OF +!0)$%8 OF PATIENTS WERE AGED YEARS AND OVER .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN OF RAT 4ESTICULAR INTERSTITIAL CELL ADENOMA ALSO OCCURRED IN OF RATS TREATED THESE PATIENTS AND YOUNGER PATIENTS AND OTHER REPORTED CLINICAL EXPERIENCE WITH MG LANSOPRAZOLE PER KG PER DAY TIMES THE RECOMMENDED LANSO HAS NOT IDENTIlED SIGNIlCANT DIFFERENCES IN RESPONSES BETWEEN GERIATRIC AND PRAZOLE HUMAN DOSE BASED ON "3! IN A YEAR TOXICITY STUDY YOUNGER PATIENTS BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE )N A MONTH CARCINOGENICITY STUDY #$ MICE WERE TREATED ORALLY WITH RULED OUT] LANSOPRAZOLE DOSES OF MG TO MG PER KG PER DAY TO TIMES THE RECOMMENDED HUMAN DOSE BASED ON "3! ,ANSOPRAZOLE PRODUCED A DOSE Renal Impairment .O DOSAGE ADJUSTMENT OF +!0)$%8 IS NECESSARY IN PATIENTS WITH RENAL RELATED INCREASED INCIDENCE OF GASTRIC %#, CELL HYPERPLASIA )T ALSO PRODUCED IMPAIRMENT 4HE PHARMACOKINETICS OF DEXLANSOPRAZOLE IN PATIENTS WITH RENAL AN INCREASED INCIDENCE OF LIVER TUMORS HEPATOCELLULAR ADENOMA PLUS IMPAIRMENT ARE NOT EXPECTED TO BE ALTERED SINCE DEXLANSOPRAZOLE IS EXTENSIVELY CARCINOMA 4HE TUMOR INCIDENCES IN MALE MICE TREATED WITH MG AND METABOLIZED IN THE LIVER TO INACTIVE METABOLITES AND NO PARENT DRUG IS MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE RECOMMENDED RECOVERED IN THE URINE FOLLOWING AN ORAL DOSE OF DEXLANSOPRAZOLE. LANSOPRAZOLE HUMAN DOSE BASED ON "3! AND FEMALE MICE TREATED WITH MG TO MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE Hepatic Impairment .O DOSAGE ADJUSTMENT FOR +!0)$%8 IS NECESSARY FOR PATIENTS WITH MILD HEPATIC RECOMMENDED HUMAN DOSE BASED ON "3! EXCEEDED THE RANGES OF BACK IMPAIRMENT #HILD 0UGH #LASS ! +!0)$%8 MG SHOULD BE CONSIDERED FOR GROUND INCIDENCES IN HISTORICAL CONTROLS FOR THIS STRAIN OF MICE ,ANSOPRAZOLE PATIENTS WITH MODERATE HEPATIC IMPAIRMENT #HILD 0UGH #LASS " .O STUDIES TREATMENT PRODUCED ADENOMA OF RETE TESTIS IN MALE MICE RECEIVING TO HAVE BEEN CONDUCTED IN PATIENTS WITH SEVERE HEPATIC IMPAIRMENT #HILD 0UGH MG PER KG PER DAY TO TIMES THE RECOMMENDED LANSOPRAZOLE #LASS # .

HUMAN DOSE BASED ON "3!

3ERUM 'ASTRIN %FFECTS 4HE EFFECT OF +!0)$%8 ON SERUM GASTRIN CONCENTRATIONS WAS EVALUATED IN APPROX IMATELY PATIENTS IN CLINICAL TRIALS UP TO WEEKS AND IN PATIENTS FOR UP TO TO MONTHS 4HE MEAN FASTING GASTRIN CONCENTRATIONS INCREASED FROM BASELINE DURING TREATMENT WITH +!0)$%8 MG AND MG DOSES )N PATIENTS TREATED FOR MORE THAN MONTHS MEAN SERUM GASTRIN LEVELS INCREASED DURING APPROXIMATELY THE lRST MONTHS OF TREATMENT AND WERE STABLE FOR THE REMAINDER OF TREATMENT -EAN SERUM GASTRIN LEVELS RETURNED TO PRE TREATMENT LEVELS WITHIN ONE MONTH OF DISCONTINUATION OF TREATMENT

+!0)$%8 IS AVAILABLE AS A DELAYED RELEASE CAPSULE +!0)$%8 MAY BE TAKEN WITHOUT REGARD TO FOOD +!0)$%8 SHOULD BE SWALLOWED WHOLE

s !LTERNATIVELY +!0)$%8 CAPSULES CAN BE OPENED AND ADMINISTERED AS FOLLOWS n /PEN CAPSULE n 3PRINKLE INTACT GRANULES ON ONE TABLESPOON OF APPLESAUCE n 3WALLOW IMMEDIATELY

$ISTRIBUTED BY %NTEROCHROMAFlN ,IKE #ELL %#, %FFECTS Takeda Pharmaceuticals America, Inc. 4HERE WERE NO REPORTS OF %#, CELL HYPERPLASIA IN GASTRIC BIOPSY SPECIMENS $EERlELD ), OBTAINED FROM PATIENTS TREATED WITH +!0)$%8 MG MG OR MG FOR 5 3 0ATENT .OS

UP TO MONTHS

AND

$URING LIFETIME EXPOSURE OF RATS DOSED DAILY WITH UP TO MG PER KG PER DAY OF LANSOPRAZOLE MARKED HYPERGASTRINEMIA WAS OBSERVED FOLLOWED BY %#, +!0)$%8 IS A TRADEMARK OF 4AKEDA 0HARMACEUTICALS .ORTH !MERICA )NC AND CELL PROLIFERATION AND FORMATION OF CARCINOID TUMORS ESPECIALLY IN FEMALE RATS USED UNDER LICENSE BY 4AKEDA 0HARMACEUTICALS !MERICA )NC !LL OTHER TRADEMARK NAMES ARE THE PROPERTY OF THEIR RESPECTIVE OWNERS [see Nonclinical Toxicology ] Ú 4AKEDA 0HARMACEUTICALS !MERICA )NC %FFECT ON #ARDIAC 2EPOLARIZATION

! STUDY WAS CONDUCTED TO ASSESS THE POTENTIAL OF +!0)$%8 TO PROLONG THE 14 14c INTERVAL IN HEALTHY ADULT SUBJECTS +!0)$%8 DOSES OF MG OR MG DID NOT DELAY CARDIAC REPOLARIZATION COMPARED TO PLACEBO 4HE POSITIVE CONTROL MOXImOXACIN PRODUCED STATISTICALLY SIGNIlCANTLY GREATER MEAN MAXIMUM AND TIME AVERAGED 14 14c INTERVALS COMPARED TO PLACEBO

&OR MORE DETAILED INFORMATION SEE THE FULL PRESCRIBING INFORMATION FOR +!0)$%8 0) 2 *ANUARY OR CONTACT 4AKEDA 0HARMACEUTICALS !MERICA )NC AT

NONCLINICAL TOXICOLOGY

, ,0$

0) 2 "RF *ANUARY

Carcinogenesis, Mutagenesis, Impairment of Fertility 4HE CARCINOGENIC POTENTIAL OF DEXLANSOPRAZOLE WAS ASSESSED USING LANSOPRA ZOLE STUDIES )N TWO MONTH CARCINOGENICITY STUDIES 3PRAGUE $AWLEY RATS Reference: 1. KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. KAPIDEX™ and Dual Delayed Release™ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc.

©2009 Takeda Pharmaceuticals North America, Inc. LPD-00256 6/09 Printed in U.S.A.

Henry:Cover 12/11/09 5:21 PM Page 274

FROM THE EDITOR

Wellness and the Governing Dynamics of Healthcare Reform

O

n October 29, 2009, a leadership summit on healthcare reform was in progress in Washington, DC. No, not Congress; the participants were not Democrats and Republicans locked in a death grip to impose, or block, government-mandated healthcare reform. This was a conference of leading healthcare authorities representing clinical, business, and policy sectors in healthcare, organizing the elements of a strategy to reform healthcare into a new paradigm that improves health, reduces costs, and encourages innovation—that endangered species of the healthcare ecosystem.

The occasion was the 2nd Annual Summit on Stakeholder Integration of American Health & Drug Benefits (AHDB), and the theme was the changeover to wellness-based system for chronic diseases, focusing on prevention, intervention, and innovation. The summit was marked by the nonpartisan environment and exchange of ideas and data and the compelling nature of the information. The summit experts were using the highest principles of medicine, science, economics, business, and policy to craft an organizing principle for healthcare. Not evidence-based medicine or benefit design, not comparative effectiveness research, not personalized medicine. These are only tools to be used in the grander, simpler vision for how health, not just healthcare, must proceed.

What makes wellness-based healthcare so important at this time of national angst is that it answers the essential governing dynamics of value-based health— cost, quality, and access. Moreover, wellness is intrinsically apolitical, providing an opportunity for consensus in healthcare policy, because wellness does not exist in a vacuum within policy but extends to the other 2 sectors—clinical and business.

But wellness is not a silver bullet; it sets out on its journey incompletely informed—nothing new to healthcare. The various stakeholder groups have been devising new systems that enable the prevention of chronic diseases, a more efficient management, and new technologies for treatment. These have been happening spontaneously, the inevitable result of progress in the many parties comprising the great “healthcare ecosystem.” They need only be arranged coherently.

Armed with vital new information on the nature of disease, insurance, policy, and people’s peculiar resistance to self-preservation (as manifested in poor adherence to treatment regimens and strong adherence to a sedentary lifestyle and juicy hamburgers), healthcare

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AMERICAN HEALTH & DRUG BENEFITS

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professionals are in a position to organize these findings into a coherent, actionable program to improve health and reduce waste spending. This program, called “wellness,” will entail the reinvention of every stakeholder—payers, purchasers, providers, patients, manufacturers, researchers, and policymakers. Change is not easy, but incessant incremental, patchwork changes to the existing healthcare system is getting intolerable.

This is not a “system”; at last year’s AHDB summit, a comparison was made to Voltaire’s great remark about the Holy Roman Empire being “neither holy, nor Roman, nor an empire.” A paradigm shift was needed to the political organization of the Holy Roman Empire, if it were to offer political relevance.

Our own shambles of a healthcare “system” is sufficient cause to inspire change, but to what? Out of the frying pan into the fire? The American healthcare process is saving countless lives and must not be abandoned wholesale. And the insistence on controlling one’s individual destiny, sometimes derisively referred to as “American exceptionalism,” has something to it.

The proceedings of the wellness summit will be published in a special supplement to AHDB in early 2010.

We hope it will offer the various stakeholders actionable steps to bring together the great forces and groups charged with administering, monitoring, and protecting the process of patient care. Meanwhile, we might resist the urge to authorize the government to reign supreme in health, not its strong suit or its tradition.

The danger to health is evident in a quote from the statesman Thomas More, “If the world is round, will the King’s command flatten it?”

Government mandate is not a good way of managing health. In contrast, wellness-based healthcare provides a rational organizing principle for medicine, business, and government to collaborate in a structure that preserves a system informed by innovation, sound medical and business practices, and good sense on the part of the populace. Let us not lose heart that such sanity is attainable. It is no longer a dream; it is coming into being and needs time, focus, and stakeholder collaboration to become a system, which we have been working without for all these years. ■

Robert E. Henry Editor-in-Chief

November/December 2009

VOL. 2

I

NO. 7

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2.5 mg, 5 mg, 10 mg and 20 mg Rx Only Brief Summary: For complete details please see full Prescribing Information for BYSTOLIC. INDICATIONS AND USAGE BYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

WARNINGS Abrupt Cessation of Therapy Patients with coronary artery disease treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC is planned, patients should be carefully observed and advised to minimize physical activity. BYSTOLIC should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that BYSTOLIC be promptly reinstituted, at least temporarily.

Cardiac Failure Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously.

If heart failure worsens, discontinuation of BYSTOLIC should be considered.

Angina and Acute Myocardial Infarction BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. Bronchospastic Diseases In general, patients with bronchospastic diseases should not receive β-blockers.

Anesthesia and Major Surgery If BYSTOLIC is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers.

Diabetes and Hypoglycemia β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia.

Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

PRECAUTIONS Use with CYP2D6 Inhibitors Nebivolol exposure increases with inhibition of CYP2D6 (see Drug Interactions).

The dose of BYSTOLIC may need to be reduced.

Impaired Renal Function BYSTOLIC should be used with caution in patients with severe renal impairment because of decreased renal clearance. BYSTOLIC has not been studied in patients receiving dialysis.

Impaired Hepatic Function BYSTOLIC should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since BYSTOLIC has not been studied in patients with severe hepatic impairment, BYSTOLIC is contraindicated in this population (see CLINICAL PHARMACOLOGY, Special Populations and DOSAGE AND ADMINISTRATION).

Risk of Anaphylactic Reactions While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

In patients with known or suspected pheochromocytoma, an α-blocker should be initiated prior to the use of any β-blocker.

Information for Patients Patients should be advised to take BYSTOLIC regularly and continuously, as directed. BYSTOLIC can be taken with or without food. If a dose is missed, the patient should take the next scheduled dose only (without doubling it). Patients should not interrupt or discontinue BYSTOLIC without consulting the physician.

Patients should know how they react to this medicine before they operate automobiles, use machinery, or engage in other tasks requiring alertness.

Patients should be advised to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of worsening congestive heart failure such as weight gain or increasing shortness of breath, or excessive bradycardia.

Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nebivolol should be used with caution in these patients.

Drug Interactions BYSTOLIC should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

BYSTOLIC should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity. In patients who are receiving BYSTOLIC and clonidine, BYSTOLIC should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) (see CLINICAL PHARMACOLOGY, Drug Interactions).

Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at 40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on a mg/m2 basis). Similar findings were not reported in mice administered doses equal to approximately 0.3 or 1.2 times the maximum recommended human dose. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human dose). Co-administration of dihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect of nebivolol in mice and not thought to be clinically relevant in man.

A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This study demonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH, or serum total testosterone.

Effects on spermatogenesis were seen in male rats and mice at ≥40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesis were not reversed and may have worsened during a four-week recovery period. The effects of nebivolol on sperm in mice, however, were partially reversible.

Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests).

Pregnancy: Teratogenic Effects. Pregnancy Category C: Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance.

In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

Labor and Delivery Nebivolol caused prolonged gestation and dystocia at doses ≥5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation).

No studies of nebivolol were conducted in pregnant women. BYSTOLIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk.

Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during nursing.

Geriatric Use Of the 2800 patients in the U.S.-sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility (see Carcinogenesis, Mutagenesis, and Impairment of Fertility).

ADVERSE REACTIONS The data described below reflect worldwide clinical trial exposure to BYSTOLIC in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. In placebo-controlled clinical trials comparing BYSTOLIC with placebo, discontinuation of therapy due to adverse events was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%).

Adverse Reactions in Controlled Trials Table 1 lists treatment-emergent signs and symptoms that were reported in three 12week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg or 20-40 mg of BYSTOLIC and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group.

Table 1. Treatment-Emergent Adverse Events with an Incidence (over 6 weeks) ≥1% in BYSTOLIC-Treated Patients and at a Higher Frequency than PlaceboTreated Patients Placebo

Headache Fatigue Dizziness Diarrhea Nausea Insomnia Chest pain Bradycardia Dyspnea Rash Peripheral edema

(n = 205) (%) 6 1 2 2 0 0 0 0 0 0 0

Nebivolol 5 mg (n = 459) (%) 9 2 2 2 1 1 0 0 0 0 1

Nebivolol 10 mg (n = 461) (%) 6 2 3 2 3 1 1 0 1 1 1

Nebivolol 20-40 mg (n = 677) (%) 7 5 4 3 2 1 1 1 1 1 1

Other Adverse Events Observed During Worldwide Clinical Trials Listed below are other reported adverse events with an incidence of at least 1% in the more than 5300 patients treated with BYSTOLIC in controlled or open-label trials, whether or not attributed to treatment, except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or events unlikely to be attributable to drug because they are common in the population.

These adverse events were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies.

Body as a Whole: asthenia.

Gastrointestinal System Disorders: abdominal pain Metabolic and Nutritional Disorders: hypercholesterolemia and hyperuricemia Nervous System Disorders: paraesthesia Laboratory In controlled monotherapy trials, BYSTOLIC was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count.

Events Identified from Spontaneous Reports of BYSTOLIC Received Worldwide The following adverse events have been identified from spontaneous reports of BYSTOLIC received worldwide and have not been listed elsewhere. These adverse events have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to BYSTOLIC. Events common in the population have generally been omitted. Because these events were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second- and third-degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.

OVERDOSAGE In clinical trials and worldwide postmarketing experience there were reports of BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse events reported with BYSTOLIC overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse events associated with β-blocker overdose include bronchospasm and heart block.

The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered.

Due to extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance.

If overdose occurs, BYSTOLIC should be stopped and general supportive and specific symptomatic treatment should be provided. Based on expected pharmacologic actions and recommendations for other β-blockers, the following general measures should be considered when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously.

Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.

Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics.

In certain cases, consideration should be given to the use of inotropic and vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline.

Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required.

In the event of intoxication where there are symptoms of shock, treatment must be continued for a sufficiently long period consistent with the 12-19 hour effective half-life of BYSTOLIC. Supportive measures should continue until clinical stability is achieved.

Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.

Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Licensed from Mylan Laboratories, Inc. Under license from Janssen Pharmaceutica N.V., Beerse, Belgium

Rev. 08/08 © 2008 Forest Laboratories, Inc.

Gottlieb_Cover 10/14/09 6:29 PM Page 214

For the treatment of hypertension

BYSTOLIC. Significant blood pressure reductions with a low incidence of side effects.1-3 www.BYSTOLIC.com Important Safety Information Patients being treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported following the abrupt cessation of therapy with beta blockers. When discontinuation is planned, the dosage should be reduced gradually over a 1- to 2-week period and the patient carefully monitored.

BYSTOLIC is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

BYSTOLIC should be used with caution in patients with peripheral vascular disease, thyrotoxicosis, in patients treated concomitantly with beta blockers and calcium channel blockers of the verapamil and diltiazem type (ECG and blood pressure should be monitored), severe renal impairment, and any degree of hepatic impairment or in patients undergoing major surgery. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously. If heart failure worsens, discontinuation of BYSTOLIC should be considered. Caution should also be used in diabetic patients as beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC).

In general, patients with bronchospastic disease should not receive beta blockers.

BYSTOLIC should not be combined with other beta blockers.

The most common adverse events with BYSTOLIC versus placebo (approximately â&#x2030;Ľ1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema.

Please see brief summary of Prescribing Information on adjacent page. Š2009 Forest Laboratories, Inc

44-1014950

01/09

References: 1. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2008. 2. Data on file. Forest Laboratories, Inc. 3. Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens. 2007;9:866-875.

Gottlieb:Cover 12/11/09 5:40 PM Page 277

COMMENTARY

How the US Government Rations Healthcare Scott Gottlieb, MD

P

resident Barack Obama deflects criticism that his healthcare plan will bring on government rationing of medical care by arguing that insurance companies ration care. Everyone knows private payers limit access to some health care. But government does it in far more Byzantine and arbitrary ways.

Consider the $450-billion Medicare program. It provides a model for—indeed its bureaucracy could well end up running—the “public option” health plan that President Obama wants to offer all Americans under the age of 65. In recent years, Medicare’s staff has been aggressively restricting coverage for costly treatments.

Looking for ways to control pending on medical products—and preserve the illusory “trust fund” that pays Medicare claims—is what shapes the culture of the organization and motivates the agency’s staff.

This often means limiting access to the costliest technologies. To do this Medicare relies on its rationing and pricing systems. National coverage decisions are assessments issued by Medicare’s medical staff that define who is eligible for new but often expensive treatments. Medicare then assigns medical products and procedures with “codes” that determine which regulated category they fall into. Finally, price “schedules” are developed by Medicare’s staff each year to assign each unique code with its own updated payment rate.

The process for getting a favorable code on a new product is a source of intense lobbying. It can make or break a technology. For a remote agency like Medicare, far removed from clinical practice, it’s easier to try and manage the use of a high-cost but specialty treatment than a much lower-cost but very widely used product.

Yet cheaper, more commonly used products can still be mispriced and account for more total cost to the agency. For example, low-tech orthotic devices and other “durable medical equipment” are a known source of wasteful spending. These medical products often evade Medicare’s attention in favor of less used but more expensive items such as a biologic cancer drug.

Take the agency’s tortured decisions concerning the

Dr Gottlieb is a resident fellow at the American Enterprise Institute and a former senior official at the Centers for Medicare and Medicaid Services. He is partner to a firm that invests in healthcare companies, and he advises health plans.

use of implantable defibrillators that jump-start stopped hearts during cardiac arrest. Medicare sharply restricted their use in the 1990s. Mounting research proved that the $30,000 devices could be saving many more lives. So in 2003 Medicare adopted a novel theory to expand coverage to some, but not everyone, who needed one. The agency said only patients with certain measures on their electrocardiograms (called “wide QRS”) seemed to benefit.

It was an easily measurable but ultimately imprecise way to allocate the devices. After another major study firmly refuted the QRS theory, Medicare expanded coverage again in 2005, potentially saving 2500 additional lives, according to a press release issued with that decision.

That experience was not unique. From 1999 to 2007, Medicare denied access in a third of the treatments it evaluated through its coverage process, taking an average of eight months to complete its reviews.

When coverage was granted, in 85% of cases the treatments were restricted, usually to patients with more advanced illnesses.

Medicare is lately increasing its use of the national coverage process and is becoming more tightfisted.

Since 2008, according to my review of Medicare data, it conditioned access in 29% of its reviews and denied new or expanded coverage in fully 53% of cases.

