AHDB September 2014, Vol 7, No 6 by Dalia Buffery

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ September 2014

Volume 7, Number 6

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

A Different Kind of Merger David B. Nash, MD, MBA CLINICAl

Cardiovascular Events and Safety Outcomes Associated with Azithromycin Therapy: A Meta-Analysis of Randomized Controlled Trials Ziyad S. Almalki, BPharm, PhD student; Jeff Jianfei Guo, BPharm, PhD ™

Stakeholder Perspective: Cardiovascular Safety of Azithromycin Therapy: Revisiting the Evidence By Raymond L. Singer, MD, MMM, CPE BUSINESS

Healthcare Costs Among Patients with Excessive Sleepiness Associated with Obstructive Sleep Apnea, Shift Work Disorder, or Narcolepsy Rashad Carlton, PharmD; Orsolya Lunacsek, PhD; Timothy Regan, BPharm; Cathryn A. Carroll, PhD Stakeholder Perspective: Out-of-Pocket Cost of Therapy Can Affect Patients’ Excessive Sleepiness and Daytime Functioning By Teresa DeLuca, MD, MBA REGULATORY

Effects of Medicare Part D on Disparity Implications of Medication Therapy Management Eligibility Criteria Junling Wang, PhD, MS; Yanru Qiao, MS; Ya-Chen Tina Shih, PhD; JoEllen Jarrett Jamison, BS; Christina A. Spivey, PhD; Liyuan Li, PhD; Jim Y. Wan, PhD; Shelley I. White-Means, PhD; Samuel Dagogo-Jack, MD, FRCP; William C. Cushman, MD; Marie Chisholm-Burns, PharmD, MPH, MBA, FCCP, FASHP Stakeholder Perspective: Medication Therapy Management, Medicare, and Disparities in Population Health By Dima M. Qato, PharmD, MPH, PhD

www.AHDBonline.com

With schizophrenia,

choosing an antipsychotic individualized to patients’ needs

can be complex.1

Not actual patients. 1. Lehman AF, Lieberman JA, Dixon LB, et al. Practice Guideline for the Treatment of Patients With Schizophrenia. 2nd ed. Arlington, VA: American Psychiatric Association; 2004. 2. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73(5):617-624. 3. Abilify Maintena [package insert]. Rockville, MD: Otsuka Pharmaceutical Company; February 2013.

INDICATION and IMPORTANT SAFETY INFORMATION for Abilify Maintena® (aripiprazole) for extended-release injectable suspension INDICATION Abilify Maintena is an atypical antipsychotic indicated for the treatment of schizophrenia. Efﬁcacy was demonstrated in a placebo-controlled, randomized-withdrawal maintenance trial in patients with schizophrenia and additional support for efﬁcacy was derived from oral aripiprazole trials.

IMPORTANT SAFETY INFORMATION Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Abilify Maintena is not approved for the treatment of patients with dementiarelated psychosis. Contraindication: Known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis. Cerebrovascular Adverse Events, Including Stroke: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with oral aripiprazole.

Accessing long-acting injectables

shouldn’t be.

Position Abilify Maintena® (aripiprazole) at parity with all long-acting injectables on your formulary. Offer the efﬁcacy* and safety of oral aripiprazole for schizophrenia in a once-monthly formulation.2,3,†

* Abilify Maintena significantly delayed the time to impending relapse vs placebo (P<0.0001) in a phase III, 52-week, double-blind, randomized-withdrawal clinical trial; Abilify Maintena (n=269) vs placebo (n=134).3 † Efficacy was demonstrated in a placebo-controlled, randomized-withdrawal maintenance trial in patients with schizophrenia and additional support for efficacy was derived from oral aripiprazole trials. In conjunction with first dose, take 14 consecutive days of concurrent oral aripiprazole (10 mg to 20 mg) or current oral antipsychotic.

IMPORTANT SAFETY INFORMATION (continued) Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as NMS may occur with administration of antipsychotic drugs, including Abilify Maintena. Rare cases of NMS occurred during aripiprazole treatment. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. Tardive Dyskinesia (TD): The risk of developing TD (a syndrome of abnormal, involuntary movements) and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. There is no known treatment for established TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Continued on next page. Please see IMPORTANT SAFETY INFORMATION continued, and BRIEF SUMMARY of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following pages.

IMPORTANT SAFETY INFORMATION for Abilify Maintena® (aripiprazole) for extended-release injectable suspension (continued) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include: Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including aripiprazole. Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting low-density lipoproteins (LDLs), and fasting/nonfasting high-density lipoproteins (HDLs). Weight Gain: Weight gain has been observed. Clinical monitoring of weight is recommended. Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension. Abilify Maintena should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension. Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia, and agranulocytosis have been reported. Patients with a history of clinically significant low white blood cell (WBC) count or drug-induced leukopenia/neutropenia should have their complete blood count monitored frequently during the first few months of therapy while receiving Abilify Maintena. In such patients, consider discontinuation of Abilify Maintena at the first sign of a clinically significant decline in WBC count in the absence of other causative factors. Seizures/Convulsions: Abilify Maintena should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold. Potential for Cognitive and Motor Impairment: Abilify Maintena may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery including automobiles until they are certain Abilify Maintena does not affect them adversely. Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Advise patients regarding appropriate care in avoiding overheating and dehydration. Appropriate care is advised for patients who may exercise strenuously, may be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or are subject to dehydration. Dysphagia: Esophageal dysmotility and aspiration have been associated with Abilify Maintena; use caution in patients at risk for aspiration pneumonia. Alcohol: Advise patients to avoid alcohol while taking Abilify Maintena. Concomitant Medication: Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the Abilify Maintena dosage may need to be increased. Avoid the concomitant use of CYP3A4 inducers with Abilify Maintena for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels. Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days. Most commonly observed adverse reaction: The safety profile of Abilify Maintena is expected to be similar to that of oral aripiprazole. In patients who tolerated and responded to oral aripiprazole and single-blind Abilify Maintena and were then randomized to receive Abilify Maintena or placebo injections, the incidence of adverse reactions was similar between the two treatment groups. The adverse reaction ≥ 5% incidence and at least twice the rate of placebo for oral aripiprazole vs placebo, respectively, was: Akathisia (8% vs 4%) in adult patients with schizophrenia. Injection Site Reactions: In the open-label, stabilization phase of a study with Abilify Maintena in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction was 6.3% for Abilify Maintena-treated patients. Dystonia is a class effect of antipsychotic drugs. Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses. Pregnancy/Nursing: Based on animal data, may cause fetal harm. Abilify Maintena should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Aripiprazole is excreted in human breast milk. 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.

» »

Please see BRIEF SUMMARY of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on adjacent pages.

ABILIFY MAINTENA™ (aripiprazole) for extended-release injectable suspension, for • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated intramuscular use BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details, please see Full with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole. Assessment of the relationship between atypical antipsychotic use and glucose Prescribing Information and Medication Guide.) abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED population. Given these confounders, the relationship between atypical antipsychotic use and PSYCHOSIS hyperglycemia-related adverse reactions is not completely understood. However, epidemiological See full prescribing information for complete boxed warning. studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at with atypical antipsychotics. Because aripiprazole was not marketed at the time these studies an increased risk of death were performed, it is not known if aripiprazole is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical • ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who psychosis are started on atypical antipsychotics should be monitored regularly for worsening of glucose INDICATIONS AND USAGE: ABILIFY MAINTENA (aripiprazole) is indicated for the treatment control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes), of schizophrenia. Efficacy was demonstrated in a placebo-controlled, randomized-withdrawal who are starting treatment with atypical antipsychotics should undergo fasting blood glucose maintenance trial in patients with schizophrenia and additional support for efficacy was derived from testing at the beginning of treatment and periodically during treatment. Any patient treated with oral aripiprazole trials. atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, CONTRAINDICATIONS: ABILIFY MAINTENA is contraindicated in patients with a known polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during hypersensitivity to aripiprazole. Hypersensitivity reactions ranging from pruritus/urticaria to treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some anaphylaxis have been reported in patients receiving aripiprazole. cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, WARNINGS AND PRECAUTIONS: Increased Mortality in Elderly Patients with Dementia- some patients required continuation of anti-diabetic treatment despite discontinuation of the Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic atypical antipsychotic drug. drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in schizophrenia or bipolar disorder, the mean change in fasting glucose in aripiprazoledrug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). 4.5%, compared to a rate of about 2.6% in the placebo group. Table 1 shows the proportion of aripiprazole-treated patients with normal and borderline Although the causes of death were varied, most of the deaths appeared to be either cardiovascular fasting glucose at baseline (median exposure 25 days) that had high fasting glucose (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies measurements compared to placebo-treated patients (median exposure 22 days). suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational Table 1: Changes in Fasting Glucose From Placebo-controlled Monotherapy Trials in Adult Patients studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of Category Change (at least once) Treatment n/N % the patients is not clear. ABILIFY MAINTENA is not approved for the treatment of patients with from Baseline Arm dementia-related psychosis. Aripiprazole 31/822 3.8 Normal to High Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia- Fasting (<100 mg/dL to ≥126 mg/dL) Placebo 22/605 3.6 Related Psychosis: In placebo-controlled clinical studies (two flexible dose and one fixed dose Glucose Aripiprazole 31/176 17.6 Borderline to High study) of dementia-related psychosis, there was an increased incidence of cerebrovascular (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Placebo 13/142 9.2 adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, in oral aripiprazoletreated patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not statistically significant dose response relationship for cerebrovascular adverse reactions in patients significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL treated with oral aripiprazole. ABILIFY MAINTENA is not approved for the treatment of patients with (n=28), respectively]. dementia-related psychosis. • Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with Neuroleptic Malignant Syndrome: A potentially fatal symptom complex sometimes referred to atypical antipsychotics. as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, There were no significant differences between aripiprazole- and placebo-treated patients in the including ABILIFY MAINTENA. Rare cases of NMS occurred during aripiprazole treatment in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total worldwide clinical database. cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and with at least 12 or 24 weeks of exposure were limited by small numbers of patients. evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and Table 2 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from (rhabdomyolysis), and acute renal failure. 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 is important to exclude cases where the clinical presentation includes both serious medical illness days, except for placebo-treated patients with baseline normal fasting LDL measurements, who (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median and symptoms (EPS). Other important considerations in the differential diagnosis include central exposure 40 to 42 days). anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and Table 2: Changes in Blood Lipid Parameters From Placebo-controlled Monotherapy Trials in Adults other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical Treatment Arm n/N % monitoring; and 3) treatment of any concomitant serious medical problems for which specific Total Cholesterol Aripiprazole 34/1357 2.5 treatments are available. There is no general agreement about specific pharmacological treatment Normal to High (<200 mg/dL to ≥240 mg/dL) Placebo 27/973 2.8 regimens for uncomplicated NMS. Aripiprazole 40/539 7.4 Fasting Triglycerides If a patient requires antipsychotic drug treatment after recovery from NMS, the potential Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 30/431 7.0 reintroduction of drug therapy should be carefully considered. The patient should be carefully Aripiprazole 2/332 0.6 Fasting LDL Cholesterol monitored, since recurrences of NMS have been reported. Normal to High (<100 mg/dL to ≥160 mg/dL) Placebo 2/268 0.7 Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements, Aripiprazole 121/1066 11.4 may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome HDL Cholesterol Placebo 99/794 12.5 appears to be highest among the elderly, especially elderly women, it is impossible to rely upon Normal to Low (≥40 mg/dL to <40 mg/dL) prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting tardive dyskinesia is unknown. LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 believed to increase as the duration of treatment and the total cumulative dose of antipsychotic (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at drugs administered to the patient increase. However, the syndrome can develop, although much 24 weeks, Total Cholesterol (fasting/ nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, less commonly, after relatively brief treatment periods at low doses. 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively. There is no known treatment for established tardive dyskinesia, although the syndrome may remit, • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, of weight is recommended. In an analysis of 13 placebo-controlled monotherapy trials, primarily however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the thereby, may possibly mask the underlying process. The effect of symptomatic suppression on the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to long-term course of the syndrome is unknown. –0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline Given these considerations, ABILIFY MAINTENA should be prescribed in a manner that is most in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should placebo-treated patients. generally be reserved for patients who suffer from a chronic illness that 1) is known to respond Table 3 shows the percentage of adult patients with weight gain ≥7% of body weight in the to antipsychotic drugs and 2) for whom alternative, equally effective, but potentially less harmful 13 pooled placebo-controlled monotherapy trials. treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response Table 3: Percentage of Patients From Placebo-controlled Trials in Adult Patients with Weight Gain ≥7% of Body Weight should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treated with ABILIFY MAINTENA Indication Treatment Arm N n (%) drug discontinuation should be considered. However, some patients may require treatment with ABILIFY MAINTENA despite the presence of the syndrome. Aripiprazole 852 69 (8.1) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes Schizophreniaa Placebo 379 12 (3.2) that include hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. While all drugs in Weight gain ≥7% Aripiprazole 719 16 (2.2) the class have been shown to produce some metabolic changes, each drug has its own specific of body weight Bipolar Maniab Placebo 598 16 (2.7) risk profile. Although the following metabolic data were collected in patients treated with oral a formulations of aripiprazole, the findings pertain to patients receiving ABILIFY MAINTENA as well. 4-6 weeks’ duration. b3 weeks’ duration.

Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension, perhaps due to its α1 -adrenergic receptor antagonism. Orthostasis occurred in 4/576 (0.7%) patients treated with ABILIFY MAINTENA during the stabilization phase, including abnormal orthostatic blood pressure (1/576, 0.2%), postural dizziness (1/576, 0.2%), presyncope (1/576, 0.2%) and orthostatic hypotension (1/576, 0.2%). In the stabilization phase, the incidence of significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 when comparing standing to supine values) was 0.2% (1/575). Leukopenia, Neutropenia, and Agranulocytosis: Class Effect: In clinical trials and post-marketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including oral aripiprazole. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ABILIFY MAINTENA at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ABILIFY MAINTENA in patients with severe neutropenia (absolute neutrophil count <1000/mm 3) and follow their WBC counts until recovery. Seizures: As with other antipsychotic drugs, use ABILIFY MAINTENA cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. Potential for Cognitive and Motor Impairment: ABILIFY MAINTENA, like other antipsychotics, may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ABILIFY MAINTENA does not affect them adversely. Body Temperature Regulation: Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY MAINTENA for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration). Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY MAINTENA. ABILIFY MAINTENA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. ADVERSE REACTIONS: The following adverse reactions are discussed in more detail in other sections of the labeling in the Full Prescribing Information: • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)] • Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.2)] • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)] • Tardive Dyskinesia [see Warnings and Precautions (5.4)] • Metabolic Changes [see Warnings and Precautions (5.5)] • Orthostatic Hypotension [see Warnings and Precautions (5.6)] • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7)] • Seizures [see Warnings and Precautions (5.8)] • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.9)] • Body Temperature Regulation [see Warnings and Precautions (5.10)] • Dysphagia [see Warnings and Precautions (5.11)] Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety Database of ABILIFY MAINTENA and Oral Aripiprazole: Aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days. ABILIFY MAINTENA 300-400 mg every 4 weeks has been evaluated for safety in 1,287 adult patients in clinical trials in schizophrenia, with approximately 1,281 patient-years of exposure to ABILIFY MAINTENA. A total of 832 patients were treated with ABILIFY MAINTENA for at least 180 days (at least 7 consecutive injections) and 630 patients treated with ABILIFY MAINTENA had at least 1 year of exposure (at least 13 consecutive injections). The conditions and duration of treatment with ABILIFY MAINTENA included double-blind and open-label studies. The safety profile of ABILIFY MAINTENA is expected to be similar to that of oral aripiprazole. Therefore, most of the safety data presented below are derived from trials with the oral formulation. In patients who tolerated and responded to treatment with oral aripiprazole and single-blind ABILIFY MAINTENA and were then randomized to receive ABILIFY MAINTENA or placebo injections under double-blind conditions, the incidence of adverse reactions was similar between the two treatment groups. Adverse Reactions of ABILIFY MAINTENA and Oral Aripiprazole: Adverse Reactions Associated with Discontinuation of Oral Aripiprazole: Based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral aripiprazole was administered to adults with schizophrenia in doses ranging from 2 mg/day to 30 mg/day, the incidence of discontinuation due to adverse reactions was 7% in oral aripiprazole-treated and 9% in placebo-treated patients. The types of adverse reactions that led to discontinuation were similar for the aripiprazole-treated and placebo-treated patients. Commonly Observed Adverse Reactions of Oral Aripiprazole: Based on a pool of five placebocontrolled trials (four 4-week and one 6-week) in which oral aripiprazole was administered to adults with schizophrenia in doses ranging from 2 mg/day to 30 mg/day, the only commonly observed adverse reaction associated with the use of oral aripiprazole in patients with schizophrenia (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) was akathisia (aripiprazole 8%; placebo 4%). Less Common Adverse Reactions in Adults Treated with Oral Aripiprazole: Table 4 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with oral aripiprazole (doses ≥2 mg/ day) and for which the incidence in patients treated with aripiprazole was greater than the incidence in patients treated with placebo in the combined dataset.

Table 4: Adverse Reactions in Short-term, Placebo-controlled Trials in Adult Patients Treated with Oral Aripiprazole Percentage of Patients Reporting Reactiona System Organ Class Oral Aripiprazole (n=1843) Placebo (n=1166) Preferred Term Eye Disorders Blurred Vision 3 1 Gastrointestinal Disorders Nausea 15 11 Constipation 11 7 Vomiting 11 6 Dyspepsia 9 7 Dry Mouth 5 4 Toothache 4 3 Abdominal Discomfort 3 2 Stomach Discomfort 3 2 General Disorders and Administration Site Conditions Fatigue 6 4 Pain 3 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 4 3 Pain in Extremity 4 2 Myalgia 2 1 Muscle Spasms 2 1 Nervous System Disorders Headache 27 23 Dizziness 10 7 Akathisia 10 4 Sedation 7 4 Extrapyramidal Disorder 5 3 Tremor 5 3 Somnolence 5 3 Psychiatric Disorders Agitation 19 17 Insomnia 18 13 Anxiety 17 13 Restlessness 5 3 Respiratory, Thoracic, and Mediastinal Disorders Pharyngolaryngeal Pain 3 2 Cough 3 2 a Adverse reactions reported by at least 2% of patients treated with oral aripiprazole, except adverse reactions which had an incidence equal to or less than placebo. An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race. Dose-Related Adverse Reactions of Oral Aripiprazole: Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed oral doses of aripiprazole (2 mg/day, 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, and 30 mg/day) to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%). Injection Site Reactions of ABILIFY MAINTENA: In the open-label, stabilization phase of a study with ABILIFY MAINTENA in patients with schizophrenia, the percent of patients reporting any injection site-related adverse reaction was 6.3% for ABILIFY MAINTENA-treated patients. The mean intensity of injection pain reported by subjects using a visual analog scale (0=no pain to 100=unbearably painful) was minimal and improved in subjects receiving ABILIFY MAINTENA from the first to the last injection in the open-label, stabilization phase (6.1 to 4.9). Investigator evaluation of the injection site for pain, swelling, redness and induration following injections of ABILIFY MAINTENA in the open-label, stabilization phase were rated as absent for 74%-96% of subjects following the first injection and 77%-96% of subjects following the last injection. Extrapyramidal Symptoms of Oral Aripiprazole: In short-term, placebo-controlled trials in schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for oral aripiprazole-treated patients was 13% vs. 12% for placebo; and the incidence of akathisiarelated events for aripiprazole-treated patients was 8% vs. 4% for placebo. Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Abnormal Involuntary Movement Scale (for dyskinesias). In the schizophrenia trials, the objectively collected data did not show a difference between aripiprazole and placebo, with the exception of the Barnes Akathisia Scale (aripiprazole, 0.08; placebo, –0.05). Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Abnormal Involuntary Movement Scale (for dyskinesias) did not show a difference between aripiprazole and placebo. Dystonia: Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials of Oral Aripiprazole: The adverse reactions reported in a 26-week, double-blind trial comparing oral aripiprazole and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for oral aripiprazole vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 ≤49 days), and were of limited duration (7/12 ≤10 days). Tremor infrequently led to discontinuation (<1%) of oral aripiprazole. In addition, in a long-term, active-controlled study, the incidence of tremor was 5% (40/859) for oral aripiprazole.

Other Adverse Reactions Observed During the Premarketing Evaluation of Oral Aripiprazole: Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with oral aripiprazole at multiple doses ≥2 mg/day during any phase of a trial within the database of 13,543 adult patients. All events assessed as possible adverse drug reactions have been included with the exception of more commonly occurring events. In addition, medically/clinically meaningful adverse reactions, particularly those that are likely to be useful to the prescriber or that have pharmacologic plausibility, have been included. Events already listed in other parts of Adverse Reactions (6), or those considered in Warnings and Precautions (5) or Overdosage (10) have been excluded. Although the reactions reported occurred during treatment with aripiprazole, they were not necessarily caused by it. Events are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in fewer than 1/1000 patients. Blood and Lymphatic System Disorders: ≥1/1000 patients and <1/100 patients - thrombocytopenia; Cardiac Disorders: ≥1/1000 patients and <1/100 patients - palpitations, cardiopulmonary failure, myocardial infarction, cardio-respiratory arrest, atrioventricular block, extrasystoles, angina pectoris, myocardial ischemia; <1/1000 patients - atrial flutter, supraventricular tachycardia, ventricular tachycardia; Eye Disorders: ≥1/1000 patients and <1/100 patients - photophobia, diplopia, eyelid edema, photopsia; Gastrointestinal Disorders: ≥1/1000 patients and <1/100 patients - gastroesophageal reflux disease, swollen tongue, esophagitis; <1/1000 patients - pancreatitis; General Disorders and Administration Site Conditions: ≥1/100 patients - asthenia, peripheral edema, chest pain; ≥1/1000 patients and <1/100 patients - face edema, angioedema; <1/1000 patients - hypothermia; Hepatobiliary Disorders: <1/1000 patients - hepatitis, jaundice; Immune System Disorders: ≥1/1000 patients and <1/100 patients - hypersensitivity; Injury, Poisoning, and Procedural Complications: ≥1/100 patients - fall; <1/1000 patients - heat stroke; Investigations: ≥1/1000 patients and <1/100 patients - blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased; <1/1000 patients - blood lactate dehydrogenase increased, glycosylated hemoglobin increased; Metabolism and Nutrition Disorders: ≥1/1000 patients and <1/100 patients - anorexia, hyponatremia, hypoglycemia, polydipsia; <1/1000 patients - diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: ≥1/1000 patients and <1/100 patients - muscle rigidity, muscular weakness, muscle tightness, mobility decreased; <1/1000 patients - rhabdomyolysis; Nervous System Disorders: ≥1/100 patients - coordination abnormal; ≥1/1000 patients and <1/100 patients - speech disorder, hypokinesia, hypotonia, myoclonus, akinesia, bradykinesia; <1/1000 patients - choreoathetosis; Psychiatric Disorders: ≥1/100 patients - suicidal ideation; ≥1/1000 patients and <1/100 patients - loss of libido, suicide attempt, hostility, libido increased, anger, anorgasmia, delirium, intentional self injury, completed suicide, tic, homicidal ideation; <1/1000 patients - catatonia, sleepwalking; Renal and Urinary Disorders: ≥1/1000 patients and <1/100 patients - urinary retention, polyuria, nocturia; Reproductive System and Breast Disorders: ≥1/1000 patients and <1/100 patients - menstruation irregular, erectile dysfunction, amenorrhea, breast pain; <1/1000 patients gynecomastia, priapism; Respiratory, Thoracic, and Mediastinal Disorders: ≥1/100 patients - nasal congestion, dyspnea; Skin and Subcutaneous Tissue Disorders: ≥1/100 patients - rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), hyperhydrosis; ≥1/1000 patients and <1/100 patients - pruritus, photosensitivity reaction, alopecia, urticaria. Postmarketing Experience: The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm). DRUG INTERACTIONS: Carbamazepine or Other CYP3A4 Inducers: Concomitant use of ABILIFY MAINTENA with carbamazepine or other CYP3A4 inducers decreases the concentrations of aripiprazole. Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days [see Indications and Usage, Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Ketoconazole or Other Strong CYP3A4 Inhibitors: Concomitant use of ABILIFY MAINTENA with ketoconazole or other CYP3A4 inhibitors for more than 14 days increases the concentrations of aripiprazole and reduction of the ABILIFY MAINTENA dose is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Due to prolonged-release characteristics of ABILIFY MAINTENA, short-term co-administration of ketoconazole or other inhibitors of CYP3A4 with ABILIFY MAINTENA does not require a dose adjustment. Quinidine or Other Strong CYP2D6 Inhibitors: Concomitant use of ABILIFY MAINTENA with quinidine or other CYP2D6 inhibitors increases the concentrations of aripiprazole after longerterm use (i.e., over 14 days) and reduction of the ABILIFY MAINTENA dose is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Due to prolonged-release characteristics of ABILIFY MAINTENA, short-term co-administration of quinidine or other CYP2D6 inhibitors with ABILIFY MAINTENA does not require a dose adjustment. CNS Depressants: Given the CNS depressant effects of aripiprazole, use caution when ABILIFY MAINTENA is taken in combination with other centrally-acting drugs or alcohol. Anti-Hypertensive Agents: Due to its α1 -adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category C: Risk Summary: Adequate and well controlled studies with aripiprazole have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs (including ABILIFY MAINTENA) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits at doses 1-10 times the oral maximum recommended human dose [MRHD] of 30 mg/day based on a mg/m2 body surface area. ABILIFY MAINTENA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations: Fetal/Neonatal Adverse Reactions: Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization. Animal Data: Pregnant rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the oral maximum recommended human dose [MRHD] of 30 mg/day on a mg/m2 body surface area) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg), undescended testes (30 mg/kg), and delayed skeletal ossification (10 mg/kg and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 mg/kg and 30 mg/kg), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg. Postnatally, delayed vaginal opening was seen at 10 mg/kg and