Medicare’s methods can also be arbitrary. Take the travails of the pharmaceutical company Sepracor and its drug Xopenex, an innovative respiratory medicine that competes with the chemically distinct and much cheaper generic albuterol. Both are inhaled aerosols used to treat asthma and chronic obstructive pulmonary disease. Xopenex has the same benefits as albuterol, but some people believe it has fewer cardiac side effects. Medicare did not agree.

The agency tried to make a “national coverage decision” on Xopenex but could not come up with a clinical justification to limit the drug’s use. So Medicare manipulated its payment process, saying it would pay Xopenex a price equivalent to the “least costly alternative” form of generic albuterol, 10 cents for a treatment compared with about $2.50 for Xopenex. Then Medicare was sued by a patient, and a federal court recently ruled that the agency exceeded its authority.

Continued

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Medicare finally succeeded in reigning in the use of Xopenex with its coding system. By issuing Xopenex the same classification as generic albuterol, it was able to pay both products the same “blended” price—an average of the cost of each individual drug. That lowered the price on Xopenex, but ironically increased

Only a small fraction of Medicare’s denied claims—about 5%—are ever formally appealed because its process is so impenetrable. what Medicare paid for the generics. It is not a stretch to say that Medicare spent hundreds of cumulative man-hours focusing on Xopenex, while other priorities languished. The question is why? There were not safety concerns. Xopenex may have been used in lieu of a cheaper alternative, but at peak Medicare sales of about $300 million it represented far less than one one-thousandth of the agency’s budget. Simply put, a few staffers inside Medicare were consumed with the drug and its higher price—revealing a process that is capricious and often disconnected from science.

Worse still is how impenetrable these programs have become. Drug and device companies spend millions of dollars trying to influence Medicare decisions. The hundreds of consultants they hire to advise them typically command $20,000-a-month retainers.

Formal patient and provider appeals to Medicare took an average of 21 months, according to a report issued in 2003 by the Government Accountability Office (using 2001 data), with delays in “administrative processing” due to “inefficiencies and incompatibility” of data systems eating up 70% of the time spent processing appeals.

There is nothing inherently wrong with a program like Medicare seeking value for taxpayers. But it should not make up the rules as it goes. When private plans ration care, patients can appeal directly to an insurer’s medical staff. Only a small fraction of Medicare’s denied claims—about 5%—are ever formally appealed because its process is so impenetrable. People can also switch insurers, and in many cases patients chose a policy because it matched their preferences in the first place. These options don’t exist in a government health program. ■

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Doctors on Healthcare Reform Betsy McCaughey Government is in the process of duplicating everything that managed care did for the last 15 years that was reviled by everybody.—Dr David Fields

D

octors from across the country were invited to the White House on October 5, but the President did most of the talking. Medical professionals are being ignored or vilified more often than consulted in the current healthcare reform debate. To broaden the discussion, the Committee to Reduce Infection Deaths invited 16 highly regarded physicians to convene at the Grand Hyatt in New York City on October 19 to reflect on the current legislative proposals. Here’s what they had to say on four key issues.

Government-Imposed Treatment Guidelines Dr Jeffrey Borer, Cardiologist, named to Castle Connolly’s America’s Top Doctors: “What’s the impact of guidelines on the doctor–patient relationship?

Guidelines step in between the doctor and the patient.

If it’s necessary to respond to guidelines rather than what you see, feel and hear when you’re evaluating a person, then perhaps you’re going to do something that isn’t really the right thing. There really isn’t an average patient. Every person that you see with a medical problem has some unusual or unique characteristic and this often has to be considered in dealing with the problem.”

Dr David Fields, Obstetrician and Gynecologist, Lenox Hill Hospital, New York: “They tend to forbid better-than-average medical care; guidelines are always average medical care...they tend to cramp the physician who can do better than average.”

Dr Borer: “One of the more common problems that people have as they get older is a disease called aortic stenosis….[W]e can relieve that aortic stenosis with an operation with really very acceptable safety, low mortality rates….If that 85 year old cannot walk down the street because he or she is too breathless to do so…or feels lightheaded or could faint and break a hip…then there is really a very good justification for offering the therapy.”

Ms McCaughey is chairman of the Committee to Reduce Infection Deaths and a former Lt Governor of New York State. For a complete transcript of the physicians’ meetings, visit www.defendyourhealthcare.us. Reprinted with permission.

Originally printed in Opinion Journal. The Wall Street Journal. November 6, 2009.

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Dr Richard Amerling, Nephrologist, Beth Israel Medical Center, New York: “The example that you give of valve surgery in an 85 year old is just not going to happen under [White House Healthcare Adviser] Ezekiel Emanuel. He’s going to just say that that’s a nonstarter. That person has outlived their useful years, no matter how long they could live beyond that.”

Dr Borer: “What we’re hearing from the President’s medical advisers is that what we have is good enough and we really shouldn’t be wanting or expecting any more.”

Dr Seymour Cohen, Oncologist, named to America’s Top Doctors: “When we went to medical school, people used to die at age 66, 67, and 68. Medicare paid for two or three years. Social Security paid for two or three years.

We’re the bad guys. We’re responsible for keeping people alive to 85. So we’re now going to try to change healthcare because people are living too long. It just doesn’t make very good sense to me.”

Shifting Resources from Specialty to Primary Care Dr Cohen: “Let’s talk about specialization for a moment….We don’t go to our general attorney when we have a patent problem, but they’re telling us to do this now in medicine. We have different types of engineers, even journalists. There’s a financial writer, there’s a sportswriter….Now in healthcare we’re telling everybody, ‘You just go to the guy who’s your general doc. He’s going to know everything and maybe we’ll find a specialist for you if the panel decides maybe you’re sick enough to need a specialist.’ It really doesn’t make sense at all.”

Dr Jeffrey Moses, Interventional Cardiologist, named to America’s Top Doctors: “If you have heart failure or heart attack or coronaries in general in the hospital you need to be treated by a cardiologist. Study after study shows that…when you have an illness and you want to have an accurate diagnosis and the most up-to-date and accurate treatment, you want a specialist.”

Patient Privacy Dr Samuel Guillory, Ophthalmologist, Refractive and Orbital Surgery, named to Castle Connolly’s New York’s Top Doctors: “We’re being asked by the executive

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branch…to break the code with patients and deliver all their records into electronic medical records.”

Cost-Cutting Methods Dr Fields: “Government is in the process of duplicating everything that managed care did for the last 15 years that was reviled by everybody and which we fought very hard to overcome. The courts finally said, ‘You can’t have withholds. You can’t pay people to deny care. You can’t have gag rules.’ The government is in the process of doing all that. Massachusetts is about to establish capitation [a fixed payment remitted at regular intervals to a medical provider] as the rule of the state. Capitation was the worst thing that ever happened to medical care.”

Dr Joel Kassimir, Dermatologist, Mt. Sinai Hospital, New York: “We’re now being told by physicians advising the president that we take the Hippocratic Oath too seriously.”

CAPTION CONTEST

Dr Tracy Pfeifer, Plastic Surgeon, President, New York Regional Society of Plastic Surgeons: “When physicians graduate from medical school we take an oath, the Hippocratic Oath, to do no harm to our patients. It’s a very important philosophy to us and we uphold it and hold it very dear to our hearts. Plato, another philosopher, used to say things like, ‘Those with a poor physical constitution should be allowed to die. The weak and the ill-constituted shall perish.’

These government programs that are being proposed I think are very scary in the sense that physicians could be induced to violate the Hippocratic Oath. There’s a limit to how much of a financial penalty each individual practitioner is going to be able to bear….If the patient is sitting in the examination room with us and they’re wondering, ‘Is the doctor not ordering a test for me because he’s going to get penalized if he does it?’

This is a major, major problem for patients and physicians alike.” ■

Submit your caption at www.AHDBonline.com.

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MICARDIS 80 mg Now for Cardiovascular (CV) Risk Reduction1 MICARDIS® (telmisartan) tablets are indicated for reduction of the risk of myocardial infarction, stroke, or death from CV causes in patients 55 years of age or older at high risk of developing major CV events who are unable to take ACE inhibitors.1 IMPORTANT SAFETY INFORMATION WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS® (telmisartan) tablets should be discontinued as soon as possible (See Warnings and Precautions).

In patients with renal artery stenosis or severe renal impairment, care should be exercised with dosing of MICARDIS. In patients with severe heart failure, decline in renal function and, rarely, acute renal failure and/or death has been associated with inhibiting the renin-angiotensin system.

Because studies with telmisartan did not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared, consider using the ACE inhibitor first.

Please see Brief Summary of Prescribing Information, including full indication, on adjacent page.

Use of MICARDIS with an ACE inhibitor is not recommended.

Reference: 1. Micardis PI. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2009.

Volume depletion and/or salt depletion should be corrected in patients before initiation of therapy or symptomatic hypotension may occur.

For additional information, please ask your local sales representative.

Copyright © 2009, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

(10/09)

MC68413

6:37:36 PM

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Table 1

WARNING: AVOID USE IN PREGNANCY When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS tablets should be discontinued as soon as possible. See Warnings and Precautions.

Adverse Events Occurring at an Incidence of ≥ 1% in Patients Treated with MICARDIS and at a Greater Rate Than in Patients Treated with placebo Te lmis a rt an ( n= 1455) %

Pl ac eb o ( n= 380) %

Upper respiratory tract infection

7

6

Back pain

3

1

Sinusitis

3

2

Diarrhea

3

2

Pharyngitis

1

0

BRIEF S UMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Hypertension: MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. Cardiovascular Risk Reduction: MICARDIS is indicated for reduction of the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients 55 years of age or older at high risk of developing major cardiovascular events who are unable to take ACE inhibitors. High risk for cardiovascular events can be evidenced by a history of coronary artery disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk diabetes (insulindependent or non-insulin dependent) with evidence of end-organ damage. MICARDIS can be used in addition to other needed treatment (such as antihypertensive, antiplatelet or lipid-lowering therapy).

Studies of telmisartan in this setting do not exclude that it may not preserve a meaningful fraction of the effect of the ACE inhibitor to which it was compared. Consider using the ACE inhibitor first, and, if it is stopped for cough only, consider re-trying the ACE inhibitor after the cough resolves. Use of telmisartan with an ACE inhibitor is not recommended.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality: Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue MICARDIS tablets as soon as possible [see Boxed Warning]. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Inform mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester that most reports of fetal toxicity have been associated with second and third trimester exposure. Nonetheless, when patients become pregnant or are considering pregnancy, have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, MICARDIS should be discontinued unless they are considered lifesaving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Hypotension: In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with MICARDIS. Either correct this condition prior to administration of MICARDIS, or start treatment under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline.

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Hyperkalemia: Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk. Impaired Hepatic Function: As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

Similar results have been reported with MICARDIS. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed.

There has been no long term use of MICARDIS in patients with unilateral or bilateral renal artery stenosis but anticipate an effect similar to that seen with ACE inhibitors. Dual Blockade of the ReninAngiotensin-Aldosterone System: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function. The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months.

Patients receiving the combination of MICARDIS and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of MICARDIS and ramipril is not recommended.

ADVERSE REACTIONS The following adverse reaction is described elsewhere in labeling: Renal dysfunction upon use with ramipril. Clinical Trials Experience: Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Hypertension: MICARDIS has been evaluated for safety in more than 3700 patients, including 1900 treated for over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have infrequently required discontinuation of therapy. In placebocontrolled trials involving 1041 patients treated with various doses of MICARDIS (20-160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo. Adverse events occurring at an incidence of ≥1% in patients treated with MICARDIS and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1.

In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, nonspecific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated). Clinical Laboratory Findings: In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia.

Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Cardiovascular Risk Reduction: Because common adverse reactions were well characterized in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% on placebo. The only serious adverse events at least 1% more common on telmisartan than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%). In clinical studies with patients at high risk of developing major cardiovascular events, cases of sepsis, including some with fatal outcomes, have been reported. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of MICARDIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, and tendon pain (including tendonitis, tenosynovitis). Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS.

USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic Effects, Pregnancy Categories C (first trimester) and D (second and third trimesters). See Warnings and Precautions. Nursing Mothers: It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving MICARDIS in hypertension clinical studies, 551 (19%) were 65 to 74 years of age and 130 (4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Of the total number of patients receiving MICARDIS in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Insufficiency: Monitor carefully and uptitrate slowly in patients with biliary obstructive disorders or hepatic insufficiency.

OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

Rx only

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Health Plan Retention and Pharmacy Costs of Newly Diagnosed Patients with Chronic Kidney Disease in a Managed Care Population Maureen Kubacki, PharmD, MBA; Chureen Carter, PharmD, MS; Alan D.L. Herrera, PharmD; Jim Wang, PhD; Janice M. Lopez, PharmD; Catherine T. Piech, MBA Background: Chronic kidney disease is prevalent in the United States, and diabetes and hypertension cause up to two thirds of all new cases. Many health plans believe that these patients do not retain their health plans for a long duration, therefore plans do not focus on prevention for this disease.

Objective: To determine health plan retention rates and direct healthcare costs of adults with newly diagnosed chronic kidney disease with diabetes or hypertension.

Methods: A total of 31,917 patients with chronic kidney disease were included in this study between January 1995 and December 2006, using a managed care database. Patients were divided into 3 subgroups for cost comparison—patients with chronic kidney disease only (n = 8836), those with chronic Maureen Kubacki kidney disease with diabetes (n = 11,252), and patients with chronic kidney disease with hypertension (n = 20,836). Follow-up of patients from index period of initial kidney disease diagnosis was 5 years. Average enrollment duration was 38 months; 60% of all patients remained enrolled at 3 years postdiagnosis.

Results: On average, patients with chronic kidney disease and diabetes and those with chronic kidney disease and hypertension remained enrolled slightly longer than chronic kidney disease–only patients (39 months, 40 months, and 36 months, respectively). The largest number of claims was for inpatient medical, followed by pharmacy and laboratory. Mean annual direct healthcare costs were higher for patients with chronic kidney disease and diabetes ($20,165) and those with chronic kidney disease and hypertension ($17,612) compared with patients with chronic kidney disease only ($9390).

Conclusion: The study findings indicate that most patients who are newly diagnosed with chronic kidney disease retain their health plan affiliation for a considerable period, including those with diabetes or hypertension. Increased direct healthcare costs were associated with the presence of comorbidities in patients with chronic kidney disease. [AHDB. 2009;2(7):283-290.]

C

hronic kidney disease (CKD) affects approximately 26 million people in the United States.1 Diabetes and hypertension cause up to two thirds of all new CKD cases.1,2 According to Medicare policy, health plans are financially responsible for the care of CKD patients for up to 33 months after they have reached the final stage of end-stage renal disease (ESRD).3 Data from the Institute for Health and Productivity Management 2001 database show that treatment costs nearly double from one stage of CKD to the next.4 The stages of CKD are defined based on the glomerular filtration rate (GFR) as determined by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines.5

Dr Kubacki is Senior Manager, Dr Carter is Associate Director, Dr Herrera is Senior Manager, Dr Wang is Associate Director, Biostatistics, Dr Lopez is Regional Associate Director, and Ms Piech is Vice President, all at Health Economics and Outcomes Research, Centocor Ortho Biotech Services, LLC, Horsham, PA.

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Insurance claims for patients with CKD average $5000 to $12,000 per patient per year (PPPY) as a patient proceeds from stage 1 (GFR ≥90 mL/min/1.73 m2) to stage 2 (GFR 60-89 mL/min/1.73 m2), $15,000 to $28,000 PPPY from stage 3 (GFR 30-59 mL/min/1.73 m2) to stage 4 (GFR 15-29 mL/min/1.73 m2), and exceed $70,000 PPPY once the patient reaches stage 5 (GFR <15 mL/min/1.73 m2).4 Progressive CKD presents a burden to employers as suggested by researchers who examined ESRD-related nonmedical costs for employers.6 It was estimated that employers may incur life insurance costs of $55,055 per ESRD-related death, disability insurance costs of $31,617 per ESRD disability, and worker replacement costs of $27,869 per ESRD-related lost worker.6 From a managed care perspective, it has been suggested that controlling and stabilizing the main comorbidities of CKD—diabetes and hypertension—may slow the progression of CKD, which would result in a reduction of healthcare costs.7 Factors that may be associated with optimal quality of care for patients with

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KEY POINTS Approximately 26 million Americans have chronic kidney disease.  About two thirds of all new cases are caused by diabetes and hypertension, suggesting that early intervention can reduce or delay the progression to this devastating and costly disease.  This study’s findings indicate that most patients who are newly diagnosed with chronic kidney disease retain their health plan for a considerable period.  In this study of 31,917 patients with chronic kidney disease, the mean annual total medical costs were $22,444 for patients with kidney disease plus diabetes, $19,667 for those with kidney disease plus hypertension, and $10,170 for patients with kidney disease only. 

CKD during the 12-month predialysis phase have been identified, including predialysis erythropoietin therapy, nephrology referrals, and phosphate binder/vitamin D administration. As many as 48.7% of patients did not have any interventions associated with optimal care, suggesting a need for proactive management of CKD in the managed care setting to reduce utilization, while improving patient outcomes.8 Similarly, a retrospective

Information regarding retention of CKD patients will enable managed care plans to understand the potential impact of treating predialysis CKD as a chronic illness on the plan and the impact on its members. Such data may encourage plans to implement early-intervention strategies and potentially minimize costly expenditures in later stages. claims analysis of 27 health plans in 19 states evaluated resource utilization in 3 defined time periods9: • Predialysis: months 2 to 6 before initial dialysis • Peridialysis: 30 days before and 30 days after dialysis • Postdialysis: months 2 and 3 after initial dialysis.

Per patient per month charges were highest in the peridialysis period ($35,292 vs $4265 for predialysis and $15,399 for postdialysis), and treatments with nutritional supplements and medications such as angiotensin-converting enzyme inhibitors and erythropoietin were suboptimal.9 A directive has been issued for managed care plans to manage CKD through early intervention to improve outcomes and reduce costs.10-12

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Although data are available that establish the cost impact of CKD, as well as identify gaps in the treatment of CKD patients at all stages, data to characterize retention among newly diagnosed CKD patients in managed care plans are limited.

Information regarding retention of CKD patients will enable managed care plans to understand the potential impact of treating predialysis CKD as a chronic illness on the plan and the impact on its members. Such data may encourage plans to implement early-intervention strategies and potentially minimize costly expenditures in later stages.

The purpose of this study was to examine the health plan retention rates and pharmacy costs among newly diagnosed CKD patients, including those with diabetes or hypertension, from a managed care perspective. The main focus was to look at the length of time patients with CKD, CKD and diabetes, and CKD and hypertension remain within a health plan after the initial CKD diagnosis, and compare the direct costs of CKD alone and the costs of CKD plus these closely related comorbidities.

Methods Data Source De-identified medical and pharmacy claims from the PharMetrics patient-centric database13 between January 1995 and December 2006 were used to conduct this analysis. The PharMetrics database was selected because it is largely representative of the commercially insured population in the United States. This longitudinal database captures de-identified medical and pharmacy claims from 85 health plans that are submitting complete patient-level data for more than 45 million managed care lives. The average member enrollment across the entire database is 2 years. Data elements used in this analysis include health plan product type, health plan payer type, enrollment records, patient demographics, diagnoses, Episode Treatment Groups (ETG) codes, and prescription records.

Study Design We utilized a retrospective cohort consisting of 3 subgroups of newly diagnosed patients with CKD: (1) CKD only, (2) CKD and diabetes, and (3) CKD and hypertension. All patients were at least 18 years old as of the date of their initial CKD diagnosis, had initiated health plan enrollment between January 1, 1995, and September 2001, and had at least 1 CKD claim, using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes:

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Figure 1 Study Timeframe Preindex period 6-Month baseline period No prior CKD diagnosis

Diagnosis period for CKD Diagnosis and index date

January 1, 1995-June 30, 1995

July 1, 1995-September 30, 2001

5-Year follow-up period

CKD indicates chronic kidney disease.

585.XX, 592.XX, 593.9, including a 180-day preindex period with no evidence of CKD (Figure 1).

Patients were excluded if they had missing member data or enrollment data of less than 6 months. Patients identified after 2001 were not included, because the objective was to have a 5-year follow-up period for the identified diagnosis. Each patient was followed for 5 years from index diagnosis, and the length of enrollment was captured at the patient level.

Subgroups were identified by segmenting the patients with CKD according to evidence of the selected comorbidities—diabetes and hypertension. Diabetes and hypertension were identified by the presence of corresponding ETG codes. The ETG coding method is an illness classification system that identifies and classifies an entire episode of care for a patient, taking into account all medical care delivered in the inpatient and outpatient setting collectively for that episode.14 The ETG system considers patient age, comorbidities, procedures, clinical complications, and pharmaceutical claims in a synergistic manner to group patients by total clinical activity.

ETG coding was selected for this study over ICD-9CM codes, because ETG codes more accurately and completely represent the patient episodic healthcare profile. ETG codes allow researchers to capture underdiagnosed cases that would otherwise be missed by ICD9-CM codes. ETG codes are already formatted and readily retrievable from the PharMetrics patient-centric database.13 Patients with no evidence of diabetes or hypertension were categorized as the CKD-only group.

CKD patients with ETG codes 278 to 281 and 908-4 were categorized as the CKD and diabetes group. CKD patients with ETG codes 27 to 30 were categorized as the CKD and hypertension group.

Outcomes Measures The overall duration of health plan enrollment was reported in days and months, as a continuous variable, for each subgroup based on patient level enrollment

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Table 1 Baseline Characteristics CKD only (n = 8836)

Characteristic Age (mean ± SD), y 45.6 (±16.2) 4169 (47.2) Male, N (%)

CKD + CKD + diabetes hypertension (n = 11,252) (n = 20,836) 58.3 (±16.6)

59.2 (±17.2)

6049 (53.8)

10,963 (52.6)

Diagnosing physician specialty, N (%) 297 (3.4) 1251 (11.1) Cardiology 507 (5.7) 1620 (14.4) Nephrology 43 (0.5) 185 (1.6) Endocrinology Internal medicine 1549 (17.5) 2608 (23.2) 1646 (18.6) 1983 (17.6) General/family practice 4794 (54.3) 3605 (32.0) Othera Geographic region, N (%) 1651 (18.7) East 5641 (63.8) Midwest 1265 (14.3) South 279 (3.2) West Plan type, N (%) HMO Indemnity PPO Point of service Missing/unknown

2194 (10.5) 3158 (15.2) 221 (1.1) 4766 (22.9) 3194 (15.3) 7303 (35.0)

2242 (19.9)

4498 (21.6)

6585 (58.5)

11,528 (55.3)

2070 (18.4)

4112 (19.7)

355 (3.2)

698 (3.3)

5307 (60.1)

8930 (79.4)

15,671 (75.2)

76 (0.9)

30 (0.3)

71 (0.3)

1305 (14.8)

840 (7.5)

2047 (9.8)

1733 (19.6)

1072 (9.5)

2251 (10.8)

415 (4.7)

380 (3.4)

796 (3.8)

a

Includes not specified (41%), urology (17.6%), and emergency department physicians (5.5%).

CKD indicates chronic kidney disease; HMO, health maintenance organization; PPO, preferred provider organization.

records. Enrollment status for each patient was analyzed and aggregated at annual intervals, and reported as a yearly categorical variable for each subgroup.

This study looked at direct healthcare costs and pharmacy costs, which together comprise total medical costs. Annualized direct healthcare costs were calculat-

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Figure 2 Patient Distribution, by Payer Typea Commercial Medicaid Medicare Risk Self-insured Unknown

CKD + diabetes

CKD + hypertension

CKD only

1%

2%

10%

12%

19% 46%

44%

2% 13%

40%

40%

63%

3% 2%

3%

a

Percentages may not equal 100% because of rounding.

CKD indicates chronic kidney disease.

ed based on health plan payments for inpatient, emergency department visits, home health visits, office visits, laboratory testing, and other outpatient claims.

Costs were divided into total inpatient, total outpatient, and total medical costs for each subgroup. The annualized cost of total pharmaceutical treatment was calculated based on health plan payments for all prescription medications. Costs were summarized for each subgroup and presented in US dollars.

Statistical Analysis Descriptive statistics were provided for both continuous and categorical variables by subgroup and overall.

All statistical analyses were performed using SAS release 9.1.3 (SAS Institute, Cary, NC).

Results Study Population A total of 31,917 eligible patients were identified and comprised the newly diagnosed CKD cohort. The study population consisted of 8836 CKD-only patients, 11,252 patients with CKD and diabetes, and 20,836 patients with CKD and hypertension. The CKD and diabetes and CKD and hypertension subgroups were not mutually exclusive, and had overlapping patients. Among 23,081 patients identified with comorbidities, 9007 (39%) patients had both diabetes and hypertension.

Table 1 (page 285) lists the study population baseline characteristics for the subgroups. The average age for all eligible patients with CKD was 55 years; of these patients, 51.2% were men. Patients with CKD and diabetes (average, 58.3 years) and those with CKD and hypertension (average, 59.2 years) were older than the

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CKD-only (average, 45.6 years) patients. The proportion of men was higher in the CKD and diabetes (53.8%) and CKD and hypertension (52.6%) subgroups compared with the CKD-only subset (47.2%).

Slight differences were seen in the initial diagnosis of CKD by physician specialty. There was a trend toward a greater proportion of patients with CKD and diabetes and patients with CKD and hypertension diagnosed with CKD by a nephrologist compared with the CKD-only subgroup. A large number of patients in each subgroup were initially diagnosed with CKD by a physician who is not specialized in cardiology, nephrology, endocrinology, or internal medicine/general family practice. The top identifiable specialties included in the â&#x20AC;&#x153;otherâ&#x20AC;? category were urology and emergency department physicians; however, the majority of physician coding was not specified.

Geographic distribution reflected representation from all 4 regions of the United States, with most patients residing in the Midwest. The majority of the patients in each subgroup belonged to a health maintenance organization.

Figure 2 outlines the distribution of patients by payer type. A greater proportion of CKD-only patients (63%) was enrolled in a commercial plan compared with those with CKD and diabetes (46%) or with CKD and hypertension (44%). Conversely, a greater proportion of patients with CKD and diabetes (40%) and CKD and hypertension (40%) had coverage through a Medicare Risk plan compared with CKD-only patients (13%).

Duration of Enrollment The average duration of enrollment was slightly

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Table 2 Annual Enrollment Persistence Status CKD only (n = 8836) N (%)

CKD + diabetes (n = 11,252) N (%)

CKD + hypertension (n = 20,836) N (%)

Overall (n = 31,917) N (%)

641 (7.3)

592 (5.3)

1053 (5.1)

1885 (5.9)

2 yrs

2897 (32.8)

2972 (26.4)

5514 (26.5)

9209 (28.9)

3 yrs

5658 (64.0)

6372 (56.6)

12,000 (57.6)

19,094 (59.8)

4 yrs

7061 (79.9)

8873 (78.9)

15,792 (75.8)

24,840 (77.8)

5 yrs

7677 (86.9)

9535 (84.7)

17,113 (82.1)

26,886 (84.2)

Duration 1 yr

CKD indicates chronic kidney disease.

Table 3 Healthcare Utilization and Expenditures CKD only (n = 8836)

CKD + diabetes CKD + hypertension Overall (n = 11,252) (n = 20,836) (n = 31,917)

27 (74.4)

43 (66.9)

37 (62.0)

36 (64.8)

Pharmacy

15 (21.4)

46 (40.4)

41 (38.7)

33 (36.2)

Emergency department

5 (13.5)

6 (11.6)

5 (11.3)

5 (11.7)

Home health

6 (17.0)

9 (18.9)

7 (17.2)

7 (18.0)

Office visits

10 (13.4)

18 (23.4)

17 (22.0)

15 (19.8)

Laboratory

13 (22.9)

26 (35.0)

23 (34.9)

20 (31.8)

Other outpatient

16 (24.8)

27 (40.2)

25 (36.8)

22 (34.9)

$20,165 ($37,685.30) $422,444 ($39,591.70) $2409 ($58,990)

$17,612 ($34,446.50) $19,667 ($36,287.90) $2185 ($5585)

$15,106 ($37,825.60) $16,748 ($39,178.80) $1793 ($4916)

Utilization and expenditures Annualized resource utilization claims, mean (SD) Inpatient

Annualized total direct healthcare costs $9390 ($44,415.70) Mean (SD) $10,170 Annualized total medical costs ($44,824.70) Mean (SD) $904 Annualized total pharmacy costs ($2748.10) Mean (SD) CKD indicates chronic kidney disease.

longer for the CKD and diabetes (1163 days; 39 months) and the CKD and hypertension (1190 days; 40 months) subgroups compared with the CKD-only (1079 days; 36 months) subgroup. Overall, newly-diagnosed CKD patients remained enrolled in their health plan at 3 years postdiagnosis. Table 2 summarizes the enrollment status at yearly intervals for the subgroups and the overall group.

When grouping the patients into subgroups of CKD only, CKD and hypertension, or CKD and diabetes, we looked at their entire diagnostic phase and follow-up period. For example, for patients to be classified as CKD only, they could not have hypertension or diabetes mellitus anytime on or after their first diagnosis of CKD up to 5 years of follow-up period.

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Costs Annual direct healthcare costs are outlined in Table 3 and Figure 3. The mean annual direct healthcare costs were substantially greater for patients with CKD and diabetes ($20,165) and those with CKD and hypertension ($17,612) compared with patients with CKD only ($9390).

Pharmacy. The mean annual pharmacy costs (Table 3, Figure 4) were substantially higher for the patients with CKD and diabetes ($2409) and CKD and hypertension ($2185) compared with the CKD-only ($904) patients.

Medical. The mean annual total medical costs (Table 3) were substantially greater for patients with CKD and diabetes ($22,444) or CKD and hypertension ($19,667) compared with patients with CKD only ($10,170).

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Figure 3 Direct Healthcare and Total Medical Costs

Figure 4 Mean Yearly Pharmacy Costs

Total medical costs Direct healthcare costs

25,000

3000

2500

Mean pharmacy costs, $

20,000

Cost, $

15,000

10,000

$2409 $2185

2000

1500

$904a

1000

500

5000

0 CKD + diabetes

0 CKD only

CKD + diabetes

CKD + hypertension

CKD indicates chronic kidney disease.

Discussion The study used ETG codes to classify the patients into 3 groups; those with CKD and hypertension and those with CKD and diabetes mellitus were given this designation at the beginning of the study and were then compared with the CKD-only group regarding enrollment duration and cost. This project was undertaken to identify the proportion of patients with newly diagnosed CKD that remain in the same health plan over time. An assumption was made that the longer a patient remains within a health plan, the better the opportunity to implement and assess the impact of early intervention strategies for disease management and overall quality of health.

Early intervention in these populations is paramount to preventing or delaying disease progression and, in parallel, to potential cost reduction for the health plan, employers, and patients/members.

Smith and colleagues documented that per-patient costs increased as the stages of CKD progressed.15 Our results of increased pharmacy costs for CKD patients with disease-related comorbidities agree with Smith and colleaguesâ&#x20AC;&#x2122; findings, which demonstrated that costs for

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CKD + hypertension

CKD only

a

P <.001.

CKD indicates chronic kidney disease.

CKD patients were much higher in those with diseaserelated comorbidities compared with those with CKD alone. Delay of disease progression to the next stage could, therefore, also have financial benefits to health plans. Implementation of an aggressive disease-specific approach by a health plan could impact patient outcomes by a possible delay of disease progression as well.

In this study, we evaluated 3 groups of newly diagnosed CKD patients stratified based on the documented coexistence of hypertension or diabetes. Patients with CKD and comorbidities tended to stay with their same health plan for approximately 3 months longer than patients with CKD only. To ensure that CKD patients were accurately identified, a frequency distribution was run, evaluating the number of patients in each subgroup (ie, CKD only, CKD and diabetes, and CKD and hypertension) with 1 claim for CKD versus those with more than 1 claim. The subgroups were similar in that approximately 70% of patients in each subgroup had at least 2 claims for CKD, providing additional validity to the diagnosis of CKD. Approximately 66% of CKD-only patients were enrolled in commercial plans, whereas a larger proportion of the patients with CKD and diabetes and CKD and hypertension were enrolled in Medicare Risk plans. The average retention time may be influenced or directed by the Medicare timeline law that dictates when Medicare coverage begins for a CKD dialysis patient. As the law extends this timeframe from the

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current 33 months to the proposed 42 months, retention time in health plans will most likely expand, further necessitating the need to intervene as early as possible in these at-risk employee populations.16 Early intervention in these populations is paramount to preventing or delaying disease progression and, in parallel, to potential cost reduction for the health plan, employers, and patients/members. Our findings, which have not been documented extensively in previous studies, support the notion that newly diagnosed patients with CKD and those with diseaserelated comorbidities retain their healthcare plans for considerable periods.

Limitations This study design has several limitations. Our goal was to highlight the amount of time patients who are actually diagnosed with CKD remain in plans, which provide a strong incentive to treat it appropriately rather than assume that patients would not be in the plan long enough to reap the benefits of treatment. We acknowledge that the number of patients diagnosed with CKD in the real world is well below what would be found if proper screening was conducted. We also acknowledge that CKD was likely more prevalent than it appears in these data we evaluated, although patients with CKD who are not diagnosed may move between plans at similar rates as those without CKD. In addition, there were potential overlaps between the CKD and diabetes and CKD and hypertension subgroups. Factors for patient disenrollment were not available due to the retrospective nature of the study.

Only newly diagnosed CKD patients were included in the study; therefore, retention periods for existing CKD patients and a healthy non-CKD cohort were not evaluated. A diagnosis of CKD was captured during the identification period only (July 1, 1995-September 30, 2001), so patients with a new CKD diagnosis during the 5-year follow-up period were not evaluated.

The study design also did not account for patients whose diagnosis of CKD might have been ruled out by further investigation. The retention rates reported may not be representative of all CKD patients, because they may be different for patients who had a previously established CKD diagnosis (not newly diagnosed).

Also, retention rates and costs were not evaluated within and between subgroups for differing stages of CKD and hypertension or severity of diabetes (eg, requiring oral or injectable medications). Direct comparison between groups in similar plan types was also not evaluated.

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This study does not account for access to healthcare differences and its impact on costs among different plans. Finally, the use of ETG codes in this analysis limited the ability to compare it with other studies using traditional diagnosis and procedure costs.

Managed care plans may benefit from earlier management strategies for CKD, because these patients could contribute to increased healthcare utilization and cost over the long-term.

Conclusion The majority of newly diagnosed CKD patients retain their health plan affiliation for a considerable period, including those with diabetes or hypertension.

Presence of these comorbidities resulted in increased total direct healthcare costs. Results of this study further support the need for early intervention in CKD. Managed care plans may benefit from earlier management strategies for CKD, because these patients could contribute to increased healthcare utilization and cost over the long-term. â&#x2013; Acknowledgment

This study was funded by Centocor Ortho Biotech Services, LLC. Disclosure Statement All the authors are employed by Centocor Ortho Biotech Services, LLC.

References

1. National Kidney Foundation. The facts about chronic kidney disease (CKD). www.kidney.org/kidneydisease/ckd/index.cfm#facts. Accessed June 28, 2008.

2. The American Society of Nephrology. Facts and Statistics. www.asn-online.org/ facts_and_statistics/faq.aspx. Accessed June 28, 2008.

3. Centers for Medicare & Medicaid Services. Medicare Coverage of Kidney Dialysis and Kidney Transplant Services. May 2008. www.medicare.gov/Publications/ Pubs/pdf/10128.pdf. Accessed June 28, 2008.

4. Sullivan S. Employer challenges with the chronic kidney disease population. J Manag Care Pharm. 2007;13(9 suppl D):S19-S21.

5. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266.

6. Kamal-Bahl SJ, Pantely S, Pyenson B, Alexander CM. Employer-paid nonmedical costs for patients with diabetes and end-stage renal disease. Prev Chronic Disease.

2006;3:A83. Epub 2006 Jun 15.

7. Rasu RS, Crawford T, Manley HJ, Balkrishnan R. Treatment of hypertension and diabetes mellitus in patients with chronic kidney disease: a review. Expert Opin Pharmacother. 2007;8:2543-2551.

8. London R, Solis A, Goldberg GA, et al. Examination of resource use and clinical interventions associated with chronic kidney disease in a managed care population.

J Manag Care Pharm. 2003;9:248-255.

9. Robbins JD, Kim JJ, Zdon G, et al. Resource use and patient care associated with chronic kidney disease in a managed care setting. J Manag Care Pharm. 2003;9:238-247.

10. Chronic kidney disease: stating the managed care case for early treatment.

Discussion and consensus of presentations of economic analyses, managed care

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organization case studies, and opportunities for intervention in a managed care setting. May 3-5, 2001, Chicago, Illinois. Am J Manag Care. 2002;8(4 suppl):S112-S120.

11. Weiner DE. Causes and consequences of chronic kidney disease: implications for managed health care. J Manag Care Pharm. 2007;13(3 suppl):S1-S9.

12. Wright A. Preparing MCOs to manage chronic kidney disease. Manag Care.

2003;Spec No:13-6; discussion 17-20.

13. IMS Health. PharMetrics patient-centric database. Watertown, MA; 2008.

14. Ingenix. Symmetry episode treatment groups: measuring health care with mean-

ingful episodes of care. 2007. www.ingenix.com/content/attachments/Symmetry ETG_WhitePaper.pdf. Accessed June 27, 2008.

15. Smith DH, Gullion CM, Nichols G, et al. Cost of medical care for chronic kidney disease and comorbidity among enrollees in a large HMO population. J Am Soc Nephrol. 2004;15:1300-1306.

16. Geisel J. House panel approves renal care cost-shift. Business Insurance. July 30, 2007. www.businessinsurance.com/article/20070730/NEWS/200010770. Accessed October 16, 2008.

STAKEHOLDER PERSPECTIVE Alignment of Incentives along the Healthcare Payer Continuum for Patients with Kidney Disease PAYERS: Payers have members and beneficiaries with certain high-cost and high-utilization diagnoses on their radar screen for a variety of reasons, and chronic kidney disease (CKD) is one such diagnosis.

As the authors of this article have nicely quantified, CKD diagnosis—alone or with comorbidities—is associated with increased costs (ie, medical and pharmacy) and greater utilization of services (ie, outpatient physician and specialty visits, dialysis, and inpatient hospitalization).

The natural progression of disease management and financial obligations often flows initially from a commercial or a Medicaid responsibility to eventually becoming a permanent Medicare responsibility.

The alignment of incentives within this payer continuum encourages the initial responsible payer to have early identification means for this diagnosis, through the use of a coding system such as the ICD9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) or through other diagnostic identifiers on the medical benefit or the drug surrogates on the pharmacy benefit.

Once members are identified, health plans are further incentivized to track and facilitate the progression of the timeline along the plan care continuum, until the next handoff or transition point to a subsequent payer. Simultaneously, during this timeframe, it is in the specific plan’s or payer’s best interest to actively case-manage these members to slow their disease progression and to minimize utilization of avoidable services, such as preventable hospitalizations.

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Proposed regulatory changes that would expand the tenure of a member’s time on a pre-Medicare coverage further encourages a payer’s active case-management of these members during the plan’s time of financial responsibility.

PATIENTS: Receiving a diagnosis of CKD elicits a variety of responses in a person, such as fear, anxiety, or planning for the future. It also becomes a decision point on how to best manage, live with, and address the forthcoming progression.

If the rate of progression can be influenced and managed medically, this becomes a time of opportunity for member engagement. Members with currently stable employment and insurance will often consider the risks associated with a job and a coverage change in light of their now having a preexisting diagnosis and its implications for a potential carrier.

Often, the thought of the potential risks in such a change make people opt to remain in their current employment and under their current medical coverage, and they begin to reach out to their existing carrier to understand the resources available to them.

Such a member-directed decision is probably one of the main contributors to health plan retention during the progression down the healthcare payer continuum for newly diagnosed patients with CKD.

November/December 2009

Jeff Januska, PharmD Director of Pharmacy CenCal Health Goleta, California

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Management Tools for Molecular Diagnostic Testing: Financial and Clinical Implications Douglas Moeller, MD Medical Director, Advanced Diagnostics Management, McKesson Health Solutions

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ow that gene tests, markers for tumor receptors, assays for rapid and precise diagnosis of infectious agents, and a variety of other molecular probes have created an entirely new world of personalized medicine, it is time to add new information management tools to capture and manage this knowledge.

With more than 1500 documented tests available for gene testing alone, new strategies are needed for naming and classifying these tests, learning when to use them, and who should pay for all these tests. Even people in the genetic-testing business are struggling to keep up with these advances, especially when one considers that much of the technology driving this explosion is quite new itself. After the completion of the Human Genome Project in 2003, many researchers turned their attention to the implications of gene testing and the clinical applications of molecular diagnostics once the genes themselves were identified.

With more than 1500 documented tests available for gene testing alone, new strategies are needed for naming and classifying these tests, learning when to use them, and who should pay for all these tests.

An immediate problem is keeping track of these new studies with a naming system that uniquely identifies each test. The coding system of the American Medical Association/Current Procedural Terminology and the Centers for Medicare & Medicaid Services/Health Care Financing Administration Common Procedural Coding System (HCPCS) that has been used to order and bill these tests has not kept pace; the current codes predominantly identify the methodology of laboratory process required and are not unique to each analyte or marker. These are sometimes called “stacking codes,” because 5 to 10 codes may be required to describe a particular analysis. Other coding systems, such as

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SNOMED (Systematized Nomenclature of Medicine) and LOINC (Logical Observation Identifiers Names and Codes), are used effectively in electronic health record systems but have more characters than can be used by payer claims systems.

New Online Testing Registry McKesson Health Solutions has proposed a solution to this challenge that would use a coding approach modeled after the S codes in the HCPCS system, where a panel of industry experts in molecular diagnostics testing would provide the oversight principles needed to automatically assign a 5-character alphanumeric code to each new test, starting with a Z and using 34 letters and numbers. Their proposal would add the newly registered test to an online master catalog or an online open registry that anyone can view.

A McKesson web-based application, Advanced Diagnostics Management, incorporates just such a test catalog into the heart of its logic. This test registry serves as the master catalog within the application (and would link directly to a universal catalog if a different national standard should emerge); this would allow a physician (or physician’s office staff) to look up a test, learn about the test and indications for it, and place an order for the test from a clinical laboratory.

Evidence-based criteria have been developed for more than 300 molecular tests using clinical guideline development principles originally developed for InterQual clinical care management criteria. In conjunction with order entry and test-reporting capabilities, this software application permits online test authorization, using established health plan coverage policies to verify the appropriateness of the test in accordance with specific diagnostic information entered by a physician’s office.

Medical and Financial Implications The implications of this approach are significant for personalized medicine. Credible information would be available to providers during the order entry process, ensuring that the appropriate test is being selected for

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the proper reason. Furthermore, this approach will ensure that health plan coverage for the test is confirmed; if it is not a covered test, then the patient could make an informed decision at that point whether to proceed with the recommended test. Once laboratories provide pricing information for self-pay tests, full transparency about financial accountability for paying for these tests will avoid unpleasant surprises later.