30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. In pregnant rats receiving aripiprazole injection intravenously (3 mg/kg/day, 9 mg/kg/day, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose, which also caused some maternal toxicity. Pregnant rabbits were treated with oral doses of 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day (2 times, 3 times, and 11 times human exposure at the oral MRHD of 30 mg/day based on AUC and 6 times, 19 times, and 65 times the oral MRHD of 30 mg/day based on mg/m2 body surface area) of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 mg/ kg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 mg/kg and 100 mg/kg), and minor skeletal variations (100 mg/kg). In pregnant rabbits receiving aripiprazole injection intravenously (3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg, which produced 5 times the human exposure at the oral MRHD based on AUC and is 6 times the oral MRHD of 30 mg/day based on mg/m2 body surface area. In a study in which rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the oral MRHD of 30 mg/day on a mg/m2 body surface area) of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were seen at this dose. In rats receiving aripiprazole injection intravenously (3 mg/kg/day, 8 mg/kg/day, and 20 mg/kg/day) from day 6 of gestation through day 20 postpartum, an increase in stillbirths was seen at 8 mg/kg and 20 mg/kg, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg. These doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development. Nursing Mothers: Aripiprazole is excreted in human breast milk. 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. Pediatric Use: Safety and effectiveness of ABILIFY MAINTENA in patients <18 years of age have not been evaluated. Geriatric Use: Safety and effectiveness of ABILIFY MAINTENA in patients >60 years of age have not been evaluated. In oral single-dose pharmacokinetic studies (with aripiprazole given in a single oral dose of 15 mg), aripiprazole clearance was 20% lower in elderly (≥65 years) subjects compared to younger adult subjects (18 to 64 years). There was no detectable age effect, however, in the population pharmacokinetic analysis of oral aripiprazole in schizophrenia patients. Also, the pharmacokinetics of oral aripiprazole after multiple doses in elderly patients appeared similar to that observed in young, healthy subjects. No dosage adjustment of ABILIFY MAINTENA is recommended for elderly patients [see also Boxed Warning and Warnings and Precautions (5.1)]. CYP2D6 Poor Metabolizers: Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM). Dosage adjustment is recommended in CYP2D6 poor metabolizers due to high aripiprazole concentrations [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. OVERDOSAGE: Human Experience: The largest known case of acute ingestion with a known outcome involved 1260 mg of oral aripiprazole (42 times the maximum recommended daily dose) in a patient who fully recovered. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Management of Overdosage: In case of overdosage, call the Poison Control Center immediately at 1-800-222-1222. PATIENT COUNSELING INFORMATION: Physicians are advised to discuss the FDA-approved patient labeling (Medication Guide) with patients for whom they prescribe ABILIFY MAINTENA. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 Marketed by Lundbeck, Deerfield, IL 60015 USA ABILIFY MAINTENA is a trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan © 2013 Otsuka Pharmaceutical Co., Ltd. 09US12L-1001B February 2013

editorial board Editor-in-Chief

David B. Nash, MD, MBA Founding Dean, The Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Thomas Jefferson University, Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson School of Population Health, Thomas Jefferson University Philadelphia, PA Laura T. Pizzi, PharmD, MPH, RPh Professor, Dept. of Pharmacy Practice Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA Aging and Wellness

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY Research

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD Operating Partner, Spindletop Capital Austin, TX HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City

Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD health & value promotion

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

Jeffrey A. Bourret, PharmD, MS, BCPS, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC PAYER-PROVIDER FINANCES

Bruce Pyenson, FSA, MAAA Principal & Consulting Actuary Milliman, Inc, New York, NY Personalized medicine

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia PHARMACOECONOMICs

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc, Norwalk, CT

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Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy Univ. of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Assistant Clinical Professor, Psychiatry, Mount Sinai School of Medicine, New York, NY Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA, FAMCP Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy Presbyterian College, Clinton, SC Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

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Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Senior Production Manager Lynn Hamilton Founding Editor-in-Chief Robert E. Henry

EDITORIAL

315 A Different Kind of Merger David B. Nash, MD, MBA CLINICAL

318 Cardiovascular Events and Safety Outcomes Associated with Azithromycin Therapy: A Meta-Analysis of Randomized Controlled Trials Ziyad S. Almalki, BPharm, PhD student; Jeff Jianfei Guo, BPharm, PhD 327 Stakeholder Perspective: Cardiovascular Safety of Azithromycin Therapy: Revisiting the Evidence By Raymond L. Singer, MD, MMM, CPE business

334 Healthcare Costs Among Patients with Excessive Sleepiness Associated with Obstructive Sleep Apnea, Shift Work Disorder, or Narcolepsy Rashad Carlton, PharmD; Orsolya Lunacsek, PhD; Timothy Regan, BPharm; Cathryn A. Carroll, PhD 340 Stakeholder Perspective: Out-of-Pocket Cost of Therapy Can Affect Patients’ Excessive Sleepiness and Daytime Functioning By Teresa DeLuca, MD, MBA

Continued on page 314

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(Continued)

REGULATORY

346 Effects of Medicare Part D on Disparity Implications of Medication Therapy Management Eligibility Criteria Junling Wang, PhD, MS; Yanru Qiao, MS; Ya-Chen Tina Shih, PhD; JoEllen Jarrett Jamison, BS; Christina A. Spivey, PhD; Liyuan Li, PhD; Jim Y. Wan, PhD; Shelley I. White-Means, PhD; Samuel Dagogo-Jack, MD, FRCP; William C. Cushman, MD; Marie Chisholm-Burns, PharmD, MPH, MBA, FCCP, FASHP 358 Stakeholder Perspective: Medication Therapy Management, Medicare, and Disparities in Population Health By Dima M. Qato, PharmD, MPH, PhD

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Editorial

A Different Kind of Merger David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Dean, Jefferson School of Population Health, Philadelphia, PA

ou never know when something important will just “fall out of the sky.” I had this experience while speaking at the St. Luke’s Health System retreat in Boise, ID, several months ago. During our lunch session, I had the privilege of sitting next to Jim Everett, President and CEO of the Treasure Valley Family YMCA in Boise. Jim has been on the board of St. Luke’s Health System for quite some time; he is also CoChair of the Idaho Business Coalition for Education Excellence—clearly a very civic-minded leader. It was Jim who shared with me the news before the issuance of the press release about the April 1, 2014, merger between Informed Medical Decisions Foundation (www. informedmedicaldecisions.org) in Boston, MA, and Healthwise (www.healthwise.org) in Boise, ID. I thought our readers of this journal would be interested to learn some of the “behind-the-scenes” details. The Informed Medical Decisions Foundation is 25 years old; Healthwise is nearly 40 years old. Their missions are closely aligned, and they have both been valued leaders in the field of patient engagement. As the nation progresses down the road toward true system reform under the Affordable Care Act (ACA), patient engagement will become even more important. Hence, the merging of Informed Medical Decisions Foundation and Healthwise takes on national significance. Why bring these 2 venerable organizations together? Why now? According to Donald W. Kemper, MPH, Founder and longtime CEO of Healthwise, “we have always valued the scientific rigor that they [the Informed Medical Decisions Foundation] have been able to put into their evidence reviews. While Healthwise has been highly responsive to changes in practice guidelines, the Foundation’s medical editors have been even closer to the core outcomes research.”1 In other words, although each organization pledges to remain free of any external funding, including support from the pharmaceutical industry, they believe that a merger would improve their core base, enabling them to continue to make the best possible and most unbiased information available to consumers throughout the marketplace. Healthwise has been a policy player in the creation of the Centers for Medicare & Medicaid Services “meaningful use” rules, which require the prescription of pa-

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tients’ specific educational resources, and the Foundation is consistently boosting the focus of policy on shared decision-making, as evidenced in the ACA. In other words, both organizations have played a critical, although perhaps behind-the-scenes, role in sculpting the ACA. Together they may be even more influential than each organization alone. Finally, again according to Mr Kemper, “people turn to Healthwise content over 180 million times every year for help with every health concern imaginable, and we’ve won ClearMark Award recognition by the Center for Plain Language 4 years running. The Foundation was particularly impressed with our technical integration with over a dozen EMR [electronic medical record] systems, which is now allowing 15% of US practicing physicians to prescribe Healthwise information to their patients.”1

As the nation progresses down the road toward true system reform under the Affordable Care Act, patient engagement will become even more important. What may be the goals for the future of this combined entity? First, the 2 boards have entered into a joint agreement (modeled, in part, after the Mayflower Compact) that defines their mission, vision, culture, and intent. The shared goal is to use their combined expertise to “help people make better health decisions.”2 How much progress have they made so far? Again, according to Kemper, the “product development teams from both organizations have combined under the Healthwise brand, and they are working hard on the next generation of patient decision aids. In addition, the policy advocacy staffs have combined under the brand of the Informed Medical Decisions Foundation to impact national policy, and, finally, the research team and the user experience team will remain somewhat at arm’s length so that the Foundation branded research outcomes will retain their well-deserved market credibility.”1 I believe that by January 2015, this combined entity, which will be known as Healthwise–Informed Medical Decisions Foundation, will have a powerful and extend-

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Editorial

ed role in influencing patient decision-making and in providing unbiased and current evidentiary-based information to help them make the best decisions. I envision a world where nearly every primary care physician in the

I envision a world where nearly every primary care physician in the United States is able to offer his or her patients an information prescription, with links to patient-oriented materials that have passed the test of the combined research staffs of Healthwise and Informed Medical Decisions Foundation. United States is able to offer his or her patients an information prescription, with links to patient-oriented materials that have passed the test of the combined research staffs of Healthwise and Informed Medical Decisions Foundation. Finally, the incoming Board of Directors of the combined entity gives me great confidence that this new or-

ganization will emerge as an even stronger player in the world of patient engagement. In addition to venerable thought leaders—such as Margaret “Peggy” E. O’Kane from the National Committee for Quality Assurance and Susan Edgman-Levitan, PA, from Massachusetts General Hospital—the Board of Directors also includes Daina Middleton, former CEO of Performics, the performance marketing agency of Publicis Groupe; Ruth Prince, the International Admissions Counselor at Boise State University (who has firsthand experience with healthcare systems overseas); and finally, Kristi Saucerman, Founder, President, and CEO of Auction Frogs, a leader in online fundraising for charitable organizations. Be on the lookout for the Healthwise–Informed Medical Decisions Foundation. They will soon be coming to a physician’s office near you. As usual, I am interested in your views and you can reach me at my e-mail, david.nash@jefferson.edu. n

References

1. Private correspondence with Donald Kemper, April 21, 2014. 2. Healthwise: Informed Medical Decisions Foundation. Helping people make better health decisions: a shared compact between Healthwise and the Informed Medical Decisions Foundation. www.informedmedicaldecisions.org/wp-content/uploads/ 2014/02/Compact_Healthwise-Foundation.pdf. Accessed July 14, 2014.