The implications for managing the healthcare process are critical; this approach permits useful information about specific tests to be made available to the provider before or as the test is being ordered. Selection of the appropriate test to evaluate a genetic coagulation defect or to quantify the disorder in a drug metabolism pathway (eg, warfarin metabolism) is now a real-time possibility. By making all this information available to the physician, the laboratory, and the patient before the test is ordered, all parties are made fully aware of their options—clinically and financially—before committing to the test itself. Because the system is online, changes could be made dynamically in a way that pro-

COST QUALITY ACCESS

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motes continuous quality improvement.

There are barriers, of course. All key stakeholders need to have confidence that all information conveyed through this system is objective and offers state-

By making all this information available to the physician, the laboratory, and the patient before the test is ordered, all parties are made fully aware of their options. of-the-art solutions. The feedback loops that support continuous quality improvement must also be fully transparent. And, finally, health plans and clinical laboratories must achieve a new level of clarity about what criteria are applied to medical coverage for emerging technology, and what criteria are useful in setting prices for new studies. ■

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November/December 2009

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GENERIC DRUG TRENDS

Increases in Drug Utilization and Patent Expirations: A Recipe for Growth of Generics’ Market Share, despite Stalling on Biosimilars Dalia Buffery, MA, ABD

A

s 2009 is coming to a close, the future of generics appears brighter than ever, with many brand-name medications pending patent expiration by 2011, accounting for about $34 billion in total sales in 2008.1 The drug patent expiration outlook

Table Drug Patent Expiration, 2009-2011 Potential patent 2008 US sales, Brand (generic) expirationa $ million 2009 Adderall XR (amphetamine salts) 1585 Ambien CR (zolpidem controlled-release) 986 b 777 CellCept (mycophenolate mofetil) Clarinex (desloratadine) 251 Prevacid (lansoprazole) 2948c Pulmicort Respules (budesonide) 876 Topamax (topiramate) 2356 Valtrex (valacyclovir) 2020 2010 Aldara (imiquimod topical cream) 375 Arimidex (anastrozole) 617 Astelin (azelastine nasal spray) 273 Cozaar (losartan) 731 282 Differin (adapalene topical)b Effexor XR (venlafaxine extended-release) 2791 1318 Flomax (tamsulosin)b Hyzaar (losartan/hydrochlorothiazide) 548 Mirapex (pramipexole) 344 2011 Aricept (donepezil) 1224 2569 Actos (pioglitazone)b Caduet (amlodipine/atorvastatin) 418 Levaquin (levofloxacin) 1719 Lipitor (atorvastatin) 6392 Patanol (olopatadine ophthalmic 256 solution)b Temodar (temozolomide) 224 Xalatan (latanoprost ophthalmic solution) 494 Zyprexa (olanzapine) 1853 a

These dates can change for many reasons, including patent protections/litigation or exclusivities. bPatent expiration assumes a pediatric extension. c Sales figure apply to the capsule formulation only.

Source: Medco 2009 Drug Trend Report. 2009, page 53.

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overshadows the recent Senate vote to extend the patent exclusivity period for biologics to 12 years, as requested by the biotechnology industry, thereby significantly delaying the introduction of potential biosimilars to the market. A biosimilars pathway now seems likely to become a reality by 2010 or 2011.

Nevertheless, with drug costs doubling in the decade between 1996 and 2006, as was recently shown in a new report from the Agency for Healthcare Research and Quality (AHRQ),2 and the continuing trend of growing utilization of generics in the United States, the growth in first-time generics will likely continue to rise (even if at a lower rate than before), further increasing the competition with brand-name products and possibly contributing to their price inflation, especially after 2011.1 According to the AHRQ report, “Prescription medications accounted for a notably higher share of total expenses for adults ages 18-44 in 2006 than in 1996 (17.6 percent versus 10.2 percent),”2 and “The average expense for a prescription medication purchase was notably higher [for that age group] in 2006 than in 1996 ($161 versus $79).”2 Similarly, Medco projects an increase in health plan drug utilization between 2009 and 2011 (from 0%-1% to 1%-2%, respectively) and in drug price (from 3%-4% to 4%-5%, respectively) per member per year,1 all pointing to the continuing trend of greater generics utilization in the coming years.

A select list of brand-name drugs expected to lose their patent by 2011, as well as their US retail sales in 2008, is listed in the Table. Many of these drugs will likely appear as generics by 2011. If by then a biosimilar pathway becomes available, as is widely anticipated in the industry, the total utilization rate of generics/biosimilars and their share of the total market are likely to increase even further. ■ References

1. Medco Health. Medco 2009 Drug Trend Report. 2009. http://filecache.drivetheweb.com/mr4enh_medco/177/2009+DRUG+T REND+REPORT.pdf. Accessed December 9, 2009.

2. MEPS. AHRQ. Trends in Health Care Expenditures for Adults Ages 1844: 2006 versus 1996. Statistical Brief #254. August 2009 (available December 9 only). www.meps.ahrq.gov/mepsweb/data_files/publications/ st254/stat254.pdf. Accessed December 10, 2009.

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Q. Which Global Generic Company’s Transdermal Patches Were Most Dispensed in the U.S. Last Year?

A.

Mylan Pharmaceuticals.* With one of the most advanced transdermal development and manufacturing facilities in the United States—brand or generic—Mylan is well-recognized as an innovator in transdermal drug delivery technology. In fact, last year 65% of all generic patches dispensed in the U.S. carried the Mylan name.* We have developed more generic transdermal patches than any company in the U.S. and all of our patches are designed with patient safety in mind. None have a bulky, liquid, gel-filled reservoir, which eliminates any concern about the dangers associated with leakage, and none have aluminum or other metals in their backing, which may cause potential burns in MRI patients. So when you need generic transdermal patches…think Mylan.

*IMS National Prescription Audit. 12 months ending December 2008.

©2009 Mylan Pharmaceuticals Inc.

MYNMKT308

2 Generics:Cover 12/11/09 5:45 PM Page 296

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Success stories from payers at the leading edge of pharmacy benefit management: CareFirst BlueCross BlueShield • Carpenters Health & Welfare Trust Fund of St. Louis • Caterpillar, Inc. Chatham Steel Corporation • City of Colorado Springs • Delta Air Lines • Essence Health Care ICON Health & Fitness • Manatee County Government • Molina Healthcare of Michigan Piedmont Community HealthCare Alliance • Procter & Gamble TML Intergovernmental Employee Benefits Pool/Public Employee Benefits Alliance University of Michigan

Visit www.pbmi.com/conference.asp to register today! © 2009, Pharmacy Benefit Management Institute, LP

All Rights Reserved

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Quality Improvement Initiatives: The Missed Opportunity for Health Plans Sara Fernandez-Lopez, PhD; Barbara Lennert, RN, BSN, MAOM Background: The increase in healthcare cost without direct improvements in health outcomes, coupled with a desire to expand access to the large uninsured population, has underscored the importance of quality initiatives and organizations that provide more affordable healthcare by maximizing value.

Objectives: To determine the knowledge of managed care organizations about quality organizations and initiatives and to identify potential opportunities in which pharmaceutical companies could collaborate with health plans in the development and implementation of quality initiatives.

Methods: We conducted a survey of 36 pharmacy directors and 15 medical directors of different plans during a Managed Care Network meeting in 2008. The represented plans cover almost 74 million lives Barbara Lennert in commercial, Medicare, and Medicaid programs, or a combination of them.

Results: The responses show limited knowledge among pharmacy and medical directors about current quality organizations and initiatives, except for quality organizations that provide health plan quality accreditation. The results also reveal an opportunity for pharmaceutical companies to collaborate with private health plans in the development of quality initiatives, especially those related to drug utilization, such as patient adherence and education and correct drug utilization.

Conclusion: Our survey shows clearly that today’s focus for managed care organizations is mostly limited to the organizations that provide health plan quality accreditation, with less focus on other organizations. [AHDB. 2009;2(7):297-304.]

M

any of today’s healthcare concerns focus on the concept of value, which can be defined as a composite of cost, quality, and access.

Expanding access through affordable healthcare insurance will only be possible if healthcare costs are contained through a focus on quality.1 Poor care quality results in costly errors, complications, and re-work. Conversely, high-quality care, namely, the right treatment at the right time, results in more cost-effective care.

This emphasis on value is underscored by a lack of correlation between the increase in healthcare spending in recent years and health outcomes, which is often the result of a lack of information and tracking systems to determine the value of different treatments.2 Greater value, therefore, can be achieved by reducing costs, increasing the quality of care, and/or increasing access. A recent report developed as a collaborative effort between different healthcare stakeholders and quality organizations calls for the development of metric systems that allow measurement and reporting the quality, as well as the cost of care.1 A new Medicare provision will provide $10 million annually to this end for fiscal years 2009-2012.3 These quality metrics are expected to help determine the value of different approaches to treatment and the definition of guide-

Dr Fernandez-Lopez is Assistant Director and Ms Lennert is Director, Xcenda, Palm Harbor, FL.

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lines that maximize value in the US healthcare system.

Private payers and some employer groups are also developing their own quality improvement initiatives, or are incorporating initiatives developed by quality organizations.4 The Centers for Medicare & Medicaid Services’ (CMS) Physician Quality Reporting Initiative (PQRI) represents the first step toward a value-based system.

PQRI is a voluntary pay-for-reporting system, in which participating professionals can earn a bonus payment for reporting to CMS on clinical quality measures specific to their practice.5 The information collected through this program will allow CMS to measure the quality of care and, in time, could lead to the establishment of a pay-for-performance (P4P) system.

Employers and private payers are also increasing their focus on value.6,7 The rise in healthcare insurance premiums has made employers consider quality measures in their insurance purchasing decisions, and in turn, more healthcare plans are seeking accreditation by national quality organizations, such as the National Committee for Quality Assurance (NCQA) and others.8

Current Quality Improvement Environment Today’s health quality organizations and initiatives are fragmented, with no definite leaders. Unlike other countries that have a more centralized system (eg, UK’s National Institute for Health and Clinical Excellence is

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KEY POINTS Quality metrics have the potential to increase the value of the US healthcare system by reducing costs and increasing access to quality care.  The goal of this survey was to evaluate the extent of knowledge of medical and pharmacy directors of current healthcare-related quality improvement initiatives.  Participants had limited knowledge of current quality organizations and initiatives, except for those that offer quality accreditation to health plans and pharmacy benefit management organizations.  This finding, however, presents an opportunity for pharmaceutical companies to collaborate with private health plans to develop quality initiatives, especially for drug utilization. 

the clear leader in developing quality measures and clinical guidelines), in the United States the variety of quality initiatives and organizations have different goals and missions and focus on different stakeholders (Figure 1).

At the federal level, CMS and the Agency for Healthcare Research and Quality (AHRQ) extend their quality measures and improvement efforts to all segments of the healthcare system through different initiatives. Other organizations focus their quality measures and improvement initiatives in 1 or 2 segments. For example, the Leapfrog Group and CheckPoint provide hospital ratings exclusively, whereas Bridges to Excellence focuses on physician quality measures. HealthGrades and different state and Figure 1 Significant Quality Organizations and Their Segment of Focus Hospitals

Medical groups

Health plans

• CMS: Hospital

• CMS: PQRI

• CMS

Quality Alliance • JCAHO • HealthGrades • CheckPoint • Leapfrog Group • State/regional QI collaboratives • Health plans

• NQF

• NCQA accredita-

• HealthGrades

tion and HEDIS • URAC • eValue8

• Bridges

to Excellence • State/regional QI collaboratives • NCQA certification programs • Health plans

Other • CMS: Home

Health Compare • CMS: Nursing

Home Compare • Pharmacy

Quality Alliance

CMS indicates Centers for Medicare & Medicaid Services; JCAHO, Joint Commission on the Accreditation of Healthcare Organizations; NCQA, National Committee for Quality Assurance; NQF, National Quality Forum; PQRI, Physician Quality Reporting Initiative; QI, quality improvement.

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regional quality initiatives, as well as individual health plans, develop their own quality measures for both types of providers—physicians and hospitals. Finally, the NCQA and URAC (formerly Utilization Review Accreditation Commission) focus on rating the quality of healthcare plans and pharmacy benefit management (PBM) organizations. Despite this fragmentation, quality organizations interact and participate in each other’s development of quality metrics and guidelines.

Two organizations stand out for specific segments. For health plans, the NCQA, with its accreditation and its Healthcare Effectiveness Data and Information Set (HEDIS) rating, represents the most followed organization, because employers often consider it the decision factor for their choice of insurance plan. For providers, the National Quality Forum (NQF) is gaining acceptance as the reference for developing national standards of care at the physician level, because many of their quality metrics are part of CMS’s PQRI initiative.

Payers’ Knowledge of Quality Organizations To determine the knowledge of healthcare plan decision makers about different quality improvement organizations and initiatives, we surveyed medical and pharmacy directors of health plans. The survey was conducted live during a single session of the March 2008 Managed Care Network (MCN) meeting of more than 100 leading medical and pharmacy directors, representing more than 150 million covered lives. The survey captured responses from 16 medical directors and 35 pharmacy directors, representing 52 health plans covering almost 74 million lives in commercial, Medicare, and Medicaid programs, or in a combination of them.

The managed care organizations (MCOs) represented in the survey included regional and national plans, as well as small plans (less than 200,000 lives) and large plans (more than 10 million lives). All participants (n = 51) responded to all questions asked during the session. Because 1 participant did not specify his/her job function, there is a discrepancy between the number of medical and pharmacy directors present and the number of health plans represented.

The survey was organized into 5 sections aimed to determine (1) pharmacy and medical directors’ level of knowledge about different quality organizations; (2) MCOs’ current collaboration/accreditation with quality organizations; (3) level of influence of different quality organizations in quality initiatives at MCOs; (4) MCOs’ interest in learning more about quality organizations and initiatives; and (5) MCOs’ openness to accept pharmaceutical companies as potential partners

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Quality Improvement Initiatives

MCOs’ Collaboration with Quality Organizations MCOs’ interaction with each quality organization is different. Both NCQA and URAC issue health plan accreditations, whereas the relationship of MCOs with other quality organizations is more collaborative. The level of interaction varies as shown in the survey results (Figure 3). NCQA was the organization with whom MCOs had the strongest relationship, with 74% of the respondents being or planning to be accredited by it.

Furthermore, 34% of the plans were currently participating in other programs offered by NCQA. This again shows a great difference with URAC, with only 30% of plans being or seeking accreditation from URAC. To further understand the reasons behind some of our observations, in January 2009 we conducted a follow-up online survey of the MCN meeting attendees on why the NCQA and URAC where best known and most referenced for quality initiatives. Many respondents commented that the NCQA is seen as almost “mandatory or expected,” and sometimes listed as a requirement from employers to consider a health plan.

Some respondents commented on the NCQA accreditation requirement by Medicare and some Medicaid state programs. Respondents who chose to seek accreditation from URAC said that they did so mainly because of the lower cost of the accreditation process and the more realistic expectations of the accreditation program for managed care plans. For pharmacy benefit

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Figure 2 Level of Knowledge of Pharmacy/Medical Directors of Different Quality Organizations High/very high

Moderate

Low/none

100 90

Respondents, %

80 70 60 50 40 30 20 10 0

NCQA

URAC

AHRQ

IHI

ICSI

NQF

PQRI

PQA

HQA

Quality organizations/initiatives AHRQ indicates Agency for Healthcare Research and Quality; HQA, Hospital Quality Alliance; ICSI, Institute for Clinical Systems Improvement; IHI, Institute for Healthcare Improvement; NCQA, National Committee for Quality Assurance; NQF, National Quality Forum; PQA, Professional Quality Assurance; PQRI, Physician Quality Reporting Initiative.

Figure 3 Health Plans Collaborating with Quality Organizations 100

Respondents, %

in quality improvement initiatives.

In the first part of the survey, participants were asked to rate their knowledge about different quality organizations. Table 1 (page 300) lists the public and private organizations covered in the first 3 sections of the survey.

Responses show that 92% of participants had high or very high knowledge of the NCQA (Figure 2). This is clearly in line with the NCQA’s focus on health plan accreditation and HEDIS ratings and the influence they have on employers’ choice of insurance. However, their knowledge of URAC (also providing quality accreditations for health plans and PBM organizations) was more varied: 42% of respondents had little or no knowledge about it (Figure 2).

Knowledge about other quality organizations included in the survey was limited. For any of those organizations, more than 70% of respondents had low or no knowledge, with the exception of AHRQ, with only 30% of respondents showing no or little knowledge.

This lack of knowledge about quality initiatives represents a missed opportunity for MCOs to include some of these measures in their programs.

80

74%

60 40

28%

26%

20

19% 8%

6%

4%

4%

4%

IHI

NQF

ICSI

PQA

HQA

0 NCQA

URAC

AHRQ

PQRI

Quality organizations/initiatives Note: For NCQA and URAC, the nature of the collaboration is defined as health plan being accredited or seeking accreditation by NCQA and/or URAC.

managers and utilization management quality programs, URAC seems to be the first choice, given its recognized brand name and experience in this arena.

MCOs’ level of collaboration with any of the other quality organizations was very low, with less than 10% of the plans participating in any quality initiatives. The reasons for the low participation may be related to the relatively low knowledge of other organizations, as well as the limited health plans resources dedicated to quality programs. Respondents commented on the cost and

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Table 1 Organizations Covered During the First 3 Sections of the Survey Organization

Mission

What does it do?

Stakeholders

Comments

AHRQ Agency in the www.ahrq.gov Department of Health and Human Services responsible for healthcare quality research

To improve the quality, safety, efficiency, and effectiveness of healthcare for all Americans

Sponsors/conducts research with evidence-based information on healthcare quality and outcomes, including comparative effectiveness of treatments

Hospitals; providers; patients; federal, state, and local policymakers; payers; health officials; academia

Formerly Agency for Health Care Policy and Research American Recovery and Reinvestment Act of 2009 designated $300 million for comparative effectiveness research

HQA National publicâ&#x20AC;&#x201C; private collaboration www.hospital qualityaliance.org to promote reporting on hospital quality of care

To facilitate continuous improvement in patient care through: Implementing hospital care quality, cost, and value measures Developing and using measure reporting in hospitals nationwide Publicly sharing hospital performance information

Runs Hospital Compare website (www.hospitalcom pare.hhs.gov), with performance information on >4000 hospitals to help consumers assess hospital quality/value to make informed decisions

Consumer representatives, physician/ nursing organizations, employers, payers, oversight organizations (eg, NQF), government agencies (eg, AHRQ)

Independent healthcare collaborative comprised of 37 medical groups representing about 85% of Minnesota physicians

To champion healthcare quality and accelerate improvement in the value of healthcare delivered to the populations served by ICSI

Develops healthcare Providers, medical guidelines and models groups that are recognized beyond Minnesota

NCQA Private, not-forwww.ncqa.org profit organization for healthcare quality improvement

To transform healthcare quality through measurement, transparency, and accountability

Provides quality recommendations to health plans; NCQA accreditation recognized by employers, regulators, and health plans as an important reference in evaluating healthcare quality

Employers, providers, public policy groups, consumer groups, health systems

NQF www.quality forum.org

Not-for-profit membership organization for developing and implementing a national strategy for healthcare quality measurement and reporting

To improve the quality of American healthcare by: Setting national performance improvement priorities and goals Endorsing national standards for measuring/ reporting on performance Promoting national goals through education and outreach programs

Consensus standards endorsed by the NQF are often used by government agencies like CMS for measuring healthcare quality

Consumers, public and private payers, providers, employers, accrediting bodies (eg, NCQA)

PQA www.pqa alliance.org

Collaborative initiative focused on improving healthcare quality at the pharmacy/ pharmacist level

To improve healthcare quality and patient safety in collaboration with key stakeholders to help them make informed choices, improve outcomes, and stimulate development of new payment models

Collects pharmacy Pharmacy/pharmacist performance data and associations, CMS, reports findings to manufacturers consumers, pharmacists, employers, health insurance plans, other healthcare decision makers

ICSI www.icsi.org

What is it?

Also provides accreditation to providers through participation in voluntary programs

Continued

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Table 1 Continued Organization

What is it?

Mission

What does it do?

Stakeholders

Comments

URAC www.urac.org

Independent, nonprofit organization promotes healthcare quality through accreditation and certification programs

To promote continuous improvement in quality/ efficiency of healthcare management

Administers accreditation programs from board accreditation to specific functions for various healthcare stakeholders (eg, hospitals, HMOs, PPOs, third-party administrators, provider groups)

Consumers, providers, employers, regulators, industry experts

Formerly the Utilization Review Accreditation Commission Originally founded to accredit health plans’ utilization review programs The scope of accreditation categories/ eligible organizations has since expanded

AHRQ indicates Agency for Healthcare Quality and Research; CMS, Centers for Medicare & Medicaid Services; HMOs, health maintenance organizations; ICSI, Institute for Clinical Systems Improvement; NCQA, National Committee for Quality Assurance; NQF, National Quality Forum; PPOs, preferred provider organizations; PQA, Professional Quality Assurance.

Influence of Quality Organizations on Healthcare Plans We also asked pharmacy and medical directors to identify which quality organizations most influenced their MCOs’ quality improvement programs. Again, NCQA had the greatest influence, with URAC a distant second (73% and 12%, respectively). No other organization had significant influence on MCOs’ quality improvement priorities: 8% of plans indicated no influence from these external organizations and/or depend on internal decisions for setting quality improvement priorities (Figure 4).

Figure 4 Medical and Pharmacy Directors’ Identification of the Quality Organization that Most Influenced Their Quality Improvement Plans 100 80

Respondents, %

resources needed for quality collaboration/accreditation, and the need to limit themselves to what was required by their clients (large employers and employer groups) and standards, mainly NCQA and sometimes URAC.

73%

60 40 20

12%

8%

4%

2%

2%

IHI

NQF

0 NCQA

URAC

Other/ AHRQ internal decisions

ICSI

PQA

HQA

Quality organizations

MCOs’ Interest in More Information The next part of the survey aimed to determine the level of interest from healthcare plans to learn more about these quality organizations. Although some respondents did not think they missed opportunities by not participating in quality programs, most of them thought they lost some benefits. The main missed opportunities cited were (1) the chance to benchmark themselves against the competition and (2) the chance to enhance their clinical and service outcomes (Figure 5).

The level of interest of medical and pharmacy directors in learning more about various organizations and initiatives is described in Table 2.

URAC’s PBM accreditation standard garnered the most interest, with 34% of respondents expressing high/very high interest in learning more about it. And more than 30% of respondents showed high/very high level of interests in Pharmacy Quality Alliance (also related to quality of pharmacy programs), AHRQ, and NQF. The other organizations were less interesting to

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learn about, including the NCQA, probably because plans already know about it.

We also assessed the level of interest in additional quality programs and/or organizations. Guidelines developed by professional specialty organizations and P4P programs at other MCOs were the areas of main interest, with no or low interest in other initiatives, such as collaborations with state and regional programs, foreign healthcare agencies, or quality measures for other healthcare sectors (Figure 6).

Pharmaceutical Companies as Partners in Quality When asked if value-added programs from pharmaceutical companies supported the quality improvement initiatives of their organizations, the large majority of responses were negative (Figure 7). Pharmacy directors were more negative in their responses compared with medical directors (71% disagreed/strongly disagreed vs 42%, respectively). In the January follow-up survey, the

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Figure 5 Level of Interest of Pharmacy/Medical Directors to Learn about Quality Organizations/Initiatives High/very high

Moderate

Low/none

100

Respondents, %

80

60

40

20

0 NQF URAC- AHRQ PBM

PQA

ICSI

URAC

PQRI

NCQA

IHI

HQA

MCOs indicates managed care organizations; P4P, pay for performance; QI, quality improvement.

Quality organizations/initiatives

Figure 6 Medical/Pharmacy Directors’ Identification of Quality Organizations of Interest 50

Respondents, %

40 30 20 10

0 P4P programs from other MCOs

QI guide- Foreign State/ QI guidelines from healthcare regional QI lines from specialty agencies collabora- advocacy societies tions groups

Other

QI in other healthcare sectors

MCOs indicates managed care organizations; P4P, pay for performance; QI, quality improvement.

reasons for these negative responses included a preference for internal quality programs without external influence, skepticism from health plans on pharmaceutical company involvement with these types of initiatives, and the complaint that many of these programs seem to be geared toward a particular branded product rather than disease states.

However, even though pharmaceutical companies were mainly not considered as quality improvement

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Table 2 Additional Quality Organizations/Initiatives of Potential Interest for MCOs Organizations/ initiatives Example P4P programs from — other MCOs QI guidelines from Guidelines developed and specialty societies endorsed by the American College of Cardiology Foreign healthcare National Institute for Health associations and Clinical Excellence State/regional QI Wisconsin Collaborative for collaboratives Healthcare Quality QI guidelines from Guidelines developed and advocacy groups endorsed by the American Heart Association QI in other healthcare QI measures for home care sectors

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partners, 36% of MCO directors express moderate to very high interest in getting more support and partnership from pharmaceutical companies. Specifically, pharmaceutical companies were viewed as more valuable in providing support in patient compliance/adherence programs, and in appropriate drug utilization programs (Figure 8).

Finally, we wanted to know how some of the larger pharmaceutical companies were rated for their current efforts to support quality improvement initiatives at MCOs. Novartis was the clear leader, with 25% of the responses, followed by GlaxoSmithKline with 19% of the responses (Figure 9). When asked in the follow-up survey about what made those companies’ support programs superior to others, the majority of respondents noted the focus on disease rather than a specific drug, the quality of the programs, the availability of nonbranded educational materials, and the flexibility of the support programs to be adapted to the specific payer quality program.

Conclusion The high increase in healthcare costs in the past decade is starting to build a focus on quality as an integral part of addressing cost-containment without lowering health outcomes. By creating their own quality metrics and systems that allow the development of clinical guidelines, and by collaboration with external quality improvement organizations, health plans can more efficiently allocate their resources to maximize

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Figure 7 Response to Statement, “Pharmaceutical Companies Support the QI Initiatives of my Organization”

Figure 8 Areas Where Pharmaceutical Companies’ Support Is Most Likely to Be Accepted Patient compliance/ adherence Appropriate drug utilization

19%

Patient education NCQA/HEDIS support Disease management

19%

Physician education

62% Other Pharmacist education 0

5

10

15

20

25

30

35

Respondents, % Disagree/strongly disagree Neutral Agree/strongly agree QI indicates quality improvement.

health outcomes for their members. Our survey shows clearly that today’s focus for MCOs is mostly limited to the organizations that provide health plan quality accreditation, such as NCQA or URAC, with less focus on other organizations. By not collaborating with these organizations, health plans may be missing opportunities to develop and adapt already existing quality measures and clinical guidelines for the benefit of their health plan needs.

Our survey also suggests an opportunity for pharmaceutical companies to increase their relationships with health plans by collaborating on quality improvement initiatives, such as patient adherence and compliance, drug utilization, and patient education. To be successful in such collaboration, pharmaceutical companies should develop evidence-based programs focused on a specific disease rather than a specific product, and offer flexible programs that could be adapted to each health plan’s need. ■

References

1. O’Kane M, Corrigan J, Foote SM, et al. Crossroads in quality. Health Aff (Millwood). 2008;27:749-758.

2. Wennberg JE, Fisher ES, Goodman DC, et al. Tracking the care of patients with severe chronic illness: The Dartmouth Atlas of Health Care 2008. April 2008. www.dartmouthatlas.org/atlases/2008_Chronic_Care_Atlas.pdf. Accessed April 20, 2009.

3. Social Secruity Act PL 110-275, §183(a)(1), added §1890, effective July 15, 2008. Contract with a consensus-based entity regarding performance measure-

HEDIS indicates Healthcare Effectiveness Data and Information Set; NCQA, National Committee for Quality Assurance.

Figure 9 Pharmaceutical Companies with the Best ValueAdded Programs to Support MCOs’ QI Initiatives Novartis GlaxoSmith Kline Other sanofiaventis Merck Pfizer Lilly J&J/OrthoMcNeil Janssen Wyeth 0

5

10

15

20

25

30

Respondents, % MCOs indicates managed care organizations; QI, quality improvement. ment. www.qualityforum.org/docs/senate_07_09_08.pdf. Accessed April 20, 2009.

4. Massachusetts employers and health plans continue to support quality care by rewarding physicians through Bridges to Excellence programs. September 25, 2007. www.bridgestoexcellence.org/Content/ContentDisplay.aspx?ContentID=97.

Accessed April 20, 2009.

5. Centers for Medicare & Medicaid Services. Physician quality reporting initiative. www.cms.hhs.gov/pqri/. Accessed April 20, 2009.

6. National Business Coalition on Health. Voices of value-based purchasing: health care leaders reflect on 15 years of leadership. 2008. www.nbch.org/documents/ voices.pdf. Accessed April 20, 2009.

7. Lo Sasso AT, Perloff L, Schield J, et al. Beyond cost: “responsible purchasing” of managed care by employers. Health Aff (Millwood). 1999;18:212-223.

8. National Committee for Quality Assurance. The State of Health Care Quality, 2007. Page 4. 2007. www.ncqa.org/Portals/0/Publications/Resource%20Library/ SOHC/SOHC_07.pdf. Accessed April 20, 2009

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STAKEHOLDER PERSPECTIVE The Missing Quality Standard for Medication Adherence PAYERS: Performance with quality standards has shown steady improvement over the years, but one that has continued to lag is medication adherence.

Best results have been seen in medications whose adherence has been highlighted in a specific quality standard. For example, the NCQA’s antidepressant drug management measure assesses patient adherence at 12 weeks and at 6 months. Medication adherence is strongly correlated with improved outcomes in depression, but for most drugs adherence is not routinely included in quality standards.

Payers and quality organizations should consider what impact a national quality standard for medication adherence across all patients for all drugs would have on stimulating collaborative and competitive efforts among all stakeholders. This single standard could become one of the most important metrics for payers in deciding which healthcare companies provide the best support for ensuring that their employees get well by adhering to their therapy. It could also catalyze collaboration between the industry and payers to develop, test, and implement innovative solutions to medication adherence beyond the current programs that mostly involve written communication to plan members, reinforcing the importance of adherence.

PHARMACEUTICAL COMPANIES: Poor medication adherence continues to be a major concern and opportunity for the pharmaceutical industry. The industry recognizes that the value a product demonstrates in a controlled clinical trial will not be translated in the real-world setting if patients do not adhere to their medication regimen. Drug companies face misperceptions of the value of their products if treatment failure is caused by poor patient adherence rather than by underperformance of the drug. The industry has a strong vested interest in doing anything possible to support medication adherence and the safe and appropriate use of their products.

Improved adherence presents an opportunity not only to improve health outcomes but also to improve revenues essential for continued investment in research and development of innovative medicines.

The industry appreciates the complexity of this issue and realizes that improving medication adherence can only be achieved by fully leveraging each stakeholder —health plans, pharmacy benefit managers (PBMs), employers, healthcare professionals, and patients and

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their families. The industry faces many obstacles in addressing this complex issue, including payers’ reluctance to work with it, requests for only unbranded disease-specific programs rather than programs developed for a specific product, complex legal agreements, and varying interpretations between what is defined as marketing versus as a component of a disease/patient management program.

Reluctance to accept industry support for productspecific patient support programs is severely limiting the competition and innovation needed to address adherence. The industry conducts more market research on professionals who prescribe their products and on patients who depend on their products to improve their well-being than on any other entity.

That research helps to develop beneficial programs for patients and family members that improve their understanding of their medical condition and medication, but because they are brand-specific, these programs are often shunned by stakeholders who could be playing a greater role in increasing their members’ awareness of these resources. To recreate what a drug company can do to build customized support programs for patients with more than 10,000 pharmaceuticals on the market is not practical for any payer, health plan, or PBM. Payers, providers, and patients could benefit from industry support.

The use of technology, interactive patient education, and patient education customized to address specific patient groups based on specific demographics are critical contributions the industry could make to improve product-specific patient education and medication adherence programs.

Not enough is being done to support high-quality, effective patient education designed to improve adherence. To gain dramatic improvement, collaborative efforts are needed that enable the industry to creatively design product-specific programs for patients in addition to unbranded education. Payer input into the design and content would allow for mutually acceptable brand-specific patient support and education, free of bias and nonpromotional.

Jeffrey A. Bourret, MS, RPh, FASHP Senior Director, Customer Marketing & Innovation, US Specialty Customers Pfizer Specialty Care Business Unit, Collegeville, PA

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The Return to Deep Science: Pharmaceutical Research & Development in a Value-Based Healthcare System On-Demand Webcast Impact of Market Trends on Drug Pipelines: The Need for Value-Based R&D AHDBonline.com/Deep-Science.aspx Mathew Sarnes, PharmD Vice President Managed Markets Division Xcenda

The Role of New Healthcare Technologies in a National Wellness Strategy AHDBonline.com/Deep-Science.aspx Robert K. Smoldt, BS, MBA Chief Administrative Officer Emeritus Executive Director Mayo Clinic Health Policy Center

Made possible by funding from

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If accepted, authors will be notified of any recommended revisions, and a revised manuscript should be resubmitted in its entirety, with all changes made.

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the references. Type all tables and all figure heads and captions in Word • References: Use up to 25-30 current, post-1990 references, cited consecutively in the text (as superscripts) and listed at the end of the manuscript. Avoid automatic numbering or footnote/endnote features (see references section) • Length: 2500-3000 words, plus tables and figures • Figures/images must be saved as individual files, at high resolution (300 dpi), as jpg, tif, or eps. Attach an individual file for each image. A copy may be included in the article but cannot substitute an electronic image file for figures.

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REFERENCES Cite references consecutively in the text (as superscripts), then place each complete reference at the end of the article under heading “References.” Use proper citation format according to the AMA Manual of Style. See examples below. Use the most up-to-date, post-1990 references, citing primary sources only.

Try to limit the number of references to about 30. Do not use automatic numbering or footnote/endnote features.

Reference examples: 1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676-680.

2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds.

Schizophrenia. Oxford, England: Blackwell Press; 2003.

3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a LfUw7_sYMRY. Accessed March 13, 2008.

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REPRINTS Reprints may be ordered at a nominal fee by contacting editorial@AHDBonline.com.

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CLINICAL

Economic Evaluation of Quality-of-Life Improvement with Second-Generation Antihistamines and Montelukast in Patients with Allergic Rhinitis Kim R. Saverno, RPh; Brian Seal, PhD; Michael J. Goodman, PhD; Kellie Meyer, PharmD Background: Allergic rhinitis causes significant economic losses and substantial reductions in quality of life. Improving a patient’s symptoms can therefore enhance the patient’s quality of life.

Objective: To measure the relative cost-effectiveness of prescription second-generation antihistamines (levocetirizine, desloratadine, and fexofenadine) and montelukast based on their impact on quality of life in patients with uncomplicated allergic rhinitis.

Methods: A retrospective, cost-effectiveness model was constructed using 1-year costs to managed care payers and using the Rhinoconjunctivitis Quality of Life Questionnaire to measure the quality of life in patients taking prescription second-generation antihistamines or montelukast for the treatment of allergic rhinitis. Clinical trial results for levocetirizine, desloratadine, fexofenadine (brand and generic), or Kellie Meyer montelukast were combined as standardized mean differences to create a pooled effectiveness measure. The costs of prescription drugs and physician office visits for allergic rhinitis were used as direct costs measures. Sensitivity was assessed by a Monte Carlo simulation run 1000 times.

Results: All the drugs in the study showed significant improvement in quality of life, with levocetirizine showing the greatest improvement. The incremental cost-effectiveness of levocetirizine dominated montelukast (incremental cost-effective ratio, –1317; 95% confidence interval, –7471, –212). The incremental cost-effectiveness favored levocetirizine compared with desloratadine and branded fexofenadine.

Conclusion: There are significant differences in the cost-effectiveness of various oral prescription agents with regard to improving quality of life of patients with allergic rhinitis. [AHDB. 2009;2(7):309-316].

A

llergic rhinitis (AR) has a significant detrimental effect on a patient’s quality of life (QoL), affecting sleep, normal daily activities, and work.1-4 Stempel and Woolf estimated that the 50 million Americans with AR spend more than $6 billion annually on prescription and nonprescription medications to relieve AR symptoms.5,6 Despite a growing body of literature on the effect of AR on QoL, there is a paucity of studies that use QoL findings to assess the cost-effectiveness of various agents used to treat AR. The recent US Food and Drug Administration (FDA) approval of the second-generation antihista-

Ms Saverno is a graduate student in Pharmaceutical Economics, Policy, and Outcomes, University of Arizona College of Pharmacy, Tucson; Dr Seal is Senior Director, sanofi-aventis, Bridgewater, NJ; Dr Goodman is Assistant Professor, University of Utah College of Pharmacy, Salt Lake City; Dr Meyer is Associate Director, Xcenda, Palm Harbor, FL.

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mine (SGA) levocetirizine, and the lack of studies that compare the cost-effectiveness of oral AR treatments in terms of QoL led to the present analysis.

Although estimates of economic impact vary widely, AR clearly has important economic implications for managed care, employers, and patients. Specifically, estimates of the direct costs to US payers range from $1.4 billion to $6 billion annually.5,7,8 These estimates may be low, however, because they exclude substantial spending on over-the-counter (OTC) allergy medications, a cost that is largely borne by the patient.5 In addition, indirect costs realized by employers through presenteeism and absenteeism represent a significant burden. When these indirect costs are considered in conjunction with direct healthcare costs, allergies are ranked as the fifth most expensive chronic condition for employers.9 Lack of rigorous economic evidence has not slowed the adoption of newer SGAs, which are among the

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KEY POINTS Despite a growing understanding of the effect of allergic rhinitis on quality of life, few studies have assessed the cost-effectiveness of various agents for this condition based on quality-of-life improvements.  This study compared the cost-effectiveness of levocetirizine and other prescription secondgeneration antihistamines and the widely used leukotriene receptor antagonist montelukast in terms of quality-of-life improvements.  It shows that levocetirizine is a cost-effective option and offers clinically meaningful improvement in quality of life.  Levocetirizine is cost-effective compared with montelukast and its cost-effective ratios are favorable compared with the other comparators in this analysis. 

most widely prescribed medications in the United States. SGAs have the advantage of fewer side effects, including less sedation, than older antihistamines,10 making them more acceptable to many patients. The purpose of this study was to estimate the comparative cost-effectiveness of QoL improvements associated with major prescription agents used for AR management.

To date, no cost-effectiveness studies have compared individual SGAs to one another or to alternative oral AR treatments based on QoL improvements. One costeffectiveness study compared SGAs with older, firstgeneration antihistamines that produced a significant sedating effect.10 However, current treatment patterns call for more advanced modeling that directly compares economic outcomes of treatment patterns with newer agents.

The present study was conducted from the perspective of prescription benefit managers from US health plans; therefore, OTC products were not included.

A recent study by some of the present authors compared the cost-effectiveness of SGAs to one another and to alternative AR treatments based on clinical symptom improvement.11 Our current analysis builds on that study by assessing the cost-effectiveness of levocetirizine relative to other prescription SGAs and the widely used leukotriene receptor antagonist montelukast in terms of QoL improvements reported by clinical trials. The present study was conducted from the perspective of pre-

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scription benefit managers from US health plans; therefore, OTC products were not included.

Methods We used a decision-analytic cost-effectiveness model developed from the perspective of managed care decision makers and using costs over a 1-year time period.

US payers typically do not include OTC products in their benefit design; therefore, our treatment comparators were limited to prescription products, including the SGAs levocetirizine, desloratadine, and fexofenadine, and the leukotriene receptor antagonist montelukast, which is also FDA approved for AR treatment.

The study population included patients with AR who had been treated with an SGA monotherapy or with montelukast. Although combination therapy with an SGA and montelukast is sometimes used for AR symptoms, combination therapy was excluded in this analysis, because clinical trial evidence supporting such combination therapy is limited, which would limit the generalizability of our findings. Patients with asthma requiring daily corticosteroid treatment were excluded, to preserve homogeneity of the population.

The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was selected for our model, because it is specific to AR, widely used, validated, and has a specific clinical interpretation.1,2,12-14 The RQLQ includes 28 items on 7 disease-specific domains: activity limitations, practical problems, nonrespiratory symptoms, nasal symptoms, eye symptoms, emotional function, and sleep. The outcome measure in our model was the composite of all 28 items.

We conducted a MEDLINE search to identify eligible articles between January 1950 and May 2007, using the comparator names levocetirizine, fexofenadine, desloratadine, and montelukast in combination with the terms RQLQ, QoL, and Rhinoconjunctivitis Quality of Life Questionnaire. Additional studies were identified by searching the references listed in these studies. Eligible studies had to (1) include monotherapy with an FDAapproved dose of one of the model comparator agents; (2) be randomized, blinded, and placebo-controlled; (3) exclude patients with asthma requiring daily corticosteroids; and (4) include RQLQ as an outcome.

Study length had to be 14 to 90 days. Patients’ age had to be 11 years or older. A total of 12 studies were included in the analysis.15-26 For each study, the standardized mean difference (SMD) between the comparator and placebo was calculated as a ratio of the RQLQ outcome to the standard deviation (see Goodman and colleagues11). To convert

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the pooled SMD into a usable measure for the costeffective ratio, the baseline mean and standard deviation of the RQLQ for placebo and the comparator were combined. Using the baseline mean and the standard deviation as the untreated standard, the mean marginal RQLQ score, assuming treatment with each comparator after removing the effect of placebo observed in the trials, was calculated as the baseline mean plus the SMD multiplied by the standard deviation.

A clinically relevant improvement was defined as a 0.5-point reduction from baseline in marginal RQLQ score—after removing the effect of placebo—which was used as the threshold for clinically relevant improvement. In contrast, Juniper and colleagues’ definition does not remove the effect of placebo.1 Our definition, although conservative, is consistent with the standards for cost-effectiveness analysis. The proportion of the population 0.5 points below the baseline mean was calculated using standard formulas for computing the area under the normal curve. The probability of clinically relevant improvement was defined as the marginal difference in the proportion of the population below the threshold for clinically relevant improvement.11 Drug costs were calculated as the expected days of therapy in a year multiplied by the daily wholesale acquisition cost.27 The model assumed 90 days of therapy for a calendar year. Medical costs for allergy-related physician office visits were calculated from an analysis of the proprietary PharMetrics dataset for a 1-year period for each model comparator agent. Medical costs were inflated to 2007 dollars, using the Bureau of Labor Statistics.28 Because levocetirizine was not available in the United States when the PharMetrics data were captured, its costs were imputed using a linear fit of the RQLQ effect size to the physician’s office visit costs for the other model comparator agents, based on a simple linear regression. Indirect costs, such as productivity, were not included, because they were not assessed in the original trials used for our analysis, and because the model’s perspective was that of a third-party payer.

The comparative cost-effectiveness of the agents was calculated as the ratio of costs to the probability of clinically relevant improvement. Incremental costeffective ratio (ICER) between agents was evaluated as the ratio of difference in cost to difference in probability of clinically relevant improvement for any alternative therapy relative to levocetirizine.

A Monte Carlo simulation, which varied the total cost by ±10%, was used to obtain 95% confidence

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Table 1 Mean QoL Effect Sizes Based on RQLQ Comparator

Mean effect size vs placebo

Desloratadine

–0.360 (95% CI, –0.539, –0.180)

Fexofenadine Levocetirizine

–0.418 (95% CI, –0.573, –0.262)

Montelukast

–0.213 (95% CI, –0.267, –0.159)

a

–0.201(95% CI, –0.301, –0.101)

a

Studies for brand and generic fexofenadine were used to calculate the mean effect.