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CLINICAL CLINICAL

Original Research

Cardiovascular Events and Safety Outcomes Associated with Azithromycin Therapy: A Meta-Analysis of Randomized Controlled Trials

Ziyad S. Almalki, BPharm, PhD student; Jeff Jianfei Guo, BPharm, PhD Stakeholder Perspective, page 327

Am Health Drug Benefits. 2014;7(6):318-328 www.AHDBonline.com Received April 17, 2014 Accepted in final form July 22, 2014

Disclosures are at end of text

BACKGROUND: Azithromycin has been used for many years for the treatment of patients with various types of bacterial infections, as well as for the secondary prevention of coronary events. There is a growing concern, however, that azithromycin may be associated with an increased cardiovascular (CV) risk and may lead to CV-related death in high-risk patients. OBJECTIVE: This systematic review of randomized controlled trials was conducted to analyze and describe the CV risk and safety outcomes associated with azithromycin therapy. METHODS: A meta-analysis was conducted based on the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases from 1990 through September 2013. Specific medical search terms in the English language included “azithromycin,” “macrolide,” “antibiotic,” “cardiovascular diseases,” and “cardiovascular events” and were used to identify relevant randomized clinical trials that assessed the risk for CV events in patients receiving azithromycin therapy or placebo. The randomized clinical trials that were selected included patients who received azithromycin or placebo for the treatment of infection or for the secondary prevention of coronary events. Major health outcome measures included mortality, hospitalization, and coronary intervention. Meta-analyses were performed using a random effects model. RESULTS: A total of 12 randomized clinical trials included 15,588 patients. Patients were divided into 2 groups, either to azithromycin therapy or to placebo. Compared with patients who had not received azithromycin, patients who had received azithromycin had an overall risk ratio (RR) of death of 0.877 (95% confidence interval [CI], 0.752-1.024; P = .097). No heterogeneity was observed (I2 = 0%). Similarly, no differences were found in the pooled RRs for hospitalization or for clinical intervention for CV events (RR, 1.005; 95% CI, 0.922-1.094; P = .915; I2 = 0% and RR, 0.999; 95% CI, 0.896-1.125; P = .984; I2 = 0%, respectively). CONCLUSION: No increased risks for mortality or for CV events associated with azithromycin therapy compared with placebo were found among patients included in the 12 randomized clinical trials reviewed in this analysis.

zithromycin is a broad-spectrum macrolide antibiotic that is frequently used to prevent or treat a wide range of bacterial infections, including upper and lower respiratory infections, skin and soft-tissue infections, as well as some sexually transmitted infections.1,2 Azithromycin was introduced in the early 1950s as the first member of a new subclass of macrolides known as azalide.1 Azithromycin was approved by the US Food and Drug Administration (FDA) in late 1991 as the first once-daily antibiotic with a 5-day course of

Mr Almalki is a Graduate Student, and Dr Guo is Professor of Pharmacoeconomics and Pharmacoepidemiology, The James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, OH. The opinions and conclusions expressed in this manuscript are solely those of the authors.

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therapy indicated for acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD), community-acquired pneumonia, pharyngitis/tonsillitis, uncomplicated skin and skin structure infections, urethritis and cervicitis, genital ulcer disease in men, and acute otitis media in children.1,2 The off-label use of azithromycin for the prevention of coronary events has been found in the recent literature, and there may be an association between Chlamydia pneumoniae infection and atherogenesis.3,4 Compared with its parent macrolide erythromycin, azithromycin is more effective against gram-negative pathogens (eg, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, and Bordetella pertussis) and has better pharmacokinetic properties.1 Azithromycin has an attractive safety proﬁle. It has been shown to be relatively free of cardiotoxic effects,

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CV Safety Outcomes Associated with Azithromycin Therapy

thus providing an advantage over other drugs in the same class.5 As a result, azithromycin has become one of the 15 most prescribed drugs and one of the best-selling antibiotics in the United States.6 According to the IMS Institute for Healthcare Informatics, approximately 48.6 million patients in the United States received a prescription for azithromycin in 2013.6 By contrast, in March 2013 an alert was issued by the FDA that warranted serious attention.7 The alert was in response to the results of an observational study by Ray and colleagues indicating that the use of azithromycin was associated with 2-fold and 3-fold increased risks for cardiovascular (CV) death compared with placebo and amoxicillin, respectively, in patients with a high baseline risk.8 That study involved patients in Tennessee with Medicaid coverage who had a high baseline risk of CV events and showed an increased risk for such events among patients who received azithromycin therapy.8 Generalizing this association to patients with a lower baseline risk of CV disease was uncertain until a nationwide historic cohort study was conducted to examine the safety of azithromycin in Danish adults aged 18 to 64 years over a period from 1997 through 2010.5 The study showed that treatment with azithromycin was not associated with an increased risk of death from CV causes among young and middle-aged patients.5 Both studies agreed that patients who had the greatest baseline risk for CV disease were at highest risk for the disease from taking azithromycin.5,8 Any antibiotic is going to have risks and benefits; however, both studies were observational, and even the most carefully executed observational study can be misleading. A double-blind, placebo-controlled trial is the best way to eliminate such potentially misleading information.9 Therefore, we conducted this current meta-analysis of all English-language published and unpublished, randomized, controlled, short- and long-term trials involving high-risk patients to investigate whether azithromycin is associated with increased CV death among this patient population.

Methods We conducted comprehensive searches of the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases using online-based search engines (OVID, PubMed) for human studies published in English between 1990 and September 2013. The search terms that were used to maximize the search specificity and sensitivity included “azithromycin,” “macrolide,” “antibiotic,” “cardiovascular diseases,” and “cardiovascular events.” We searched and evaluated all reference lists of articles that met the inclusion criteria; online resources, such as CV

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Key Points Azithromycin is used for treating bacterial infections and for the secondary prevention of coronary events, but recent concerns have been raised that it may increase CV risk. ➤ This is the first meta-analysis of the cardiac safety of azithromycin in randomized clinical trials (either treatment or prevention). ➤ No significant association was found between azithromycin therapy and the risk for death or hospitalization from CV causes. ➤ Patients receiving azithromycin had a 0.877 overall risk ratio of death compared with those who had not received this drug. ➤ Hospitalization rates were 7.6% among 7498 patient receiving azithromycin and 10.1% among 7478 patients receiving placebo. ➤ The combined mortality rate was 3.7% in the azithromycin groups and 4.2% in the placebo groups. ➤ Additional trials and follow-up are needed to study patients with preexisting bacterial infections and CV risk factors in relation to the effects of azithromycin therapy. ➤

and infectious disease conference abstracts; as well as clinicaltrials.gov to ensure that we included all published and unpublished studies.

Eligibility Criteria To be included in this analysis, studies had to be prospective, randomized, placebo-controlled clinical trials involving humans and comparing azithromycin therapy with placebo or with standard of care. The population of interest was clearly defined as any patients who have been identified in the literature review as high risk for CV complications, such as patients with a history of heart problems, established coronary artery disease (CAD), myocardial infarction (MI), unstable angina, or peripheral artery disease (PAD); COPD; or critically ill patients (eg, patients with severe sepsis). The selected clinical trials included azithromycin for the treatment of infection or for the secondary prevention of coronary events. All studies had to have data on clinical cardiac end points and had to report the risk ratio (RR) of CV events that were associated with the use of azithromycin. Studies that did not report RR and confidence intervals (CIs) but reported enough information to calculate them were also included. Recent studies were included in the analysis if their data were duplicated in more than 1 study.

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CLINICAL

Figure 1 Flow Diagram of the Articles Reviewed Electronic database: PubMed (N = 5970) Cochrane (N = 262) 6110 articles excluded 1565 reviews 1266 not in human 542 not in high-risk population 2737 not controlled clinical trials 37 articles included after title and abstract screened 25 abstracts excluded, no CV end points reported 12 studies included in the analysis: Patients with CAD (n = 5) Patients with COPD (n = 3) Patients with ACS (n = 2) Patients with PAD (n = 1) Patients with severe sepsis (n = 1)

ACS indicates acute coronary syndrome; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; PAD, peripheral artery disease.

Data Extraction Data were extracted and the study characteristics were recorded, including the author(s), year of publication, study design (randomized or observational, placebo or active-controlled, blinded or open-label), study sample size, duration of follow-up, and the dosing regimen. All studies reporting CV outcomes were collected and were stratified into 3 subgroups—mortality, hospitalization, and coronary intervention. The first study subgroup, mortality, included all studies that reported patients who died from CV causes, such as death resulting from arrhythmias, severe congestive heart failure, cardiogenic shock, or MI, or any other underlying cause of death consistent with a CV cause. The hospitalization subgroup included studies that reported the number of hospitalized patients as a result of nonfatal MI, stroke, or unstable angina, or any cardiac condition that required hospitalization (eg, resuscitated cardiac arrest). The final subgroup, coronary intervention, included all studies that reported patients who had coronary artery bypass grafting surgery or percutaneous coronary intervention. The RRs of CV events associated with the use of azithromycin and its 95% CI were collected or were calculated for each study.

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Statistical Analysis In the analysis, methods based on RRs were used. RRs were calculated using a random effects model (because we assumed that the treatment effect in all the studies included are not identical), and RRs and 95% CIs were used for each outcome. Statistical heterogeneity scores were assessed with the Higgins I2 test (a value of <40% was regarded as “heterogeneity might not be important” and a value of >75% as “considerable heterogeneity”). A sensitivity analysis was performed by removing some trials, recalculating the combined RRs for the remaining studies, and examining whether there were any serious changes in the overall results. Publication bias was assessed by visual inspection of a funnel plot of the logarithm of effect size versus the standard error for each trial. We looked at adequacies of the blinding of randomization, the blinding of treatment assignment, and the completeness of follow-up in each study to assess the quality of the study by using a scoring system developed by Jadad and colleagues.10 Meta-analyses were performed using the Comprehensive Meta-Analysis software (Biostat, Englewood, NJ) and SAS software version 9.3 for Windows (SAS Institute Inc, Cary, NC). Results A total of 6232 studies were identified after removing duplicate publications. Of the initial qualifying studies, 6110 articles were excluded, because they were not randomized clinical trials (these were reviews, editorials, letters to the editor, case reports, or meta-analyses). A total of 25 articles were excluded because they did not report clinical end points (Figure 1). Characteristics of Studies Included in the Analysis A total of 12 randomized controlled trials published between 1997 and 2013 met the inclusion criteria for this meta-analysis.11-22 These randomized clinical trials involved a total of 15,588 patients who received active treatment or placebo. The details of these studies are summarized in Table 1.11-22 Of these 12 studies, 9 were double-blinded trials and 3 were open-label trials. A total of 5 studies randomized patients with stable CAD, 3 trials randomized patients presenting with COPD, and 2 trials randomized patients with acute coronary syndrome. Patients with PAD or with severe sepsis were involved in 2 of the studies. The baseline characteristics of the patients are presented in Table 2. All 12 studies included patients aged ≥65 years. The mean duration of follow-up ranged from 18 weeks to 6 years. Most trials were rated as being of good methodologic quality (randomized, double-blinded, and placebo-controlled studies); however, 1 study was

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CV Safety Outcomes Associated with Azithromycin Therapy

Table 1 Selected Randomized Clinical Trials with Azithromycin Therapy Disease Patients, Study Year Blinding state N Regimen

Follow-up Quality duration score

Gupta et al11

1997

Doubleblinded

CAD

3- to 6-day course of azithromycin 500 mg or placebo

18 mo

ACADEMIC12

1999

Doubleblinded

CAD

302

3-day course of azithromycin 500 mg, then 500 mg/wk or placebo for 3 months

2 yrs

STAMINA13

2002

Doubleblinded

ACS

325

Azithromycin 500 mg/day for 3 days + omeprazole 20 mg twice daily + metronidazole 400 mg twice daily or placebo for 1 week

1 yr

WIZARD14

2003

Doubleblinded

CAD

7747

3-day course of azithromycin 600 mg, then 600 mg/wk for 11 weeks

18 mo

AZACS15

2003

Doubleblinded

ACS

1439

Azithromycin 500 mg on day 1, then 250 mg/day or placebo for 4 days

6 mo

ACES16

2005

Doubleblinded

CAD

4012

Azithromycin 600 mg/wk or placebo for 1 year

3.9 yrs

SPACE17

2005

Doubleblinded

PAD

509

3-day course of azithromycin 500 mg/day or placebo

2 yrs

Blasi et al18

2010 Open-label

COPD

Azithromycin 500 mg 3 days/wk for 6 months or standard of care

6 mo

Albert et al19

2011

COPD

997

Azithromycin 250 mg/day or placebo for 1 year

1 yr

Dogra20

2012 Open-label

CAD

Azithromycin 500 mg once daily for 5 days, repeated after a gap of 10 days (total of 24 courses) or standard of care