CI indicates confidence interval; RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire.

interval (CI) values. The effectiveness measure (SMD) for each product varied within the 95% CI range for the pooled SMD across each comparator. Random draws were run 1000 times (using Microsoft Excel 2003, Service Pack 2). Exact 95% CI values for the cost-effective ratios were calculated as the 26th and 974th ordered values in the simulation.

Significance for a cost-effective ratio was defined by a CI that did not overlap the point estimate; significance for an ICER was defined as a CI that did not overlap 0.0.

Results Effects on Quality of Life Table 1 compares the mean QoL effect size for each comparator agent versus placebo. All comparators were significantly better than placebo in improving QoL.15-26 Levocetirizine demonstrated greater QoL improvement (–0.418; 95% CI, –0.573, –0.262), as measured by the pooled RQLQ SMD, than desloratadine (–0.360; 95% CI, –0.539, –0.180), montelukast (–0.213; 95% CI, –0.267, –0.159), or fexofenadine (–0.201; 95% CI, –0.301, –0.101).

Table 2 summarizes the annual drug and medical expenditures for each comparator, as well as each agent’s efficacy, expressed as the probability of a clinically relevant improvement in RQLQ. The medical costs for AR physician office visits were highest for montelukast. Annual AR drug costs, assuming 90 days of therapy, ranged from $168 to $275. Column 5 of Table 2 translates the SMDs into a probability of clinically relevant improvement. Applying these probability estimates to a population of 10,000 AR patients, levocetirizine would lead to clinically relevant improvement in an additional 810 patients compared with montelukast, or 231 additional patients compared with desloratadine.

Cost-Effectiveness Table 3 outlines the results of this study. Levocet-

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Table 2 Model Inputs: Probability of QoL Improvement (Efficacy) Based on RQLQ Values Marginal probability of Annual drug Annual medical a clinically significant Treatment arm cost, $ cost, $ Total cost, $ RQLQ improvement, %a

Probability of a clinically significant RQLQ improvement, %a

Levocetirizine

203

322

525

16.1

49.1

Desloratadine

249

326

575

13.8

46.8

Fexofenadine (generic) Fexofenadine (brand) Montelukast

168

326

494

7.6

40.6

216

326

542

7.6

40.6

275

356

631

8.0

41.0

a

At baseline, assuming a normal distribution, 33% of the sample had RQLQ values below the threshold for clinically significant improvement (0.5 points difference). Column 6 shows the proportion of the population with a mean below the threshold after treatment. Column 5 shows the marginal effect given treatment with the target drug (the last column minus 33%). Column 5 was used in the cost-effectiveness analysis calculations.

RQLQ indicates Rhinoconjunctivitis Quality of Life Questionnaire.

Table 3 Cost-Effectiveness Ratios Treatment arm Levocetirizine

CE ratio, cost per patient with clinically significant improvement, $ 3255 (95% CI, 2293, 5238)

ICER, $a —

Desloratadine

4165 (95% CI, 2704, 8167)

Fexofenadine (generic)

6535 (95% CI, 4183, 12,866)

–2189 (95% CI, –10,138, 17,275) 361 (95% CI, –1166, 3574)

Fexofenadine (brand)

7168 (95% CI, 4625, 13,770)

–198 (95% CI, –3241, 1186)

Montelukast

7871 (95% CI, 5990, 10,721)

–1317 (95% CI, –7471, –212)

a

Negative ICERs are dominated.

CE indicates cost-effective; CI, confidence interval; ICERs, incremental cost-effective ratios.

irizine had the lowest average cost ($3255) for a clinically relevant RQLQ improvement, followed by desloratadine ($4165). Montelukast had the highest cost ($7871) per clinically relevant RQLQ improvement and lower efficacy compared with the other comparators.

When the ICERs are positive, a tradeoff is required between cost and effectiveness.

Negative ICERs (Table 3) can reflect either lower cost and higher effectiveness or higher cost and lower effectiveness, which are generally reported as “dominated.” All the comparators in this study are less effective in terms of RQLQ improvement than levocetirizine. Generic fexofenadine is less costly than levocetirizine but results in lower RQLQ improvement.

The other comparators have lower RQLQ improvement and are more costly than levocetirizine.

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The statistical significance of the ICERs is shown with CI values. The wide CI values reflect the relatively small sample sizes and the resulting large variation in the RQLQ measures in the Monte Carlo simulation.

Only the comparison between levocetirizine and montelukast is significant (95% CI, –7471, –212). Because the CIs overlapped zero for the other comparators, another way to understand ICERs is to examine how many times the simulated ICER is negative, which indicates that levocetirizine dominated the comparator in that simulation. The number of negative ICERs of 1000 simulations is 601 for desloratadine, 273 for generic fexofenadine, 644 for branded fexofenadine, and 993 for montelukast. In the case of desloratadine, negative ICERs indicate that 60% of the time levocetirizine has greater RQLQ improvement and is less costly.

When the ICERs are positive, a tradeoff is required between cost and effectiveness. The tradeoff for a positive ICER is between lower cost and lower effectiveness

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for one product compared with higher cost, as well as greater clinical benefit for the other. For example, the positive ICER for generic fexofenadine (Table 3) reflects its lower cost and lower impact on RQLQ compared with the greater clinical benefit of levocetirizine.

Decision makers will need to weigh the additional clinical benefit against the additional cost.

Discussion The 4 model comparators vary substantially in their ability to improve QoL for patients with uncomplicated AR. This variation, combined with significant variation in the costs of the comparators, make this costeffectiveness analysis important for formulary decision makers, clinicians treating AR, and patients undergoing treatment. The results favor levocetirizine, which has the lowest average cost-effective ratio.

To our knowledge, this is the first published analysis of the cost per patient with clinically relevant improvement in RQLQ of the individual SGAs and the only leukotriene receptor antagonist indicated for the treatment of AR. This is surprising given the prevalence and the large economic impact of AR in direct and indirect costs. Sullivan and colleagues noted that the lack of a standard outcome measure across AR studies could contribute to the scant number of studies about cost-effectiveness of AR therapies.29 The effectiveness measure in the present study is important clinically and is consistent with the need for economic decisions that focus on QoL.30 The choice to use the RQLQ as the basis of our cost-effectiveness model was based on several factors. The RQLQ is reproducible, can assess the impact of treatment over multiple dimensions, and has a strict clinical interpretation that has been validated in many studies.1,12-14 Our results, however, are conservative. To make the denominator of the cost-effectiveness ratio consistent with standards in economic modeling, we removed the effect observed for placebo from the calculation of clinically relevant improvement. This reduces the number of persons in a population whom we classify as having clinically relevant improvement. A change that is smaller than the clinically relevant threshold may nevertheless represent meaningful improvement in symptom relief for many patients. An alternative measure, the number needed to treat to achieve 1 person with improvement, has been suggested for interpreting the RQLQ.31 Our analysis was designed specifically to assess the cost-effectiveness of levocetirizine relative to other oral prescription medications for the management of AR symptoms, where effectiveness is defined as clinically

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relevant improvement in RQLQ. Our model indicates that levocetirizine has greater RQLQ improvement and is less costly than montelukast for the management of AR in patients without asthma who require daily corticosteroids. However, because the 95% CI of the ICERs comparing levocetirizine with the other comparators cross zero, levocetirizine does not have complete dominance over the SGA comparators.

Several prescription and OTC medications are approved for the relief of AR symptoms, including nasal corticosteroids, antihistamines, decongestants, and leukotriene receptor antagonists.

The 95% CI of the ICER comparing levocetirizine with desloratadine was wide (â&#x20AC;&#x201C;$10,138 and $17,275, respectively; Table 3) for 2 reasons. First, only 2 trials had usable data for changes in RQLQ for levocetirizine, and only 1 study for desloratadine. With such few studies, the resulting variability from the SMD in RQLQ score was large. Second, the difference in probability of a clinically relevant improvement between the 2 drugs was small (16.1% and 13.8%, respectively). When the denominator in an ICER is a probability, a small difference between the 2 comparators leads to very large CI estimates. As additional comparator-specific information on QoL becomes available, the precision of these estimates will be increased and judgments about their relative effectiveness and cost-effectiveness will become more accurate.

Overall, the ICER CI values were very wide, which again reflects the lack of multiple studies for the comparators. For example, the variation for montelukast is smaller than for desloratadine, because there are more montelukast trials with RQLQ data. Although the results are valid for the specific sample sizes, the relatively small number of studies results in CI values that might have obscured effects of clinical significance for improved QoL.32 Several prescription and OTC medications are approved for the relief of AR symptoms, including nasal corticosteroids, antihistamines, decongestants, and leukotriene receptor antagonists. Although the use of these agents and combination therapy is common for AR management, it was unreasonable to include all these options in our analysis, because of the lack of RQLQ outcomes data and because of the sheer number

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of potential comparators. We therefore opted to include comparators available only by prescription, because our goal was to address issues relevant to prescription drug benefit managers. Many health plans do not reimburse for OTC medications.33 Our model included direct costs only, specifically drug costs and outpatient physician office visit costs for AR. The literature indicates that a sizable amount of the economic burden associated with AR is because of lost productivity from absenteeism and presenteeism.34 An employee survey showed that employees with AR were absent roughly 3.6 days annually due to this condition and lost 2.3 hours per workday in productivity when symptoms were present. In our analysis, indirect costs were excluded due to lack of data substantiating differences in indirect costs between individual model comparators, which may be related to the short duration of most AR clinical trials. Other costs not accounted for in our model include costs associated with lack of effectiveness and adverse events.

Our analysis shows that levocetirizine is a cost-effective option for the treatment of AR that produces clinically meaningful improvement in QoL based on the RQLQ. Limitations Several potential limitations of this study warrant discussion. Our rigorous inclusion criteria might have led to unintended bias. For example, Meltzer and colleagues only reported on the significance of a single RQLQ domain, so this study was not included in our analysis.35 In addition, the AR patient population is broad, ranging from young children to the elderly and from relatively healthy patients to patients with severe respiratory conditions. Our decision to exclude clinical trials that enrolled children younger than 11 years old or AR patients with concomitant asthma treated with daily corticosteroids does not accurately reflect the overall population with AR. It is estimated that nearly 40% of individuals with allergies have asthma.36 Furthermore, 60% to 78% of individuals with asthma have AR.36 Montelukast is FDA-approved for the management of asthma and AR, whereas the SGAs are not approved for the treatment of asthma.37-40 Therefore, we chose to eliminate studies involving patients with asthma requiring daily corticosteroids so as to not bias the results with respect to montelukast. About 40% of individuals younger than age 12 suffer from AR.6

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Therefore, although our results are robust to the general population, specific subpopulations are not represented, and the cost-effectiveness in the young and in those with significant comorbidities remains to be examined in future research.

We also did not include OTC SGAs, such as loratadine and cetirizine, in our analysis. We believe that this is justified, because the audience for this study is health plan decision makers. Historically, when drugs have been moved to an OTC status, this typically has removed them from coverage by managed care.41 Therefore, our intended audience is served by this exclusion. In addition, cost and QoL data are not available for all OTC agents.

We only included physician office visits and AR drug costs, and excluded costs for emergency department visits or hospitalizations. Patients with AR without asthma are unlikely to be hospitalized, visit the emergency department, or use additional drugs.

There may be some limitations to using the PharMetrics database to obtain the cost inputs for the analysis. For example, diagnosis codes from claims are based on payment rather than on clinical practice.

Therefore, diagnoses from claims data may be less specific than diagnoses or narrative in a medical record.

This limitation, however, is offset by the coding bias being consistent across all comparators. In addition, the PharMetrics data contain few elderly patients; however, as with the coding bias noted, this should result in a consistent effect across all comparators.

We also did not separate seasonal and perennial AR. All the agents included in our analysis have an indication for both seasonal and perennial AR, except for fexofenadine, which is only indicated for seasonal AR. In addition, the availability of the clinical trial data would have been limited if we separated our analysis by seasonal and perennial AR, potentially reducing the robustness of the QoL estimates.

Finally, we did not formally analyze statistical heterogeneity in our calculation of comparative effectiveness. Because our goal was to model the economics rather than conduct a full-fledged meta-analysis of comparative effectiveness of AR medications, it was beyond this studyâ&#x20AC;&#x2122;s scope to rigorously exclude studies that might introduce heterogeneity. Estimates derived from a full meta-analysis would provide tighter CI values for effectiveness measures, but they would also limit the generalizability of the results.

Conclusion Our analysis shows that levocetirizine is a cost-

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effective option for the treatment of AR that produces clinically meaningful improvement in QoL based on the RQLQ. Levocetirizine is cost-effective compared with montelukast, and its cost-effective ratios are favorable compared with the other comparators in this analysis. Further research is warranted to assess patients with AR and comorbid asthma who require daily corticosteroids and in younger populations, as well as to address the effect of different therapies on indirect costs of AR. Acknowledgments Laurie Kozbelt and Jeanne Hawkins of Xcenda, LLC, Palm Harbor, FL, provided technical assistance in conducting this study and in preparing this manuscript.

Disclosure Statement This study was funded by UCB, Inc, and sanofi-aventis US, LLC. Ms Saverno and Dr Goodman were employed and Dr Meyer is currently employed by Xcenda, which provides consulting services to various pharmaceutical companies, including UCB and sanofiaventis. Dr Seal is employed by sanofi-aventis. â&#x2013;

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1. Juniper EF, Guyatt GH, Griffith LE, Ferrie PJ. Interpretation of rhinoconjunctivitis quality of life questionnaire data. J Allergy Clin Immunol. 1996;98:843-845.

2. Juniper EF, Oâ&#x20AC;&#x2122;Byrne PM, Guyatt GH, et al. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14:902-907.

3. Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc. 2007;28:3-9.

4. Schoenwetter WF, Dupclay L Jr, Appajosyula S, et al. Economic impact and quality-of-life burden of allergic rhinitis. Curr Med Res Opin. 2004;20:305-317.

5. Stempel DA, Woolf R. The cost of treating allergic rhinitis. Curr Allergy Asthma Rep. 2002;2:223-230.

6. American Academy of Allergy, Asthma, and Immunology. Allergy statistics. www.aaaai.org/media/resources/media_kit/allergy_statistics.stm. Accessed January 22, 2008.

7. Malone DC, Lawson KA, Smith DH, et al. A cost of illness study of allergic rhinitis in the United States. J Allergy Clin Immunol. 1997;99(1 pt 1):22-27.

8. Reed SD, Lee TA, McCrory DC. The economic burden of allergic rhinitis: a critical evaluation of the literature. Pharmacoeconomics. 2004;22:345-361.

9. Goetzel RZ, Long SR, Ozminkowski RJ, et al. Health, absence, disability, and presenteeism cost estimates of certain physical and mental health conditions affecting U.S. employers. J Occup Environ Med. 2004;46:398-412.

10. Sullivan PW, Nichol MB. The economic impact of payer policies after the Rxto-OTC switch of second-generation antihistamines. Value Health. 2004;7:402-412.

11. Goodman MJ, Jhaveri M, Saverno K, et al. Cost-effectiveness of second-generation antihistamines and montelukast in relieving nasal symptoms of allergic rhinitis.

Am Health Drug Benefits. 2008;1(8):26-34.

12. Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy. 1991;21:77-83.

13. Juniper EF, Thompson AK, Roberts JN. Can the standard gamble and rating scale be used to measure quality of life in rhinoconjunctivitis? Comparison with the RQLQ and SF-36. Allergy. 2002;57:201-206.

14. Juniper EF, Rohrbaugh T, Meltzer EO. A questionnaire to measure quality of life in adults with nocturnal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2003; 111:484-490.

15. Bachert C, Bousquet J, Canonica GW, et al. Levocetirizine improves quality of life and reduces costs in long-term management of persistent allergic rhinitis. J Allergy Clin Immunol. 2004;114:838-844.

16. Lombardo G, Quattrocchi P, Lombardo GR, et al. Concomitant levocetirizine and montelukast in the treatment of seasonal allergic rhinitis: influence on clinical symptoms. IT J Allergy Clin Immunol. 2006;16:63-68.

17. Meltzer EO, Casale TB, Nathan RA, Thompson AK. Once-daily fexofenadine HCl improves quality of life and reduces work and activity impairment in patients with seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 1999;83:311-317.

18. Meltzer EO, Malmstrom K, Lu S, et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized, placebo-controlled clinical trial. J Allergy Clin Immunol. 2000;105:917-922.

19. Nayak AS, Philip G, Lu S, et al. Efficacy and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis: a multicenter, randomized, double-blind, placebo-controlled trial performed in the fall. Ann Allergy Asthma Immunol. 2002;88:592-600.

20. Okubo K, Gotoh M, Shimada K, et al. Fexofenadine improves the quality of life and work productivity in Japanese patients with seasonal allergic rhinitis during the peak cedar pollinosis season. Int Arch Allergy Immunol. 2005;136:148-154.

21. Patel P, Philip G, Yang W, et al. Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95:551-557.

22. Philip G, Malmstrom K, Hampel FC, et al. Montelukast for treating seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial performed in the spring. Clin Exp Allergy. 2002;32:1020-1028.

23. Pradalier A, Neukirch C, Dreyfus I, Devillier P. Desloratadine improves quality of life and symptom severity in patients with allergic rhinitis. Allergy. 2007;62:1331-1334.

24. Tanner LA, Reilly M, Meltzer EO, et al. Effect of fexofenadine HCl on quality of life and work, classroom, and daily activity impairment in patients with seasonal allergic rhinitis. Am J Manag Care. 1999;5(suppl):S235-S247.

25. van Adelsberg J, Philip G, Pedinoff AJ, et al. Montelukast improves symptoms of seasonal allergic rhinitis over a 4-week treatment period. Allergy. 2003;58:1268-1276.

26. van Adelsberg J, Philip G, LaForce CF, et al. Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis.

Ann Allergy Asthma Immunol. 2003;90:214-222.

27. RED BOOK for Windows. Volume 46; 2007. [Requires password to access online.]

28. US Department of Labor, Bureau of Labor Statistics. Consumer price index.

US medical care, 1982-84=100-CUUR0000SAM. http://data.bls.gov/cgi-bin/survey most?cu. Accessed January 22, 2008.

29. Sullivan PW, Follin SL, Nichol MB. Transitioning the second-generation antihistamines to over-the-counter status. A cost-effectiveness analysis. Med Care. 2003; 41:1382-1395.

30. Gold MR. Cost-effectiveness in Health and Medicine. New York, NY: Oxford University; 1996.

31. Guyatt GH, Juniper EF, Walter SD, et al. Interpreting treatment effects in randomised trials. BMJ. 1998;316:690-693.

32. Kirk RE. Practical significance: a concept whose time has come. Educ Psychol Meas. 1996;56:746-759.

33. Hay JW, Leahy M. Cost and utilization impacts of oral antihistamines in the California Medi-Cal program. Value Health. 2005;8:506-516.

34. Lamb CE, Ratner PH, Johnson CE, et al. Economic impact of workplace productivity losses due to allergic rhinitis compared with select medical conditions in the United States from an employer perspective. Curr Med Res Opin. 2006;22: 1203-1210.

35. Meltzer EO, Jalowayski AA, Vogt K, et al. Effect of desloratadine therapy on symptom scores and measures of nasal patency in seasonal allergic rhinitis: results of a single-center, placebo-controlled trial. Ann Allergy Asthma Immunol. 2006;96: 363-368.

36. Crown WH, Olufade A, Smith MW, Nathan R. Seasonal versus perennial allergic rhinitis: drug and medical resource use patterns. Value Health. 2003;6:448-456.

37. Clarinex [package insert]. Kenilworth, NJ: Schering Co; 2005.

38. Xyzal [package insert]. Smyrna, GA: UCB; 2007.

39. Singulair [package insert]. Whitehouse Station, NJ: Merck & Co; 2007.

40. Allegra [package insert]. Bridgewater, NJ: sanofi-aventis US; 2008.

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Stakeholder Perspective next page

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STAKEHOLDER PERSPECTIVE Allergic Rhinitis: A Serious Condition with Many Safe and Effective Pharmaceutical Options Allergic rhinitis can be a very devastating chronic condition, affecting patients’ ability to work productively, hamper their desire for recreation activities, and even prevent a restful sleep. The present article

by Meyer and colleagues focuses on quality-of-life (QoL) issues that patients with allergic rhinitis may struggle with on a daily basis. The article also makes a comparison between the second-generation nonsedating antihistamines and montelukast as alternatives for the treatment of this disease.

The good thing is that many safe and effective pharmaceutical products are available that work well for the treatment of the symptoms associated with allergic rhinitis, allowing patients to have normal, productive, and active lives. The many pharmaceutical products available work in a number of ways, including oral systemic products and nasally inhaled products.

PAYERS: Payers will typically have copay incentives for patients to use medications that may be available as generics, or even older products, such as some of the first-generation nonsedating antihistamines that are available over the counter (OTC) and provide relief from the symptoms of allergic rhinitis. These same copay incentives may also apply for nasally inhaled products that may be more attractive than the copay a patient may have for second-generation nonsedating antihistamines or for montelukast.

PATIENTS: Patients can take advantage of inexpensive products for this condition or reduced copays and often have good results in getting symptomatic relief and increased QoL, while avoiding having to deal with a cost difficulty for their medication.

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Patients working closely with their physician can reach the best decision of what type of medication will enable them to have their best response to the treatment and enhance their ongoing QoL. PROVIDERS: Physicians have a large arsenal of medications available to combat allergic rhinitis and often may not be driven to use the more expensive second-generation nonsedating antihistamines or montelukast, unless a patient is unable to get symptomatic relief from first-line products, or the patient has had an adverse reaction to a systemic or a nasally inhaled medication.