Berkhof et al21

2013

COPD

Azithromycin 250 mg 3 times/wk or placebo

Faverio et al22

2013 Open-label Severe sepsis with previous heart problems

Azithromycin 600 mg/day for 5 days or standard of care medication

Doubleblinded

18 wks

6 yrs

ACS indicates acute coronary syndrome; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; PAD, peripheral artery disease.

only available as an abstract, and the full text could not be retrieved for full evaluation.22

Treatment The majority of the trials included 2 study groups, a treatment group and a placebo group. The treatment courses in the 12 trials varied in duration from 3 days to 1 year. Azithromycin was the only drug included in the treatment groups in most of the studies, except the STAMINA study (which included azithromycin combined with metronidazole and a proton pump inhibitor [omeprazole]) and the studies by Blasi and colleagues, Dogra, and Faverio and colleagues (which included azithromycin combined with standard of care).13,18,20,22 Outcome Analyses The mortality outcomes were presented in 11 trials. Figure 2 shows the RRs and the 95% CI of death associated with the use of azithromycin in each study, as

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well as for all of the studies combined. Compared with patients who had not taken azithromycin, patients who had taken azithromycin had an overall RR of death of 0.877 (95% CI, 0.752-1.024; P = .097). The combined mortality rate was 3.7% among 7769 treated patients versus 4.2% of 7723 patients in the placebo groups. To assess the potential impact of the results of a poorer quality study, we performed a sensitivity analysis by calculating the RR using all the studies, and then excluding the 1 poorer quality study,22 as shown in Table 3. No change in the overall results of the analysis was detected. As for hospitalization, 9 trials reported hospitalization outcomes (Figure 3). No significant correlation between the use of azithromycin and the risk of hospitalization resulting from CV causes was observed in these studies (RR, 1.005; 95% CI, 0.922-1.094; P = .915) and no heterogeneity was found (I2 = 0%). The overall hospitalization rate was 7.6% among the 7498 patients receiving

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322

Age, mean, yrs (SD)

12 (30)

18 (45)

35 (88)

Previous MI

Diabetes mellitus

Dyslipidemia

Smoking

American Health & Drug Benefits

Aspirin

Statins

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64.4 (9.9)

Age, mean, yrs (SD)

September 2014

ACE inhibitors

Aspirin

Statins

194 (77)

202 (80)

66 (26)

162 (64)

146 (58)

65.5 (9.7)

170 (67)

0 (0)

2 (18)

4 (36)

72 (7)

10 (91)

37 (35)

17 (16)

14 (13)

17 (16)

21 (20)

66 (9)

68 (64)

1 (9)

1 (9.1)

4 (46)

73 (7)

9 (82)

119 (21)

65 (9)

329 (49)

127 (23)

66 (8)

332 (49)

SOC AZ PL (N = 11) (N = 570) (N = 572)

Albert et al19

36 (32)

20 (18)

11 (10)

12 (11)

26 (24)

66 (9)

78 (70)

20 (62)

56 (NR)

26 (81)

AZ (N = 32)

22 (69)

27 (84)

20 (62)

4 (12)

32 (100)

6 (19)

849 (22)

2587 (67)

3339 (87)

1651 (43)

2338 (61)

603 (16)

2381 (62)

7 (87)

6 (75)

7 (87)

6 (75)

0 (0)

6 (75)

1 (12)

5 (45)

60 (NR)

9 (82)

SOC (N = 8)

Dogra20

2588 (67)

3358 (87)

1623 (42)

2310 (60)

663 (17)

2405 (62)

788 (20)

1718 (45)

62 (NR)

1764 (46)

3123 (81)

3209 (83)

444 (62)

394 (55)

505 (70)

374 (52)

438 (61)

205 (28)

414 (57)

65 (0.5)

14 (33)

67 (9)

31 (74)

AZ (N = 42)

513 (71)

15 (36)

68 (10)

32 (76)

PL (N = 42)

Berkhof et al21

443 (62)

384 (54)

500 (70)

374 (52)

426 (59)

193 (27)

179 (25)

418 (58)

65 (0.5)

530 (74)

1546 (77)

1767 (88)

723 (36)

1205 (60)

1446 (72)

1626 (81)

422 (21)

1165 (58)

1345 (67)

65 (NR)

1586 (79)

–

AZ (N = 24)

–

SOC (N = 27)

Faverio et al22

1503 (75)

1743 (87)

681 (34)

1182 (59)

1523 (76)

1683 (84)

461 (23)

1082 (54)

1343 (67)

65 (NR)

1603 (80)

ACE indicates angiotensin-converting enzyme; AZ, azithromycin; MI, myocardial infarction; NR, data not reported; PL, placebo; SOC, standard of care; SD, standard deviation; SE, standard error.

SE rather than SD.

Beta-blockers

Medications, N (%)

206 (80)

Smoking

77 (30)

Diabetes mellitus

210 (82)

148 (58)

Previous MI

Dyslipidemia

149 (58)

Hypertension

Risk factors, N (%)

178 (69)

55 (36)

17 (11)

88 (58)

68 (45)

63 (11)

138 (91)

Blasi et al18

57 (38)

17 (11)

95 (63)

59 (39)

64 (10)

129 (86)

AZ PL AZ (N = 257) (N = 252) (N = 11)

Male, N (%)

Characteristics

15 (75)

7 (35)

8 (40)

20 (100)

SPACE17

ACE inhibitors

Study

Beta-blockers

Medications, N (%)

7 (18)

40 (100)

Hypertension

4 (20)

58 (7)

60 (9)

Risk factors, N (%)

20 (100)

40 (100)

ACADEMIC12 STAMINA13 WIZARD14 AZACS15 ACES16 Gupta et al11 PL AZ PL AZ PL AZ PL AZ PL AZ PL AZ (N = 40) (N = 20) (N = 150) (N = 152) (N = 111) (N = 107) (N = 3866) (N = 3856) (N = 716) (N = 723) (N = 2004) (N = 2008)

Male, N (%)

Characteristics

Study

Table 2 Baseline Characteristics of Randomized Clinical Trials Discussed in This Study

CLINICAL

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CV Safety Outcomes Associated with Azithromycin Therapy

Figure 2 Effect of Azithromycin Treatment on Total Mortality Events/ Statistics for each study center Total, N Risk ratio

Study

Events/ Total, N

Risk ratio and 95% CI

Lower Upper limit limit P value Azithromycin Placebo

0.500 0.033 Gupta et al11 0.928 0.759 WIZARD14 0.507 0.046 ACADEMIC12 0.941 0.632 ACES16 0.801 0.468 AZACS15 0.964 0.287 STAMINA13 1.125 0.074 Faverio et al22 0.784 0.447 SPACE17 0.729 0.387 Albert et al19 0.400 0.098 Blasi et al18 0.091 0.004 Dogra20 0.877 0.752 Overall CI indicates confidence interval.

7.585 1.135 5.529 1.400 1.371 3.235 17.022 1.376 1.372 1.640 2.048 1.024

.617 .469 .577 .763 .418 .953 .932 .397 .327 .203 .131 .097

1/40 175/3866 1/150 46/2004 23/716 5/111 1/24 20/257 16/558 2/11 0/32

Relative weight

1/20 188/3856 2/152 49/2008 29/723 5/107 1/27 25/252 22/559 5/11 0.01 0.1 1 10 100 1/8 Favors azithromycin Favors placebo

Table 3 Quality Assessment of the Studies Included According to the Jadad Scale Was the Was the method Was the study randomization Was the study of double described as scheme described described as blinding Study randomized? and appropriate? double blind? appropriate? Gupta et al11

Was there a description of dropouts and withdrawals?

Quality score

Yes

Uncertaina

Yes

ACADEMIC

Yes

STAMINA

Yes

WIZARD

Yes

AZACS15

Yes

ACES16

Yes

SPACE17

Yes

Uncertaina

Yes

Albert et al

Yes

Dogra

Yes

Uncertain

Yes

Berkhof et al

Yes

Faverio et al

Yes

Uncertain

Blasi et al18 19

20 21

0.32 59.03 0.42 15.08 8.26 1.63 0.32 7.56 5.95 1.20 0.25

Uncertain

Uncertain means either lack of information or not applicable.

active treatment compared with a 10.1% rate among the 7478 patients receiving placebo. Regarding coronary intervention, 5 of the trials reported outcomes of coronary intervention (Figure 4). The analysis showed no relationship between azithromycin use and coronary intervention rate (RR, 0.999; 95% CI, 0.896-1.114; P = .984). Higgins I2 showed no heterogeneity among the studies in any of the subgroups (I2 = 0%). In the sensitivity analyses, no change in the overall estimate was observed after

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removing the poorer quality study and recalculating the combined RRs for the remaining studies. On visual inspection of the funnel plot, the plot appeared roughly symmetrical, suggesting that the likelihood of publication bias is relatively low (Figure 5).

Discussion The findings from this meta-analysis of prospective studies show that either azithromycin therapy decreases CV and cardiac events or there are no differences in CV

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Figure 3 Effect of Antibiotic Treatment on Hospitalization Rate Events/ Events/ Statistics for each study center Total, N Total, N Risk Lower Upper Study ratio limit limit P value Azithromycin Placebo 1.000 0.200 Gupta et al11 1.017 0.778 WIZARD13 2.027 0.377 ACADEMIC12 0.902 0.577 ACES16 1.061 0.754 AZACS15 1.299 0.812 STAMINA13 0.984 0.891 Albert et al19 2.000 0.188 Berkhof et al21 1.400 0.638 Blasi et al18 1.005 0.922 Overall CI indicates confidence interval.

5.004 1.329 10.899 1.409 1.493 2.078 1.086 21.225 3.074 1.094

1.000 .903 .411 .650 .733 .274 .742 .565 .402 .915

2/40 105/3866 4/150 36/2004 62/716 31/111 323/558 2/42 7/11

1/20 103/3856 2/152 40/2008 59/723 23/107 329/559 1/42 5/11

Figure 4 Effect of Antibiotic Treatment on Coronary Intervention Rate Events/ Events/ Statistics for each study center Total, N Total, N Lower Upper Study Risk ratio limit limit P value Azithromycin Placebo 0.760 1.730 ACADEMIC12 1.029 0.849 ACES16 1.112 0.794 AZACS15 0.968 0.837 WIZARD14 0.500 0.052 Dogra20 0.999 0.896 Overall CI indicates confidence interval.

3.338 1.246 1.558 1.120 4.849

.716 .772 .535 .659 .550

1.114

.984

3/150 192/2004 65/716 326/3866 2/32

events and clinical cardiac outcomes compared with the use of placebo in these patient populations. All the trials included generally failed to produce convincing evidence to prove that azithromycin could cause CV events among high-risk patients. To our knowledge, this is the first meta-analysis conducted after the FDA alert was issued in March 20137 that has investigated whether azithromycin is associated with increased risk for CV events in the long-term. Our findings appear to conflict with the study by Ray and colleagues.8 There are several important differences between the observational studies included in the study by Ray and colleagues8 and the selected randomized controlled trials included in the present meta-analysis, which may, to some extent, explain the different findings. First, Ray and colleagues assessed the risk for CV death in patients receiving azithromycin, amoxicillin, ciprofloxacin, levofloxacin, or no antibiotics, based on retrospective data from the Tennessee Medicaid claims.8 Ray and colleagues specifically focused on the risk associated with the typical 5-day duration of the administration of azith-

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Risk ratio and 95% CI Relative weight

0.01 0.1 1 10 100 Favors azithromycin Favors placebo

0.28 10.16 0.26 3.68 6.29 3.32 74.65 0.13 1.18

Risk ratio and 95% CI Relative weight

4/152 187/2008 59/723 336/3856 1/8 0.01 0.1 1 10 100 Favors azithromycin Favors placebo

0.54 32.50 10.51 56.22 0.23

romycin.8 It is unclear what was the disease state for which the patients with the Tennessee Medicaid coverage were receiving azithromycin therapy.8 The present meta-analysis specifically selected all randomized clinical trial data with azithromycin used for the treatment or for the secondary prevention of coronary diseases. Recently, several studies have found a substantial incidence of CV events, such as congestive heart failure or cardiac arrhythmia, occurring during or soon after a hospital admission for pneumonia.23 Therefore, it is dif足 ficult to determine the potential cause for these CV events. Many studies have suggested that macrolides have an advantage over other antibacterial agents in treating patients who have pneumonia that requires a minimum of 5 days of therapy.24,25 It is difficult to detect or to examine the benefits of therapy with azithromycin after the fifth day of treatment in the study by Ray and colleagues.8 Their study included patients with infections that required only 5 days of therapy with azithromycin, and infections such as pneumonia that require a longer duration of therapy

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CV Safety Outcomes Associated with Azithromycin Therapy

Figure 5 Funnel Plots to Assess Publication Bias Funnel plot of studies included in Figure 2 Standard error

Bias assessment plot

0.0

0.4

0.8

1.2

1.6 –4 –2 0 2 4

Log (relative risk)

Funnel plot of studies included in Figure 3 Standard error

Bias assessment plot

0.0

0.5

0.1

1.5 –3.0 –0.5

2.0

4.5

Log (relative risk)

Funnel plot of studies included in Figure 4 Bias assessment plot Standard error

0.0

0.3

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Log (relative risk)

NOTE: Logs of the risk ratios were plotted against the standard error of the risk ratio of each study to identify asymmetry in the distribution of trials.

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might have been excluded. Therefore, the benefits of azithromycin in reducing mortality as mentioned above24,25 compared with nonmacrolide therapies in patients with pneumonia were not examined in the study by Ray and colleagues.8 Finally, the population of the Tennessee Medicaid beneficiaries may have a higher prevalence of coexisting conditions and higher mortality rates compared with patients in the randomized clinical trials included in the present meta-analysis.5,8 It has been proven that patients with preexisting heart disease face the highest risk for CV events, even before taking azithromycin, as a result of the inflammation caused by some infectious pathogens.26 Some studies suggest that CV events could be a result of inflammation that contributes to the pathogenesis of CV disease, such as atherosclerosis.27 These studies have investigated the possibility of infectious pathogens, such as Herpesviridae, influenza virus, Cytomegalovirus, enteroviruses, Helicobacter pylori, periodontal pathogens, and C. pneumoniae in causing negative CV effects.27,28 For example, Saikku and colleagues reported that C. pneumoniae is associated with the development of CAD as well as MI.29 In addition, previous studies also show that seasonal influenza-like illnesses may cause acute thrombotic vascular events in patients with previously stable CAD and cerebrovascular disease.30 In another study, a statistically significant association was discovered between evidence of inflammation and coronary events.31 This study used 2 markers, C-reactive protein and serum amyloid A, to predict the risk of first MI and other atherosclerotic events in healthy patients. These markers appear to predict the risks for coronary events and ischemic complications among high-risk patients.31 Our meta-analysis has several strengths. All the studies included in this analysis have a prospective design, which eliminates the possibility of recall and selection bias. Studies with a long duration of follow-up were included to assess the long-term effects of azithromycin on the development of CV events. The characteristics of patients in the primary studies were always comparable. Little evidence of publication bias was found in the studies.

Limitations Some limitations exist in the present study. The trials selected are varied in follow-up durations, ranging from 6 months to 6 years; however, most trials that examined azithromycin therapy followed the patients between 1 and 2 years. The primary CV end points also vary between the studies. Some of the selected studies reported all of the CV end points, whereas some did not. Similarly, some of the studies specified the causes of

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hospitalization, and other studies did not. We were therefore unable to distinguish if patients were hospitalized for acute angina or for MI. The treatment regimen and duration of azithromycin therapy were used either for treatment or for secondary prevention. Finally, the results of the present study may not be applicable for all other populations.

Conclusions The findings in this meta-analysis indicate that there is no increased risk for mortality or for CV events with the use of azithromycin therapy among patients enrolled in the treatment or prevention clinical trials included in this analysis. Future research considerations are warranted to study a larger number of patients with preexisting bacterial infection and CV risk factors, and longer follow-up duration of trials is needed to detect any potential long-term negative or positive effects, including CV effects, of azithromycin therapy. n Acknowledgment The authors would like to thank K. Lindsay Foltz for her English-language editing in the early version of the manuscript. Author Disclosure Statement Mr Almalki and Dr Guo reported no conflicts of interest related to the content of this article. No funding was provided for this study.

References

1. Hoepelman IM, Schneider MM. Azithromycin: the first of the tissue-selective azalides. Int J Antimicrob Agents. 1995;5:145-167. 2. Zithromax (azithromycin) tablets and oral suspension [product information]. New York, NY: Pfizer Inc; June 2014. 3. Mawhorter SD, Lauer MA. Is atherosclerosis an infectious disease? Clev Clin J Med. 2001;68:449-458. 4. Belland RJ, Ouellette SP, Gieffers J, Byrne GI. Chlamydia pneumoniae and atherosclerosis. Cell Microbiol. 2004;6:117-127. 5. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368:1704-1712. 6. IMS Institute for Healthcare Informatics. Medicine use and shifting costs of healthcare: a review of the use of medicines in the United States in 2013. April 2014. www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/IMS%20 Health%20Institute/Reports/Secure/IIHI_US_Use_of_Meds_for_2013.pdf. Accessed August 25, 2014. 7. US Food and Drug Administration. Azithromycin (Zithromax or Zmax). Drug safety communication: risk of potentially fatal heart rhythms. March 12, 2013. www. fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ ucm343350.htm. Accessed August 25, 2014. 8. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-1890. 9. Noseworthy JH, Ebers GC, Vandervoort MK, et al. The impact of blinding on the

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results of a randomized, placebo-controlled multiple sclerosis clinical trial. Neurology. 1994;44:16-20. 10. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12. 11. Gupta S, Leatham EW, Carrington D, et al. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation. 1997;96:404-407. 12. Anderson JL, Muhlestein JB, Carlquist J, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: the Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation. 1999;99:1540-1547. 13. Stone AF, Mendall MA, Kaski J-C, et al. Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). Circulation. 2002;106:1219-1223. 14. O’Connor CM, Dunne MW, Pfeffer MA, et al; for the Investigators in the WIZARD Study. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003;290:1459-1466. 15. Cercek B, Shah PK, Noc M, et al; for the AZACS Investigators. Effect of shortterm treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet. 2003;361:809-813. 16. Grayston JT, Kronmal RA, Jackson LA, et al; for the ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352: 1637-1645. 17. Vainas T, Stassen FR, Schurink GW, et al. Secondary prevention of atherosclerosis through Chlamydia pneumoniae eradication (SPACE Trial): a randomised clinical trial in patients with peripheral arterial disease. Eur J Vasc Endovasc Surg. 2005; 29:403-411. 18. Blasi F, Bonardi D, Aliberti S, et al. Long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy. Pulm Pharmacol Ther. 2010; 23:200-207. 19. Albert RK, Connett J, Bailey WC, et al; for the COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011; 365:689-698. Erratum in: N Engl J Med. 2012;366:1356. 20. Dogra J. Oral azithromycin in extended dosage schedule for chronic, subclinical Chlamydia pneumoniae infection causing coronary artery disease: a probable cure in sight? Results of a controlled preliminary trial. Int J Gen Med. 2012;5:505-509. 21. Berkhof FF, Doornewaard-ten Hertog NE, Uil SM, et al. Azithromycin and coughspecific health status in patients with chronic obstructive pulmonary disease and chronic cough: a randomised controlled trial. Respir Res. 2013;14:125. 22. Faverio P, Arango A, Anzueto A, et al. Azithromycin-related cardiovascular events and deaths in severe septic patients. Chest. 2013;144(4_MeetingAbstracts):422A. 23. Perry TW, Pugh MJ, Waterer GW, et al. Incidence of cardiovascular events after hospital admission for pneumonia. Am J Med. 2011;124:244-251. 24. Martin-Loeches I, Lisboa T, Rodriguez A, et al. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med. 2010;36:612-620. 25. Rodríguez A, Mendia A, Sirvent JM, et al; for the CAPUCI Study Group. Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock. Crit Care Med. 2007;35:1493-1498. 26. Clayton TC, Thompson M, Meade TW. Recent respiratory infection and risk of cardiovascular disease: case-control study through a general practice database. Eur Heart J. 2008;29:96-103. 27. Libby P, Egan D, Skarlatos S. Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research. Circulation. 1997;96:4095-4103. 28. Leinonen M, Saikku P. Evidence for infectious agents in cardiovascular disease and atherosclerosis. Lancet Infect Dis. 2002;2:11-17. 29. Saikku P, Leinonen M, Tenkanen L, et al. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study. Ann Intern Med. 1992;116:273-278. 30. Smeeth L, Thomas SL, Hall AJ, et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med. 2004;351:2611-2618. 31. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation. 1998;98:839-844.

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CV Safety Outcomes Associated with Azithromycin Therapy

Stakeholder Perspective Cardiovascular Safety of Azithromycin Therapy: Revisiting the Evidence By Raymond L. Singer, MD, MMM, CPE Chief, Division of Cardiothoracic Surgery, Vice Chair, Quality and Patient Safety, Department of Surgery, Lehigh Valley Health Network, PA

PATIENTS: Antibiotics are not always appropriate, but many patients believe that they must receive an antibiotic to treat common viral infections, including the “common cold,” flu, and many bronchial, sinus, and ear infections. Taking antibiotics will not cure these conditions, nor will it prevent those associated with sick people from getting infected. Moreover, the excessive inappropriate use of antibiotics has contributed to the worldwide bacterial antibiotic resistance, leading to “superbugs” that are becoming increasingly more difficult to treat with antibiotics. And, germane to the new meta- analysis by Almalki and Guo in this issue of the journal, the use of antibiotics—specifically the broad-spectrum macrolide antibiotics—may cause harmful, even life-threatening side effects. Azithromycin has become one of the most popular antibiotics prescribed to patients because of its ease of administration, tolerance, and broad-spectrum activity. It is popular among patients because it is a once-daily drug that can be taken for only 3 days as a full-course therapy. Indeed, people often make sure they have an azithromycin prescription on hand for an upcoming family event or a vacation. For now, azithromycin remains a very effective antibiotic when used correctly to treat a range of common bacterial infections. It also remains a safe drug. However, like all drugs, there is a risk–benefit ratio involved, and patients must become educated about the proper indications, administration, compliance, and ramifications. In 2001, a concern arose regarding azithromycin’s use and the associated risk for sudden cardiac death. In 2012, the US Food and Drug Administration (FDA) revised the “warning and precautions” section of the product information label for azithromycin to warn about the potential risk for fatal arrhythmias, specifically QT interval prolongation (ie, QT ≥440 ms) and torsades de pointes. Recent studies, including the present meta-analysis by Almalki and Guo, suggest that although azithromycin may increase the relative risk for a cardiovascular (CV) event, for most otherwise healthy patients, the risk is rather low. Therefore, patients must use appropriate caution based on their individual diagnosis and

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risk factors. If a patient has known risk factors, such as an electrocardiogram with a baseline QT prolongation, careful consideration must be made for an alternative antibiotic; or, if azithromycin is deemed medically necessary, careful consideration should be made to hospitalize the patient so as to provide inpatient administration of the drug with cardiac monitoring, until the treatment is completed. PROVIDERS: Providers should feel confident in prescribing azithromycin in the majority of patients who require the drug based on preferential bacterial susceptibility and/or patient allergies to other alternative antibiotics. That said, it is equally important for providers to know the concerns surrounding potential adverse events and be able to assess the risk factors and make modifications as necessary to reduce the risk for drug-induced cardiac events. Beginning with a report of azithromycin-induced torsades de pointes in 2001, azithromycin has been linked to life-threatening cardiac arrhythmias.1 From 2004 to 2011, the FDA Adverse Event Reporting System received 203 reports of azithromycin-associated CV events, including QT prolongation, torsades de pointes, ventricular arrhythmias, and, in some cases, sudden cardiac death.2 In 2012, Ray and colleagues conducted an observational, nonrandomized study of patients in the Tennessee Medicaid program and found a 2.88-fold increased risk for CV death in patients taking azithromycin and a 2.49-fold increased risk in patients taking amoxicillin compared with patients not taking antibiotics.3 Although the study had limitations, it was largely the publication of this study that led the FDA to revise the “warning and precautions” section of the azithromycin label regarding the risk for fatal arrhythmias. In 2013, a prospective study by Svanström and colleagues found no increased risk for CV death with azithromycin in the general population, suggesting that the risk for azithromycin-associated CV mortality is limited to high-risk patients.4 This study may therefore be complementary to the study by Ray and colleagues rather than contradictory. So who are these high-risk patients? First, patients

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Stakeholder Perspective Continued with a baseline prolonged QT interval are at risk for delayed repolarization and ventricular arrhythmias. Associated modifiable risk factors may include electrolyte disturbances, specifically hypocalcemia, hypokalemia, and hypomagnesemia. These should all be addressed before azithromycin therapy. Other nonmodifiable risk factors include acute coronary syndrome, heart failure, and hypertrophic cardiomyopathy. In the case of azithromycin, providers must search for a prolonged QT interval and associated CV risk factors. Taking all this information into account, providers must weigh the benefits and risks of azithromycin and appropriately monitor patients who are at high risk for life-threatening CV adverse events. PAYERS: The excessive use of antibiotics worldwide has created alarming health and health-related economic burdens to society at large. Bacterial resistance leading to “superbugs” is becoming an increasingly frightening threat to the successful treatment of historically common infections, leading to prolonged hospitalizations, morbidity, loss of income, and death. Pharmaceutical companies are finding it increasingly challenging to stay ahead of the antibiotic resistance challenge. Governments are concerned not only because of the impact on the population but also because of the real threat of bioterrorism and the power of pathogens as

vehicles of terror and war. A worldwide outbreak could cause economic collapse and chaos. Even in the absence of such doomsday scenarios, payers are carrying the current burden of covering the cost of overprescribing antibiotics, as well as the potentially avoidable complications of these drugs. Furthermore, as the vicious drug-resistance cycle continues, payers indirectly carry the burden of the cost for research and development by pharmaceutical companies to continue to bring better and safer drugs to market. One particular adverse event that could be minimized is the risk for CV events associated with azithromycin. The findings in this fine meta-analysis by Almalki and Guo support the safety of this drug. However, as long as the jury is still out, payers should encourage thoughtful use and prescription patterns by providers. Payers should also continue to examine and review the clinical outcomes, adverse events, and the costs associated with azithromycin therapy. n 1. Arellano-Rodrigo E, García A, Mont L, Roqué M. Torsade de pointes and cardiorespiratory arrest induced by azithromycin in a patient with congenital long QT syndrome [in Spanish]. Med Clin (Barc). 2001;117:118-119. 2. Giudicessi JR, Ackerman MJ. Azithromycin and risk of sudden cardiac death: guilty as charged or falsely accused? Cleve Clin J Med. 2013;80:539-544. 3. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881-1890. 4. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368:1704-1712.