CARE STRATEGY: The care strategy that all stakeholders have to consider involves far more than just limiting the decision to a choice among the second-generation nonsedating antihistamines. Stakeholders—including providers, patients, and payers— can have a profound effect on the patient’s well-being by working together to use proven clinical guidelines and medication choices according to the best interest of each patient. This allows the optimization of patients’ QoL, while also focusing on the best overall treatment cost, whether using an OTC agent for those who are able to take advantage of these options, prescription medications, or a second-generation nonsedating antihistamine or montelukast, if that is determined to be the best treatment for the individual patient.

Paul Anthony Polansky, BSPharm, MBA Executive VP & Chief Pharmacy Officer Sanovia Corporation, Philadelphia, PA

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Partnership. People.

Programs. Passion.

The Flexibility You Need. The Integrity You Deserve.

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Visit Takeda on the Web at www.tpna.com.

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EXECUTIVE SUMMARIES

Health Plan Retention and Pharmacy Costs of Newly Diagnosed Patients with CKD in a Managed Care Population Maureen Kubacki, PharmD, MBA; Chureen Carter, PharmD, MS; Alan D.L. Herrera, PharmD; Jim Wang, PhD; Janice M. Lopez, PharmD; Catherine T. Piech, MBA

Approximately 26 million Americans have chronic kidney disease (CKD) and about 66% of all new cases of CKD are caused by diabetes or hypertension. The findings from this study involving 31,917 patients with CKD show that contrary to common perceptions in managed care, patients who are newly diagnosed with CKD retain their health plans for many years. On average, patients with CKD plus diabetes or hypertension remained enrolled in their health plans slightly longer than patients with CKD only. The largest number of

claims was for inpatient medical costs, followed by pharmacy and laboratory services. Mean annual direct healthcare costs were higher for patients with CKD plus diabetes ($20,165) or CKD plus hypertension ($17,612) compared with those with CKD only ($9390). The mean annual total medical costs were $22,444 for CKD plus diabetes, $19,667 for CKD plus hypertension, and $10,170 for patients with CKD only. Therefore, early intervention to prevent or delay the progression from diabetes or hypertension to CKD can also reduce costs.

Quality Improvements Initiatives: The Missed Opportunity for Health Plans Sara Fernandez-Lopez, PhD; Barbara Lennert, RN, BSN, MAOM

Quality metrics have the potential to increase the value of the US healthcare system by reducing costs and increasing access to quality care. A recent survey of medical and pharmacy directors in managed care plans evaluated the extent of knowledge of these experts of available health-related quality improvement initiatives undertaken by different organizations. Survey results show that medical and pharmacy directors have limited knowledge of current quality organizations/initiatives, except for the 2 organizations that offer quali-

ty accreditation to health plans or to pharmacy benefit management organizationsâ&#x20AC;&#x201D;NCQA and URAC. This finding, the authors suggest, presents an opportunity for pharmaceutical companies to collaborate with private health plans to develop quality initiatives, especially for drug utilization. They note that to collaborate with health plans successfully, pharmaceutical companies should develop evidence-based programs that are focused on a specific disease state rather than on a specific product.

Economic Evaluation of Quality-of-Life Improvement with Second-Generation Antihistamines and Montelukast in Patients with Allergic Rhinitis Kim R. Saverno, RPh; Brian Seal, PhD; Michael J. Goodman, PhD; Kellie Meyer, PharmD

Allergic rhinitis has a significant effect on the patientâ&#x20AC;&#x2122;s quality of life (QoL), in addition to the economic cost to employers and the healthcare system, but few studies have assessed the cost-effectiveness of various agents for this condition based on QoL improvements. That was the exact goal of this retrospective analysis. The authors constructed a cost-effectiveness model based on 1-year costs to managed care payers and the Rhinoconjunctivitis Quality of Life Questionnaire to measure the QoL in patients taking prescription second-generation antihistamines or montelukast for the treatment of allergic rhini-

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tis. Results showed that all these agents had significant improvement in QoL, with levocetirizine showing the greatest improvement. However, the authors did not include in their analysis over-the counter (OTC) secondgeneration agents, such as loratadine or cetirizine, in part because their analysis was directed at decision makers in health plans, who do not include OTC agents in their benefit plans. Historically, when drugs have been moved to an OTC status, this typically has removed them from coverage by managed care plans. In addition, cost and QoL data are not available for all OTC agents.

November/December 2009

VOL. 2

NO. 7

Covers:Cover 12/11/09 4:27 PM Page C3

Brief Summary of Prescribing Information Brief Summary of USAGE Prescribing Information INDICATIONS AND ® (aspirin/extended-release AGGRENOX dipyridamole) is indicated to reduce the risk of stroke in patients who have had transient ischINDICATIONS AND USAGE ® emia of the brain or completed ischemicdipyridamole) stroke due to is thrombosis.

AGGRENOX (aspirin/extended-release indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.

CONTRAINDICATIONS CONTRAINDICATIONS AGGRENOX is contraindicated in patients with hypersensitivity to dipyridamole, aspirin or any of the other product components.

AGGRENOX (aspirin/extended-release is contraindicated in patients with hypersensitivity drug to dipyridamole, aspirin or any with of the Allergy: Aspirin is contraindicated in dipyridamole) patients with known allergy to nonsteroidal anti-inflammatory products and in patients other product of components. the syndrome asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema or bronchospasm (asthma).

Allergy:Syndrome: Aspirin is contraindicated patients withinknown allergy to nonsteroidal drug products andbecause in patients with Reye’s Aspirin shouldinnot be used children or teenagers for viralanti-inflammatory infections, with or without fever, of the riskthe of asthma,with rhinitis, and nasaluse polyps.

Aspirin may cause urticaria, angioedema or bronchospasm (asthma). ofsyndrome Reye’s syndrome concomitant of aspirin in certain viralsevere illnesses.

Reye’s Syndrome: Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye’s WARNINGS syndrome with concomitant use of aspirin in certain viral illnesses.

Alcohol Warning: Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks WARNINGS involved with chronic, heavy alcohol use while taking aspirin.

Alcohol Warning: Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved Coagulation Abnormalities: Eventaking low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can with chronic, heavy alcohol use while aspirin. adversely affect patients with inherited or acquired (liver disease or vitamin K deficiency) bleeding disorders.

Coagulation Abnormalities: Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can Gastrointestinal (GI)with Side Effects: GI side effects includeorstomach heartburn, nausea, vomiting, and gross GI bleeding. adversely affect patients inherited or acquired (liver disease vitamin Kpain, deficiency) bleeding disorders.

Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain Gastrointestinal (GI) Side GI even side effects pain,GIheartburn, nausea, vomiting, and gross bleeding.

Although alert for signs of ulceration andEffects: bleeding, in the include absencestomach of previous symptoms.

Physicians should informGIpatients about the minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs signs and symptoms of GI side effects and what steps to take if they occur. of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms Peptic Ulcer withifathey history of GI side effectsDisease: and what Patients steps to take occur.of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation, and bleeding.

Peptic Ulcer Disease: Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal Pregnancy: irritation, and AGGRENOX bleeding. can cause fetal harm when administered to a pregnant woman. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence for intracranial hemorrhage in premature infants, stillbirths and neonatal Pregnancy: fetalof harm wheneffects administered to a pregnant woman. Maternal aspirin useonduring stages of death.

BecauseAGGRENOX of the abovecan andcause because the known of nonsteroidal anti-inflammatory drugs (NSAIDs) the fetallater cardiovaspregnancy causeoflow weight, increasedAGGRENOX incidence for intracranial hemorrhage in premature stillbirths and neonatal death. cular systemmay (closure thebirth ductus arteriosus), should be avoided in the third trimesterinfants, of pregnancy.

Because of the above and because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system Aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested (closure of the ductus arteriosus), AGGRENOX should be avoided in the third trimester of pregnancy. fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of Aspirin has beenand shown be teratogenic in rats (spina bifida, exencephaly, and resorption coelosomia)rate andinrabbits (congested fetuses, 330 mg/kg/day 110 to mg/kg/day, respectively.

These doses, which alsomicrophthalmia resulted in a high rats (63% of implantaagenesis of skull upper jaw, with malformation the head, and diaphanous at oralcontained doses of 330 mg/kg/day and 2 basis, tions versus 5% inand controls), are,generalized on a mg/medema about 66 and 44oftimes, respectively, the doseskin) of aspirin in the maximum 110 mg/kg/day,daily respectively.

These doses, which also resulted instudies a high resorption rate in rats (63% of performed implantations versusrabbits 5% in and controls), recommended human dose of AGGRENOX. Reproduction with dipyridamole have been in mice, rats 2 a mg/m basis, about 66 and times,and respectively, the dose of aspirin contained the25 maximum recommended daily human dose atare, oralondoses of up to 125 mg/kg, 4044 mg/kg 1000 mg/kg, respectively (about 11⁄2, 2inand times the maximum recommended dailyof AGGRENOX. Reproduction studies with dipyridamole haverevealed been performed in mice, rabbits ratsdue at tooral doses of upWhen to 125 mg/kg, 2 basis) and have human oral dose, respectively, on a mg/m no evidence of harm to theand fetus dipyridamole.

330 mg 40 mg/kg and was 1000combined mg/kg, respectively 1 1⁄2, 2 and 25 times therat, maximum recommended daily human oralindicating dose, respectively, on a aspirin/kg/day with 75 mg(about dipyridamole/kg/day in the the resorption rate approached 100%, potentiation 2 basis) andfetal havetoxicity. revealed no are evidence of harmand to well-controlled the fetus due tostudies dipyridamole.

Whenwomen.

330 mg aspirin/kg/day was combined with ofmg/m aspirin-related There no adequate in pregnant If AGGRENOX is used during preg75 mgor dipyridamole/kg/day in thepregnant rat, the resorption rateAGGRENOX, approached the 100%, indicating fetal toxicity. nancy, if the patient becomes while taking patient shouldpotentiation be apprisedofofaspirin-related the potential hazard to the There fetus. are no adequate and well-controlled studies in pregnant women. If AGGRENOX is used during pregnancy, or if the patient becomes pregnant while PRECAUTIONS taking AGGRENOX, the patient should be apprised of the potential hazard to the fetus.

General PRECAUTIONS AGGRENOX General is not interchangeable with the individual components of aspirin and Persantine® Tablets.

AGGRENOX (aspirin/extended-release dipyridamole) not and interchangeable individual components aspirin Coronary Artery Disease: Dipyridamole has a vasodilatoryiseffect should be usedwith with the caution in patients with severe of coronary and Persantine artery disease (e.g.,® Tablets. unstable angina or recently sustained myocardial infarction). Chest pain may be aggravated in patients with underlying coronaryArtery artery Disease: disease who are receiving Coronary Dipyridamole hasdipyridamole. a vasodilatory effect and should be used with caution in patients with severe coronary artery disease (e.g., unstable angina or recently sustained myocardial infarction).

Chest pain mayinfarction be aggravated underlying coronary For stroke or TIA patients for whom aspirin is indicated to prevent recurrent myocardial (MI) inorpatients angina with pectoris, the aspirin in artery disease whonotareprovide receiving dipyridamole. this product may adequate treatment for the cardiac indications.

For strokeInsufficiency: or TIA patients for whom aspirin is indicated to prevent recurrent myocardial infarction (MI) in or angina pectoris, aspirin in this Hepatic Elevations of hepatic enzymes and hepatic failure have been reported association withthedipyridamole product may not provide adequate treatment for the cardiac indications. administration.

Hepatic Insufficiency: Elevations hepatic and hepatic failure have been reported in association withperipheral dipyridamole administration.

Hypotension: Dipyridamole shouldofbe usedenzymes with caution in patients with hypotension since it can produce vasodilation.

Hypotension: be used caution patients(glomerular with hypotension since can than produce peripheral vasodilation.

Renal Failure:Dipyridamole Avoid aspirinshould in patients withwith severe renalinfailure filtration rateitless 10 mL/minute).

RenalofFailure: Avoid withofsevere renal failurebleeding (glomerular rate less thanin10themL/minute).

Risk Bleeding: In aspirin ESPS2 inthepatients incidence gastrointestinal wasfiltration 68 patients (4.1%) AGGRENOX group, 36 patients (2.2%) the extended-release dipyridamole group, 52 patientsbleeding (3.2%) inwas the68 aspirin group, andin34thepatients (2.1%)group, in the36 placebo groups.

Risk ofinBleeding: In ESPS2 the incidence of gastrointestinal patients (4.1%) AGGRENOX patients (2.2%) in the extended-release dipyridamole group,was 52 9patients (3.2%) in the aspirin group, andgroup, 34 patients (2.1%) in theinplacebo groups.

The incidence of intracranial hemorrhage patients (0.6%) in the AGGRENOX 6 patients (0.5%) the extended-release dipyridamole 6 patientshemorrhage (0.4%) in thewas aspirin group (0.6%) and 7 patients (0.4%) in thegroup, placebo groups. (0.5%) in the extended-release The incidencegroup, of intracranial 9 patients in the AGGRENOX 6 patients dipyridamoleTests group, 6 patients (0.4%) in the aspirin group and 7 patients (0.4%) in the placebo groups.

Laboratory Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria and Laboratory Tests prolonged time.

Aspirin hasbleeding been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria and prolonged bleeding time.associated with elevated hepatic enzymes.

Dipyridamole has been Dipyridamole has been associated with elevated hepatic enzymes.

Drug Interactions Drug Interactions drug-drug interaction studies were conducted with the AGGRENOX formulation. The following information was No pharmacokinetic No pharmacokinetic drug-drug interaction studies were conducted with the AGGRENOX formulation. The following information was obtained obtained from the literature. from the literature.

Adenosine: Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of Adenosine:dosage Dipyridamole been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine adenosine may behas necessary. dosage may Converting be necessary.

Angiotensin Enzyme (ACE) Inhibitors: Due to the indirect effect of aspirin on the renin-angiotensin conversion pathway, the Angiotensin Converting Enzymeeffects (ACE)ofInhibitors: Due to thebeindirect effectby of concomitant aspirin on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive ACE inhibitors may diminished administration of aspirin. hyponatremic and hypotensive of ACE may becan diminished by concomitant administration of aspirin. (and toxicity) due Acetazolamide: Concurrent useeffects of aspirin andinhibitors acetazolamide lead to high serum concentrations of acetazolamide use offor aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to toAcetazolamide: competition atConcurrent the renal tubule secretion. competition atTherapy the renal(heparin tubule forand secretion.

Anticoagulant warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drugAnticoagulant Therapy (heparin warfarin): Patients on anticoagulation therapy are binding at increased for bleeding because of drug-drug drug interactions and effects on and platelets.

Aspirin can displace warfarin from protein sites,risk leading to prolongation both the interactions and onbleeding platelets. time.

Aspirin can displace warfarin protein binding sites, leading toincreasing prolongation of bothrisk. the prothrombin prothrombin timeeffects and the Aspirin can increase thefrom anticoagulant activity of heparin, bleeding time and the bleeding time.acid Aspirin increase the anticoagulant activity heparin,acid, increasing bleeding risk. in the total concentration Anticonvulsants: Salicylic can can displace protein-bound phenytoin andofvalproic leading to a decrease Salicylic acidincan displace protein-bound ofAnticonvulsants: phenytoin and an increase serum valproic acid levels. phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin andThe an increase in serum valproic levels.may be diminished by the concomitant administration of aspirin due to inhibition Beta Blockers: hypotensive effects of betaacid blockers Blockers: The hypotensive of beta renal blockers mayflow be and diminished the retention. concomitant administration of aspirin due to inhibition of ofBeta renal prostaglandins, leading effects to decreased blood salt andbyfluid renal prostaglandins, leading to decreasedmay renalcounteract blood flowthe andanticholinesterase salt and fluid retention.

Cholinesterase Inhibitors: Dipyridamole effect of cholinesterase inhibitors, thereby potentially Cholinesterase Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis. aggravating myasthenia gravis.

Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the conDiuretics:administration The effectiveness of diuretics in inhibition patients with underlying renal or cardiovascular disease may beblood diminished by the comitant of aspirin due to of renal prostaglandins, leading to decreased renal flow and saltconcomitant and fluid administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. retention.

Methotrexate:Salicylate Salicylate can inhibit methotrexate, leading to bone marrow toxicity, especially in the elderly or renal or impaired.

Methotrexate: inhibitrenal renalclearance clearanceof of methotrexate, leading to bone marrow toxicity, especially in the elderly renal impaired.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to decreased renal function.Anti-Inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to Nonsteroidal decreased renal function.

Oral Hypoglycemics: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.

Oral Hypoglycemics: Moderateand doses of aspirin maySalicylates increase the effectiveness of oral hypoglycemic drugs,agents. leading to hypoglycemia.

Uricosuric Agents (probenecid sulfinpyrazone): antagonize the uricosuric action of uricosuric Uricosuric Agents (probenecid and sulfinpyrazone): Carcinogenesis, Mutagenesis, Impairment ofSalicylates Fertility antagonize the uricosuric action of uricosuric agents.

Carcinogenesis, of the Fertility In studies in which Mutagenesis, dipyridamole wasImpairment administered in feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in andinupwhich to 142dipyridamole weeks in females), there was noinevidence The highest dose administered studies Inmales studies was administered the feedoftodrug-related mice (up to carcinogenesis.

111 weeks in males and females) and rats (up in to these 128 weeks 2 mg/kg/day) on aweeks mg/min basis, aboutthere equivalent the maximum recommended daily human oral (MRHD) mice and about in(75males and upwas, to 142 females), was notoevidence of drug-related carcinogenesis.

The dose highest dose in administered in twice studies the MRHD rats. these (75inmg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) inCombinations mice and about twice the MRHD rats. (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and of dipyridamole and in aspirin hamsters), oralofmicronucleus mice(1:5 andratio) hamsters) oral dominant lethaltest, testin(invivo mice).

Aspirin, alone, induced chromosome Combinations dipyridamoletests and (in aspirin testedand negative in the Ames chromosome aberration tests (in mice aberrations in cultured human fibroblasts. tests of dipyridamole alone with bacterial mammalian systems werechromonegative. and hamsters), oral micronucleus tests (inMutagenicity mice and hamsters) and oral dominant lethal test (inand mice).

Aspirin,cell alone, induced some aberrations cultured human fibroblasts. tests offordipyridamole alone with bacterial andperformance. mammalian cell systems Combinations of in dipyridamole and aspirin have Mutagenicity not been evaluated effects on fertility and reproductive There was no were negative. evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times 2 the MRHD on of a mg/m basis). Aand significant in number of corpora lutea with consequent reduction in performance. implantations There and livewas fetuses Combinations dipyridamole aspirin reduction have not been evaluated for effects on2 fertility and reproductive no was, however, observed at 1250 mg/kg (more thanwas 30 times the MRHD a mg/m basis).rats Aspirin inhibits in rats. evidence of impaired fertility when dipyridamole administered to on male and female at oral dosesovulation up to 500 mg/kg/day (about 12 times the MRHD on a mg/m2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations Pregnancy and live fetuses was, Pregnancy however, observed (more than 30 times the MRHD on a mg/m2 basis). Aspirin inhibits ovulation in rats.

Teratogenic Effects: CategoryatD1250 (see mg/kg WARNINGS) Labor and Delivery Pregnancy Aspirin can Effects: result inPregnancy excessive Category blood lossD at(see delivery as well as prolonged gestation and prolonged labor. Because of these effects on the Teratogenic WARNINGS) mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy (see WARNINGS, Pregnancy), Labor and Delivery AGGRENOX should be avoided in the third trimester of pregnancy and during labor and delivery.

Aspirin canMothers result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on Nursing the mother and because of adverse fetal effects seenmilk. withCaution aspirin should during be theexercised later stages of AGGRENOX pregnancy (see WARNINGS, Pregnancy), Both dipyridamole and aspirin are excreted in human when is administered to a nursing woman.

AGGRENOX should be avoided in the third trimester of pregnancy and during labor and delivery.

Pediatric Use Nursing Safety andMothers effectiveness of AGGRENOX in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric populationand is not recommended Both dipyridamole aspirin are excreted(see in CONTRAINDICATIONS). human milk. Caution should be exercised when AGGRENOX is administered to a nursing woman.

ADVERSE REACTIONS Pediatric Use A 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of AGGRENOX (aspirin/extended-release placebo, extended-release dipyridamole alone aspirin component, alone. The study wasthis conducted Safety and effectiveness ofdipyridamole) AGGRENOX inwith pediatric patients have not been studied. Due to and the aspirin use of product in a totalpediatric of 6602population male and female who had(see experienced a previous ischemic stroke or transient ischemia of the brain within three months the is notpatients recommended CONTRAINDICATIONS). prior to randomization.

ADVERSE REACTIONS 1 presents the incidence of adverse events that occurred in 1% orwas moreconducted of patientstotreated with the AGGRENOX the incidence was also ATable 24-month, multicenter, double-blind, randomized study (ESPS2) compare efficacy where and safety of AGGRENOX greater than in those patients treateddipyridamole with placebo. alone There isand no clear benefit of the dipyridamole/aspirin combination overofaspirin to safety. with placebo, extended-release aspirin alone.

The study was conducted in a total 6602with malerespect and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within three months prior to randomization.