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Diabetes, Obesity—The ever-growing epidemics of these twin metabolic conditions mandate a thorough examination of best therapies, adherence issues, access, and prevention strategies. Gastrointestinal conditions—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, and inflammatory bowel disorder, remains a challenge. Infectious Diseases—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance. MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, adherence, best practices, and reimbursement.

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Live7”

AUBAGIO® (teriﬂunomide) tablets for oral administration

Rx Only

Brief Summary of Prescribing Information

WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY Hepatotoxicity Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3)]. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)]. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Risk of Teratogenicity Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO treatment [see Contraindications (4.2), Warnings and Precautions (5.2), and Use in Specific Populations (8.1)].

Aubagio_PI_Brief Summary.indd 1

2/1/13 5:00 PM

Live10”

1. INDICATIONS AND USAGE AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis [see Clinical Studies (14) in the full prescribing information]. 2. DOSAGE AND ADMINISTRATION The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food. Monitoring to assess safety • Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)]. • Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)]. • Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test [see Warnings and Precautions (5.4)]. • Check blood pressure before start of AUBAGIO treatment and periodically thereafter [see Warnings and Precautions (5.9)]. 4. CONTRAINDICATIONS 4.1. Severe Hepatic Impairment Patients with severe hepatic impairment [see Warnings and Precautions (5.1)]. 4.2 Patients Who are Pregnant or Women of Childbearing Potential Not Using Reliable Contraception AUBAGIO may cause fetal harm when administered to a pregnant woman. In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically. Nonclinical studies indicate further that the intended pharmacologic action of the drug is involved in the mechanism of developmental toxicity [see Use in Specific Populations (8.1)]. AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated [see Warnings and Precautions (5.3)]. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling. [see Warnings and Precautions and Use in Specific Populations (5.2, 8.1)] 4.3. Current treatment with leflunomide Co-administration of teriflunomide with leflunomide is contraindicated. 5. WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)]. In placebo-controlled trials, ALT greater than three times the ULN occurred in 14/429 (3%) and 21/415 (5%) of patients on teriflunomide 7 mg and 14 mg, respectively, and 17/421 (4%) of

patients on placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months. One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. Teriflunomideinduced liver injury in this patient could not be ruled out. Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs. Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue teriflunomide and start an accelerated elimination procedure [see Warnings and Precautions (5.3)] and monitor liver tests weekly until normalized. If teriflunomide-induced liver injury is unlikely because some other probable cause has been found, resumption of teriflunomide therapy may be considered. 5.2 Use in Women of Childbearing Potential There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women. However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or fetal death when administered to a pregnant woman [see Contraindications (4.2)]. Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus from AUBAGIO [see Warnings and Precautions (5.3)]. Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk. [see Contraindications (4.2), Warnings and Precautions (5.3) and Use in Specific Populations (8.1)] 5.3 Procedure for Accelerated Elimination of Teriflunomide Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures: • Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used. • Administration of 50 g oral activated charcoal powder every 12 hours for 11 days. If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly. At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations. Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment. 5.4 Bone Marrow Effects/Immunosuppression Potential/Infections White Blood Cell (WBC) count decrease A mean decrease in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1.5×109/L was observed in 10% and 15% of patients on AUBAGIO 7 mg and 14 mg , respectively, compared with 5% of patients on placebo; lymphocyte count <0.8×109/L was observed in 7% and 10% of patients on AUBAGIO 7 mg and 14 mg, respectively, compared with 5% of patients on placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression. Risk of Infection / Tuberculosis Screening Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician. AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like teriflunomide that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections. In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with teriflunomide 7 mg (1.4%) or 14 mg (2.2%) compared to placebo (2.1%).

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AUBAGIO® (teriflunomide) tablets for oral administration and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure [see Warnings and Precautions (5.3)]. 5.11 Concomitant Use with Immunosuppressive or Immunomodulating Therapies Co-administration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which teriflunomide was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established. In any situation in which the decision is made to switch from AUBAGIO to another agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment [see Warnings and Precautions (5.3)]. 6. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: • Hepatotoxicity [see Contraindications (4.1) and Warnings and Precautions (5.1)] • Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4)] • Peripheral Neuropathy [see Warnings and Precautions (5.5)] • Acute Renal Failure [see Warnings and Precautions (5.6)] • Hyperkalemia [see Warnings and Precautions (5.7)] • Serious Skin Reactions [see Warnings and Precautions (5.8)] • Blood Pressure Effects [see Warnings and Precautions (5.9)] • Respiratory Effects [see Warnings and Precautions (5.10) The most frequent adverse reactions for AUBAGIO (incidence ≥10% and ≥2% greater than placebo) in the placebo-controlled studies were ALT increased, alopecia, diarrhea, influenza, nausea, and paresthesia. Alopecia was the most common cause of discontinuation because of adverse events in controlled clinical studies as compared to placebo (0.5% and 1.4% of patients on AUBAGIO 7 mg and 14 mg, respectively, and 0% on placebo). If desired, teriflunomide can be rapidly cleared from the body by the use of an accelerated elimination procedure [see Warnings and Precautions (5.3)]. 6.1 Clinical Trial Experience A total of 844 patients on teriflunomide (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of MS (RMS). Approximately 72% of patients were female and the mean age was 38 years. Study 1 was a 108-week placebo-controlled clinical study in 1086 RMS patients treated with teriflunomide 7 mg (n=368), teriflunomide 14 mg (n=358), or placebo (n=360). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Table 1 Adverse Reactions in Study 1 (occurring in ≥ 2% of patients, and reported for teriflunomide 7 mg or 14 mg at ≥ 2% higher rate than for placebo) Teriflunomide PRIMARY SYSTEM ORGAN 14 mg 7 mg Placebo CLASS (N=358) (N=368) (N=360) Preferred Term (%) INFECTIONS AND INFESTATIONS Influenza 12% 9% 10% Upper respiratory tract infection 9% 9% 7% Bronchitis 8% 5% 6% Sinusitis 6% 4% 4% Cystitis 4% 2% 1% Gastroenteritis viral 4% 2% 1% Oral herpes 4% 2% 2% BLOOD AND LYMPHATIC SYSTEM DISORDERS Neutropenia 4% 2% 0.3% Leukopenia 1% 2% 0.3% IMMUNE SYSTEM DISORDERS Seasonal allergy 3% 2% 1% PSYCHIATRIC DISORDERS Anxiety 4% 3% 2% NERVOUS SYSTEM DISORDERS Headache 19% 22% 18% Paraesthesia 10% 9% 8% Sciatica 3% 1% 1% Burning sensation 3% 2% 1% Carpal tunnel syndrome 3% 1% 0.3% EYE DISORDERS Vision blurred 3% 3% 1% Conjunctivitis 1% 3% 1% CARDIAC DISORDERS Palpitations 2% 3% 1%

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However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking teriflunomide 14 mg for 1.7 years. Fatal infections have been reported in the post-marketing setting, in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed. In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test. AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO. Vaccination No clinical data are available on the efficacy and safety of vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is, however, not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO. Malignancy The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with teriflunomide. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO. 5.5 Peripheral Neuropathy In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients taking AUBAGIO than in patients taking placebo. In one 108-week placebo-controlled study in 1086 patients with multiple sclerosis, the incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.2% (4 patients) and 1.9% (6 patients) on 7 mg and 14 mg of AUBAGIO, respectively, compared with 0% on placebo. Treatment was discontinued in 2 patients with polyneuropathy, one on each dose; one of them recovered following treatment discontinuation. The other cases of peripheral neuropathy did not resolve with continued treatment. There have also been reports of peripheral neuropathy in patients receiving leflunomide. Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure [see Warnings and Precautions (5.3)]. 5.6 Acute Renal Failure In placebo-controlled trials, 10 of 844 (1.2%) of AUBAGIO-treated subjects had transient acute renal failure with a creatinine measurement increased by 100% or more of their baseline serum creatinine value, compared to 0 of 421 placebo-treated subjects. Seven of the 10 subjects had a nadir creatinine clearance less than 30 cc/minute. In each of the 10 subjects, the serum creatinine level was normal on the next reported measurement (6–48 days from the increase in creatinine) with continued teriflunomide use. These increased creatinine measurements occurred between 12 weeks and 2 years after first dose of teriflunomide. Of the 6 subjects with available serum potassium measurements, 3 (50%) had hyperkalemia (measurements of 6.7, >7.3, and >7.3 mmol/L). No associated symptoms were documented. AUBAGIO causes increases in renal uric acid clearance with mean decreases in serum uric acid of 20–30%. Acute uric acid nephropathy is a likely explanation for the cases of transient acute renal failure seen with teriflunomide. Although symptoms associated with acute uric acid nephropathy, such as loin pain or flank pain, were not reported, this information was not systematically collected. No inciting factors, such as dehydration, exercise, or increase in physical activity in the 30 days prior to the adverse event were reported, but this information was not systematically collected. 5.7 Hyperkalemia In placebo-controlled trials, treatment-emergent hyperkalemia >7.0 mmol/L occurred in 8/829 (1.0%) of teriflunomide-treated subjects, compared to 1/414 (0.2%) of placebo-treated subjects. Two teriflunomide-treated subjects had hyperkalemia >7.0 mmol/L with acute renal failure. Possible causes in other cases were not documented. Check serum potassium level in AUBAGIO-treated patients with symptoms of hyperkalemia or with acute renal failure. 5.8 Skin Reactions Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure [see Warnings and Precautions (5.3)]. 5.9 Blood Pressure Increase In placebo-controlled studies, mean change from baseline in systolic blood pressure was 2.9 mmHg and 2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -1.3 mmHg for placebo. The change from baseline in diastolic blood pressure was 1.4 mmHg and 1.3 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.9 mmHg for placebo. Hypertension was reported as an adverse reaction in 4% of patients treated with 7 mg or 14 mg of AUBAGIO, compared with 2% on placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO. 5.10 Respiratory Effects Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. A similar risk would be expected for teriflunomide [see Clinical Pharmacology (12.3) in the full prescribing information]. Interstitial lung disease may be fatal. Interstitial lung disease may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy

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Table 1 Adverse Reactions in Study 1 (occurring in ≥ 2% of patients, and reported for teriﬂunomide 7 mg or 14 mg at ≥ 2% higher rate than for placebo) (continued) Teriﬂunomide PRIMARY SYSTEM ORGAN 14 mg 7 mg Placebo CLASS (N=358) (N=368) (N=360) Preferred Term (%) VASCULAR DISORDERS Hypertension 4% 4% 2% GASTROINTESTINAL DISORDERS Diarrhoea 18% 15% 9% Nausea 14% 9% 7% Abdominal pain upper 6% 5% 4% Toothache 4% 4% 2% Abdominal distension 1% 2% 0.3% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia 13% 10% 3% Acne 3% 1% 1% Pruritus 3% 4% 2% MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Musculoskeletal pain 4% 5% 3% Myalgia 3% 4% 2% INVESTIGATIONS Alanine aminotransferase 14% 12% 7% increased 3% 5% 1% Gamma-glutamyltransferase increased Aspartate aminotransferase 3% 2% 1% increased Weight decreased 2% 3% 1% Neutrophil count decreased 2% 3% 0.3% White blood cell count decreased 1% 3% 0%