T

Table Adverse Events in in ESPS2* Table1:1:Incidence Incidenceofof Adverse Events ESPS2* Individual Treatment GroupTreatment Group Individual BodySystem/Preferred System/Preferred Term ER-DP Alone Alone Placebo Body Term AGGRENOXAGGRENOXER-DP Alone ASAASA Alone Placebo Total Number of Patients 1650 1654 1649 Total Number of Patients 1650 1654 16491649 1649 Total Number of Patients at Least Total Number (%)(%) of Patients WithWith at Least One Adverse Event (80.2%) 1304 (79.1%) OneOn-Treatment On-Treatment Adverse Event 1319 (79.9%) 1319 (79.9%)1305 (78.9%) 1305 (78.9%) 13231323 (80.2%) 1304 (79.1%) Central Peripheral Nervous System Disorders Central& & Peripheral Nervous System Disorders Headache 647 (39.2%)647 (39.2%)634 (38.3%) 558 558 (33.8%) 543 (32.9%) Headache 634 (38.3%) (33.8%) 543 (32.9%) Convulsions 28 (1.7%)28 (1.7%) 15 (0.9%) 28 28(1.7%) 2626 (1.6%) (1.6%) Convulsions 15 (0.9%) (1.7%) Gastro-Intestinal System Disorders Gastro-Intestinal System Disorders Dyspepsia 303 (18.4%) 299 299 (18.1%) 275 (16.7%) Dyspepsia 303 (18.4%)288 (17.4%) 288 (17.4%) (18.1%) 275 (16.7%) Abdominal Pain 255 (15.4%) (15.9%) 239 (14.5%) Abdominal Pain 289 (17.5%)289 (17.5%)255 (15.4%) 262 262 (15.9%) 239 (14.5%) Nausea 264 (16.0%)254 (15.4%) 254 (15.4%) (12.7%) 232 (14.1%) Nausea 264 (16.0%) 210 210 (12.7%) 232 (14.1%) Diarrhea 257 (15.5%) (6.8%) 161 (9.8%) Diarrhea 210 (12.7%)210 (12.7%)257 (15.5%) 112 112(6.8%) 161 (9.8%) Vomiting 138 (8.4%)129 (7.8%) 129 (7.8%) (6.1%) 118 (7.2%) Vomiting 138 (8.4%) 101 101(6.1%) 118 (7.2%) Hemorrhage Rectum 22 (1.3%) (1.0%) Hemorrhage Rectum 26 (1.6%)26 (1.6%) 22 (1.3%) 16 16(1.0%) 1313 (0.8%) (0.8%) Melena 10 (0.6%) (1.2%) Melena 31 (1.9%)31 (1.9%) 10 (0.6%) 20 20(1.2%) 1313 (0.8%) (0.8%) Hemorrhoids 13 (0.8%) (0.6%) Hemorrhoids 16 (1.0%)16 (1.0%) 13 (0.8%) 10 10(0.6%) 1010 (0.6%) (0.6%) Hemorrhage 5 (0.3%) (0.9%) GIGIHemorrhage 20 (1.2%)20 (1.2%) 5 (0.3%) 15 15(0.9%) 77 (0.4%) (0.4%) Body as a Whole General Disorders Body as a Whole - General Disorders Pain 105 (6.4%) 88 (5.3%) 103 (6.2%) 99 (6.0%) Pain 105 (6.4%) 88 (5.3%) 103 (6.2%) 99 (6.0%) Fatigue 95 (5.8%) 93 (5.6%) 97 (5.9%) 90 (5.5%) Fatigue 95 (5.8%) 93 (5.6%) 97 (5.9%) 90 (5.5%) Back Pain 76 (4.6%) 77 (4.7%) 74 (4.5%) 65 (3.9%) Back Pain 76 (4.6%) 77 (4.7%) 74 (4.5%) 65 (3.9%) Accidental Injury 42 (2.5%) 24 (1.5%) 51 (3.1%) 37 (2.2%) Accidental Injury 42 (2.5%) 51 (3.1%) 37 (2.2%) Malaise 27 (1.6%) 24 (1.5%) 23 (1.4%) 26 (1.6%) 22 (1.3%) Malaise 27 (1.6%)29 (1.8%) 23 (1.4%) 26 17(1.6%) 2218 (1.1%) (1.3%) Asthenia 19 (1.1%) (1.0%) Asthenia 29 (1.8%)17 (1.0%) 19 (1.1%) 17 16(1.0%) 188 (0.5%) (1.1%) Syncope 13 (0.8%) (1.0%) Syncope 17 (1.0%) 13 (0.8%) 16 (1.0%) 8 (0.5%) Psychiatric Disorders Psychiatric AmnesiaDisorders 39 (2.4%) 40 (2.4%) 57 (3.5%) 34 (2.1%) Amnesia 39 (2.4%)18 (1.1%) 40 (2.4%) 57 22(3.5%) 3415 (0.9%) (2.1%) Confusion 9 (0.5%) (1.3%) Confusion 18 (1.1%)19 (1.2%) 9 (0.5%) 22 10(1.3%) 1515 (0.9%) (0.9%) Anorexia 17 (1.0%) (0.6%) Anorexia 19 (1.2%)20 (1.2%) 17 (1.0%) 10 18(0.6%) 159 (0.5%) (0.9%) Somnolence 13 (0.8%) (1.1%) Somnolence 20 (1.2%) 13 (0.8%) 18 (1.1%) 9 (0.5%) Musculoskeletal System Disorders Musculoskeletal System Disorders Arthralgia 91 (5.5%) 75 (4.5%) 91 (5.5%) 76 (4.6%) Arthralgia 91 (5.5%) 75 (4.5%) 91 (5.5%) 76 (4.6%) Arthritis 34 (2.1%) 25 (1.5%) 17 (1.0%) 19 (1.2%) Arthritis 34 (2.1%)18 (1.1%) 25 (1.5%) 17 13(1.0%) 1914 (0.8%) (1.2%) Arthrosis 22 (1.3%) (0.8%) Myalgia 16 (1.0%) (0.7%) Arthrosis 18 (1.1%)20 (1.2%) 22 (1.3%) 13 11(0.8%) 1411 (0.7%) (0.8%) Respiratory System Disorders Myalgia 20 (1.2%) 16 (1.0%) 11 (0.7%) 11 (0.7%) CoughingSystem Disorders 25 (1.5%) 18 (1.1%) 32 (1.9%) 21 (1.3%) Respiratory Upper Respiratory Tract Infection 9 (0.5%) (1.0%) Coughing 25 (1.5%)16 (1.0%) 18 (1.1%) 32 16(1.9%) 2114 (0.8%) (1.3%) Cardiovascular Upper Respiratory Disorders, Tract InfectionGeneral 16 (1.0%) 9 (0.5%) 16 (1.0%) 14 (0.8%) Cardiac Failure 26 (1.6%) 17 (1.0%) 30 (1.8%) 25 (1.5%) Cardiovascular Disorders, General Platelet, Bleeding & Clotting Disorders Cardiac Failure 26 (1.6%) 17 (1.0%) 30 (1.8%) 25 (1.5%) Hemorrhage NOS 52 (3.2%) 24 (1.5%) 46 (2.8%) 24 (1.5%) Platelet, Bleeding & Clotting Disorders Epistaxis NOS 16 (1.0%) (2.7%) Hemorrhage 52 (3.2%)39 (2.4%) 24 (1.5%) 46 45(2.8%) 2425 (1.5%) (1.5%) Purpura 23 (1.4%) 8 (0.5%) 9 (0.5%) Epistaxis 39 (2.4%) 16 (1.0%) 45 (2.7%) 257 (0.4%) (1.5%) Neoplasm Purpura 23 (1.4%) 8 (0.5%) 9 (0.5%) 7 (0.4%) Neoplasm NOS 28 (1.7%) 16 (1.0%) 23 (1.4%) 20 (1.2%) Neoplasm Red Blood Cell Disorders Neoplasm NOS 28 (1.7%) 16 (1.0%) 23 (1.4%) 20 (1.2%) Anemia 27 (1.6%) 16 (1.0%) 19 (1.2%) 9 (0.5%) Red Blood Cell Disorders *Reported treatment where the treated with placebo.

Anemia by ≥1% of patients during AGGRENOX 27 (1.6%) 16incidence (1.0%)was greater than 19in those (1.2%) 9 (0.5%) Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. *Reported of patients during AGGRENOX treatment where the incidence was greater than in those treated with placebo.

NOS =bynot≥1% otherwise specified.

Note: ER-DP = extended-release 200 mg; aspirin 25 mg. The dosage regimen for all treatment groups19% is BID. Discontinuation due to adversedipyridamole events in ESPS2 wasASA 25%= for AGGRENOX, 25% for extended-release dipyridamole, for aspirin, otherwise specified. and NOS 21% =fornotplacebo (refer to Table 2).

Discontinuation due to adverse events in ESPS2 was 25% for AGGRENOX, 25% for extended-release dipyridamole, 19% for aspirin, and Table 2: Incidence of Adverse Events that Led to the Discontinuation of Treatment: 21% for placebo (refer to Table 2).

Adverse Events with an Incidence of ≥1% in the AGGRENOX group Table 2: Incidence of Adverse Events that Led to the Discontinuation of Treatment: Treatment Groups Adverse Events with an Incidence of ≥ 1% in the AGGRENOX group AGGRENOX ER-DP ASA Placebo Treatment Total Number of Patients 1650 1654 Groups 1649 1649 AGGRENOX ER-DP ASA Placebo Patients with at least one Adverse Event Total of Patientsdiscontinuation 1650 417 (25%) 1654 419 (25%) 1649 thatNumber led to treatment 318 (19%) 3521649 (21%) Patients with at least one Adverse Event Headache 165 (10%) 166 (10%) 57 (3%) 69 (4%) thatDizziness led to treatment discontinuation 417 (25%) 85 (5%) 419 (25%)97 (6%) 318 69 (19%) 352 (21%) (4%) 68 (4%) Headache 165 (10%) 91 (6%) 166 (10%)95 (6%) 57 51 (3%)(3%) 69 (3%) (4%) Nausea 53 Dizziness 85 (5%) 74 (4%) 97 (6%) 64 (4%) 69 56 (4%)(3%) 68 (3%) (4%) Abdominal Pain 52 Nausea 91 (6%) 59 (4%) 95 (6%) 61 (4%) 51 49 (3%)(3%) 53 (3%) (3%) Dyspepsia 46 Abdominal 74 (4%) 53 (3%) 64 (4%) 52 (3%) 56 28 (3%)(2%) 52 (1%) (3%) Vomiting Pain 24 Diarrhea 9 (<1%) 16 Dyspepsia 59 (4%) 35 (2%) 61 (4%) 41 (2%) 49 (3%) 46 (<1%) (3%) Stroke 73 Vomiting 53 (3%) 39 (2%) 52 (3%) 48 (3%) 28 57 (2%)(3%) 24 (4%) (1%) Transient Ischemic Attack (2%) 48 Diarrhea 35 (2%) 35 (2%) 41 (2%) 40 (2%) 9 26 (<1%) 16 (3%) (<1%) Angina Pectoris 26 Stroke 39 (2%) 23 (1%) 48 (3%) 20 (1%) 57 16 (3%)(<1%) 73 (2%) (4%) Note: ER-DP = extended-release dipyridamole 35 200 (2%) mg; ASA = aspirin 2540 mg.(2%) The dosage regimen for26all treatment groups is BID. Transient Ischemic Attack (2%) 48 (3%) Anginaadverse Pectoris events: 23 (1%) 20 (1%) 16 (<1%) 26 (2%) Other Adverse reactions that occurreddipyridamole in less than 200 1% mg; of patients treated 25 withmg.

AGGRENOX the ESPS2 study and that were ismedically Note: ER-DP = extended-release ASA = aspirin The dosageinregimen for all treatment groups BID. judged to be possibly related to either dipyridamole or aspirin are listed below (see WARNINGS). Body as a Whole: Allergic reaction, fever.

Other adverse events: Cardiovascular: Hypotension. Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, Adverse reactions that occurred in less than 1% of patients treated with AGGRENOX in the ESPS2 study and that were medically judged be subarachnoid hemorrhage. Gastrointestinal: Gastritis, ulceration and perforation. Hearing and Vestibular Disorders: Tinnitus, and to deafpossibly related with to either dipyridamole or aspirin arehave listeddifficulty below (see WARNINGS). a Whole: Allergic reaction, fever. ness. Patients high frequency hearing loss may perceiving tinnitus. InBody theseaspatients, tinnitus cannot be used as Cardiovascular: Hypotension.

Central dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, a clinical indicator of salicylism.

HeartNervous Rate andSystem: RhythmComa, Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardia. subarachnoid hemorrhage.

Gastrointestinal: Gastritis, ulceration and perforation. andMetabolic Vestibular&Disorders: and Hyperglydeafness.

Liver and Biliary System Disorders: Cholelithiasis, jaundice, hepatic function Hearing abnormal.

NutritionalTinnitus, Disorders: Patients with high frequency hearing loss may have difficulty perceiving tinnitus.

In these patients, tinnitus cannot be used as a clinical cemia, thirst. Platelet, Bleeding and Clotting Disorders: Hematoma, gingival bleeding. Psychiatric Disorders: Agitation. Reproductive: indicator salicylism. Heart Rate andHyperpnea, Rhythm Disorders: palpitation, arrhythmia, supraventricular tachycardia.

Liver and Biliary Uterine ofhemorrhage.

Respiratory: asthma,Tachycardia, bronchospasm, hemoptysis, pulmonary edema. Special Senses Other DisorSystem Disorders: Cholelithiasis, jaundice,Disorders: hepatic function abnormal. & Nutritional Disorders:and Hyperglycemia, thirst. Vascular Platelet, ders: Taste loss. Skin and Appendages Pruritus, urticaria.Metabolic Urogenital: Renal insufficiency failure, hematuria.

Bleeding and Clotting Disorders: Hematoma, gingival bleeding.

Psychiatric Disorders: Agitation.

Reproductive: Uterine hemorrhage.

(Extracardiac) Disorders: Flushing.

Respiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema. Special Senses Other Disorders: Taste loss. Skin and The following is a list Pruritus, of additional adverse reactionsRenal that insufficiency have been reported eitherhematuria. in the literature or (Extracardiac) are from postmarketing Appendages Disorders: urticaria.

Urogenital: and failure, Vascular Disorders:spontaneFlushing. ous reports for either dipyridamole or aspirin. Body as a Whole: Hypothermia, chest pain. Cardiovascular: Angina pectoris. Central The following is a list of additional reactions that have been reported either inacidosis, the literature or are from postmarketing spontaneous Nervous System: Cerebral edema.adverse Fluid and Electrolyte: Hyperkalemia, metabolic respiratory alkalosis, hypokalemia.

Gastroreports for either dipyridamole orsyndrome, aspirin. Body as a Whole: Hypothermia, chest pain.Disorders: Cardiovascular: Angina Central Nervous System: intestinal: Pancreatitis, Reye’s hematemesis.

Hearing and Vestibular Hearing loss.pectoris.

Hypersensitivity: Acute anaphyCerebral edema. Fluid andLiver Electrolyte: Hyperkalemia, metabolicHepatitis, acidosis, hepatic respiratory alkalosis, hypokalemia.Rhabdomyolysis.

Gastrointestinal: Metabolic Pancreatitis,& laxis, laryngeal edema. and Biliary System Disorders: failure.

Musculoskeletal: Reye’ s syndrome, hematemesis.

Hearing and Vestibular Disorders: Hearing loss.

Hypersensitivity: Acute anaphylaxis, laryngeal edema.

Nutritional Disorders: Hypoglycemia, dehydration. Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time,Liver disand Biliary System Disorders: Hepatitis, coagulopathy, hepatic failure. thrombocytopenia.

Musculoskeletal: Rhabdomyolysis.

Metabolic &pregnancy Nutritionaland Disorders: Hypoglycemia, seminated intravascular coagulation, Reproductive: Prolonged labor, stillbirths, lower dehydration. andand Clotting Disorders: Prolongation of the prothrombin time, Skin disseminated intravascular coagulation, birth weightPlatelet, infants, Bleeding antepartum postpartum bleeding.

Respiratory: Tachypnea, dyspnea. and Appendages Disorders: Rash, coagulopathy, thrombocytopenia.

Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and alopecia, angioedema, Stevens-Johnson syndrome, pruritus, urticaria, skin hemorrhages such as bruising, ecchymosis, and hematoma. postpartum Tachypnea, dyspnea.

Skin and Vascular Appendages Disorders:Disorders): Rash, alopecia, angioedema, Urogenital:bleeding.

InterstitialRespiratory: nephritis, papillary necrosis, proteinuria.

(Extracardiac Allergic vasculitis. Stevens-Johnson syndrome, pruritus, urticaria, skin hemorrhages such as bruising, ecchymosis, and hematoma. Urogenital: Interstitial nephritis, papillary The following is a list of additional adverseDisorders): events thatAllergic have been reported either in the literature or are from postmarketing spontaneous necrosis, proteinuria.

Vascular (Extracardiac vasculitis. reports for either dipyridamole or aspirin. The causal relationship of these adverse events has not been established: anorexia, aplastic The following is a list of thrombocytosis. additional adverse events that have been reported either in the literature or are from postmarketing spontaneous anemia, pancytopenia, reports for either dipyridamole or aspirin. The causal relationship of these adverse events has not been established: anorexia, aplastic anemia, Laboratorythrombocytosis.

Changes pancytopenia, Over the course of the 24-month study (ESPS2), patients treated with AGGRENOX showed a decline (mean change from baseline) in Laboratory Changes 3. hemoglobin of hematocrit 0.75%, and erythrocyte 0.13x106/mm Over the course 0.25 of theg/dL, 24-month studyof(ESPS2), patients treatedcount with of AGGRENOX showed a decline (mean change from baseline) in OVERDOSAGE hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm3.

Because of the dose ratio of dipyridamole to aspirin, overdosage of AGGRENOX is likely to be dominated by signs and symptoms of OVERDOSAGE dipyridamole of real or to suspected medical attention or contact a Poison dipyridamole) Control Centerisimmediately.

Because of the overdose. dose ratioInofcase dipyridamole aspirin, overdose, overdosageseek of AGGRENOX (aspirin/extended-release likely to be Careful medical management is essential. dominated by signs and symptoms of dipyridamole overdose. In case of real or suspected overdose, seek medical attention or contact a Poison Control Center immediately. Careful medical management is essential.

DOSAGE AND ADMINISTRATION The recommended dose of AGGRENOX capsules is one capsule given orally twice daily, one in the morning and one in the evening. The DOSAGE AND ADMINISTRATION ® capsules should be swallowed whole without chewing. AGGRENOX capsulescapsules may be administered or without food.daily, one in the (aspirin/extended-release dipyridamole) is one capsulewith given orally twice The recommended dose of Aggrenox morning and one in the evening.

The capsules should be swallowed whole chewing.

AGGRENOX capsules be administered with Alternative Regimen in Case of Intolerable Headaches: In thewithout event of intolerable headaches duringmay initial treatment, switch ortowithout food. one capsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become lessRegimen of a problem as treatment continues, patients should returnoftointolerable the usualheadaches regimen as sooninitial as possible, within Alternative in Case of Intolerable Headaches: In the event during treatment,usually switch to one one week. capsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become less of a problem as treatment patients should the usual regimen as soonof asaspirin possible,and usually within one®week.

AGGRENOX is notcontinues, interchangeable withreturn the to individual components Persantine Tablets.Rx only AGGRENOX not interchangeable with the individual aspirin and Persantine® Tablets.

Marketed by:isBoehringer Ingelheim Pharmaceuticals Inc., components Ridgefield, CTof06877 USA Marketed by: Boehringer IngelheimIngelheim Pharmaceuticals Ridgefield, CT 06877 USA Germany Manufactured by: Boehringer PharmaInc., GmbH & Co. KG, Biberach, Manufactured by: Boehringer Pharma GmbH &GmbH Co. KG, © Biberach, Germany Licensed from: BoehringerIngelheim Ingelheim International Copyright Boehringer Ingelheim International GmbH 2007 Licensed from: Boehringer Ingelheim International GmbH © Copyright Boehringer Ingelheim International GmbH 2007 ALLRIGHTS RIGHTS RESERVED PatentPatent No. 6,015,577 42633/US/7 AG/BS/42633 AG49262 ALL RESERVED No. 6,015,577 42633/US/7 AG/BS/42633 AG49265 R

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Covers:Cover 12/11/09 4:28 PM Page C4

Pick the TIA or ischemic stroke patients out of the crowd.

AGGRENOX may be right for many of them.

AGGRENOX has been shown to be twice as effective as low-dose aspirin when compared to placebo.1 • In ESPS 2, relative risk reductions were 37.0% for AGGRENOX vs placebo; 18.1% for aspirin vs placebo; 23.1% for AGGRENOX vs aspirin alone ESPS 2 = European Stroke Prevention Study 2.

CHOOSE AGGRENOX FOR SECONDARY STROKE RISK REDUCTION THAT MAY BE RIGHT FOR MANY PATIENTS. Important Safety afety Information Aggrenox® (aspirin/extended-release dipyridamole) 25 mg/200 mg capsules is indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.

In ESPS 2, the most common adverse event with AGGRENOX was headache (39.2% vs. 32.9% with placebo), which was more frequent at the onset of therapy but diminished over time. Bleeding (including GI and intracranial bleeding) was comparable to aspirin (8.7% vs. 8.2%) and higher than placebo (8.7% vs. 4.5%). GI side effects (such as dyspepsia, stomach pain, heartburn, nausea, and vomiting) were other common adverse events.

AGGRENOX contains aspirin. Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks associated with chronic, heavy alcohol use while taking aspirin. Even low doses of aspirin can increase bleeding time, which can adversely affect patients with bleeding disorders. Patients with a history of active peptic ulcer disease should avoid using aspirin. Aspirin should be avoided in the third trimester of pregnancy. Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps occurring in combination.

Reference: 1. Diener H-C, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996; 143:1-13.

Please see reverse side for Brief Summary of Prescribing Information.

Copyright © 2009, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in the U.S.A.

(08/09)

AG66794