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Genzyme Corporation 500 Kendall Street Cambridge, MA 02142 A SANOFI COMPANY September 2012a TER-BPLR-SA-SEP12

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Cardiovascular deaths Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between teriflunomide and cardiovascular death has not been established. Hypophosphatemia In clinical trials, 18% of teriflunomide-treated subjects had mild hypophosphatemia (≥ 0.6 mmol/L and < lower limit of normal), compared to 9% of placebo-treated subjects; 5% of teriflunomide-treated subjects had moderate hypophosphatemia (≥0.3 mmol/L and <0.6 mmol/ L), compared to 1% of placebo-treated subjects. No subject in either treatment group had a serum phosphorus <0.3 mmol/L. 7. DRUG INTERACTIONS Effect of teriflunomide on CYP2C8 substrates There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose. Therefore, monitoring patients with concomitant use of drugs metabolized by CYP2C8, such as repaglinide, paclitaxel, pioglitazone, or rosiglitazone is recommended as they may have higher exposure. Effect of teriflunomide on warfarin A 25% decrease in peak international normalized ratio (INR) was observed when teriflunomide was coadministered with warfarin as compared with warfarin alone. Therefore, when warfarin is coadministered with teriflunomide, close INR follow-up and monitoring is recommended. Effect of teriflunomide on oral contraceptives There was an increase in mean ethinylestradiol Cmax and AUC0–24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0–24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide. Consideration should be given to the type or dose of oral contraceptives used in combination with teriflunomide. Effect of teriflunomide on CYP1A2 substrates Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 18% and 55% respectively, suggesting that teriflunomide may be in vivo a weak inducer of CYP1A2. Therefore, patients should be monitored when teriflunomide is coadministered with drugs metabolized by CYP1A2 (such as duloxetine, alosetron, theophylline, and tizanidine), as the efficacy of such drugs could be reduced. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Contraindications (4.2) and Warnings and Precautions (5.2)] When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity. Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).

AUBAGIO® (teriflunomide) tablets for oral administration Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD. In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD. In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Use in Males AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)]. Pregnancy Registry Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to AUBAGIO. Physicians are encouraged to enroll pregnant women in the AUBAGIO pregnancy registry, or pregnant women may enroll themselves, by calling 1-800-745-4447, option 2. 8.3 Nursing Mothers Teriflunomide was detected in rat milk following a single oral dose of teriflunomide. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from AUBAGIO 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of AUBAGIO did not include patients over 65 years old. 8.6 Hepatic Impairment No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated. Teriflunomide is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1) and Warnings and Precautions (5.1)]. 8.7 Renal Impairment No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. 10. OVERDOSAGE There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects. In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination [see Warnings and Precautions (5.3)].

BUSINESS BUSINESS

Original Research

Healthcare Costs Among Patients with Excessive Sleepiness Associated with Obstructive Sleep Apnea, Shift Work Disorder, or Narcolepsy Rashad Carlton, PharmD; Orsolya Lunacsek, PhD; Timothy Regan, BPharm; Cathryn A. Carroll, PhD Background: Excessive daytime sleepiness affects nearly 20% of the general population and is as-

Stakeholder Perspective, sociated with many medical conditions, including shift work disorder (SWD), obstructive sleep apnea page 339 (OSA), and narcolepsy. Excessive sleepiness imposes a significant clinical, quality-of-life, safety, and

Am Health Drug Benefits. 2014;7(6):334-340 www.AHDBonline.com Received March 26, 2014 Accepted in final form July 7, 2014

Disclosures are at end of text

economic burden on society. Objective: To compare healthcare costs for patients receiving initial therapy with armodafinil or with modafinil for the treatment of excessive sleepiness associated with OSA, SWD, or narcolepsy. Methods: A retrospective cohort analysis of medical and pharmacy claims was conducted using the IMS LifeLink Health Plan Claims Database. Patients aged â&#x2030;Ľ18 years who had a pharmacy claim for armodafinil or for modafinil between June 1, 2009, and February 28, 2012, and had 6 months of continuous eligibility before the index prescription date, as well as International Classification of Diseases, Ninth Revision diagnosis for either OSA (327.23), SWD (327.36), or narcolepsy (347.0x) were included in the study. Patients were placed into 1 of 2 treatment cohorts based on their index prescription and followed for 1 month minimum and 34 months maximum. The annualized all-cause costs were calculated by multiplying the average per-month medical and pharmacy costs for each patient by 12 months. The daily average consumption (DACON) for armodafinil or for modafinil was calculated by dividing the total units dispensed of either drug by the prescription days supply. Results: A total of 5693 patients receiving armodafinil and 9212 patients receiving modafinil were included in this study. A lower DACON was observed for armodafinil (1.04) compared with modafinil (1.47). The postindex mean medical costs were significantly lower for the armodafinil cohort compared with the modafinil cohort after adjusting for baseline differences ($11,363 vs $13,775, respectively; P = .005). The mean monthly drug-specific pharmacy costs were lower for the armodafinil cohort compared with the modafinil cohort ($166 vs $326, respectively; P <.001). In addition, lower total healthcare costs were observed for the armodafinil cohort compared with the modafinil cohort after correcting for baseline differences ($18,309 vs $23,530, respectively; P <.001). Conclusion: As shown in this analysis, armodafinil may have real-world DACON advantages and may be associated with lower overall healthcare costs compared with modafinil.

xcessive daytime sleepiness occurring at least 3 times weekly affects nearly 20% of the population and severe excessive daytime sleepiness affects approximately 5% of the population, with men and women equally affected.1 Excessive sleepiness, defined as the ongoing inability to maintain alertness during the waking episodes,2 imposes a significant clinical, quality-of-life, safety, and economic burden on society.3 In Dr Carlton is Assistant Director, Global Health Economics and Outcomes Research, Xcenda, Palm Harbor, FL; Dr Lunacsek is Associate Director, Applied Data Analytics, Xcenda, Palm Harbor, FL; Mr Regan is Executive Director, Strategic Accounts, Xcenda, Palm Harbor, FL; Dr Carroll is Senior Director, Market Access, Xcenda, Palm Harbor, FL.

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2007, the National Highway Traffic Safety Administration estimated that sleep problems contributed to more than 100,000 motor vehicle crashes in the United States, resulting in an estimated 1550 deaths, 71,000 injuries, and $12.5 billion in monetary losses annually.4 Excessive daytime sleepiness is associated with many medical conditions, including shift work disorder (SWD), obstructive sleep apnea (OSA), and narcolepsy.3 The prevalence of excessive sleepiness among night shift workers and among rotating shift workers is 14.1% and 8.1%, respectively; the corresponding prevalence of SWD is 10% among shift workers aged 18 to 65 years.5 An estimated 9% of women and 24% of men aged 30 to 60 years have at least mild OSA.6 Excessive daytime sleepiness is the most common symptom of OSA.7,8 Re-

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Healthcare Costs in Patients with Excessive Sleepiness

sidual excessive sleepiness is present in 6% to 12% of patients with OSA even after treatment with continuous positive airway pressure.8 The prevalence of narcolepsy is estimated to be between 25 and 50 persons per 100,000 people.9 Almost all patients with narcolepsy experience periods of extreme daytime sleepiness and sudden bouts of sleep that can strike at any time.10 Because of the high prevalence and significant economic impact of excessive sleepiness, attention is warranted for the selection of the most appropriate and cost-effective, wake-promoting treatment. Armodafinil and modafinil improve wakefulness in patients with excessive sleepiness associated with SWD, treated OSA, and narcolepsy.11-18 Armodafinil is the longer-lasting, R-isomer of racemic modafinil. A comparison of armodafinil and modafinil on a milligram-to-milligram basis showed that armodafinil sustained higher plasma concentrations than modafinil, as indicated by a 37% higher maximum plasma concentration, and a 69% greater area under the curve.19 This present study was conducted to explore any potential differences in all-cause healthcare costs and the individual cost components (ie, inpatient visits, emergency department visits, physician office visits, outpatient visits, and other visits) between patients prescribed initial armodafinil therapy and patients prescribed initial modafinil therapy for the treatment of excessive sleepiness associated with OSA, SWD, or narcolepsy.

Methods Data Source This retrospective cohort study was based on data from the IMS LifeLink Health Plan Claims Database, a nationally representative database containing data from more than 79 health plans in the United States. This is the largest, most comprehensive database of integrated medical and pharmacy claims for approximately 87 million de-identified individuals as of March 2012, with the majority of them (82%) commercially insured. Patients in the database are tracked longitudinally using 3 component files: medical claims, pharmacy claims, and eligibility for insurance coverage. The medical claims file contains data on the diagnostic and therapeutic services rendered in the inpatient and outpatient settings. The pharmacy claims file contains data on the prescription drugs dispensed in the retail and mail-order settings. The eligibility file contains demographic characteristics and periods of eligibility for enrollment in the plan for each patient. Patient Selection The study included patients with a pharmacy claim for armodafinil or for modafinil between June 1, 2009,

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Key Points Excessive daytime sleepiness is associated with medical conditions, such as shift work disorder, obstructive sleep apnea, and narcolepsy, and carries a significant clinical and economic burden. ➤ This is the first large, real-world economic analysis comparing the differences in healthcare costs associated with armodafinil and modafinil for the treatment of excessive sleepiness. ➤ This study was conducted between June 2009 and February 2012, before the generic form of modafinil became available. ➤ The results show that armodafinil had a lower daily average consumption (DACON) compared with modafinil (1.04 vs 1.47, respectively). ➤ The postindex mean annualized medical costs were significantly lower with armodafinil ($11,363) compared with modafinil ($13,775). ➤ Total annualized healthcare costs were also lower with armodafinil ($18,309) compared with modafinil ($23,530). ➤ Based on this analysis, armodafinil provides realworld DACON advantages and may be associated with lower overall healthcare utilization and costs compared with modafinil. ➤

and February 28, 2012. The fill date of the patients’ first armodafinil or modafinil prescription within this time frame was designated as the index date. Patients were included in this study if they were aged at least 18 years at the index date, and were continuously eligible for insurance coverage for 6 months before the index (ie, preindex) date and at least 1 month after the index (ie, postindex) date. In addition, patients were required to have an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for at least 1 of the US Food and Drug Administration–approved indications for armodafinil or for modafinil—OSA (327.23), SWD (327.36), or narcolepsy (347.0x)—in the 6-month preindex period or on the index date. Patients were not required to be treatment naïve to all therapies for OSA, SWD, or narcolepsy, but patients with an index prescription fill date for armodafinil or for modafinil before June 1, 2009, or after February 28, 2012, were excluded from this study. The cohort assignment was based on an intent-totreat approach, and patients meeting the selection criteria were placed into 1 of 2 treatment cohorts according to their index prescription; patients remained in that cohort throughout the study period. The patients were

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Figure 1 Analysis Timeline Enrollment period Preindex period

Follow-up period Minimum: 1 month Maximum: 34 months

(6 months)

Index

(First armodafinil or modafinil prescription)

December 1, 2008

June 1, 2009

February 28, 2012

March 31, 2012

Armodafinil commercially available

followed until the earlier of either their health plan enrollment end date, or the end of the analysis period on March 31, 2012 (Figure 1). This allowed for patients to be followed for a minimum of 1 month and a maximum of 34 months after their index date. The 6-month period before the index date was used to assess baseline characteristics, healthcare costs, and resource utilization.

Outcomes The all-cause healthcare costs were calculated from all claims regardless of the diagnosis codes. The costs were defined as the allowed amount on claims; the allowed amount typically reflects the amount paid by the health plan plus any member liability (ie, copay, deductible, or coinsurance) for the service. The allowed amount was chosen as the cost measure, because it best represents the actual cost amount received from all payers. The total medical costs and the component costs for inpatient hospitalizations, emergency department visits, physician office visits, outpatient visits, and other visits (ie, laboratory and diagnostic claims that were not part of a hospitalization, emergency department visits, physician office visits, or outpatient visits) were evaluated. The pharmacy costs included all medications for which claims were filed (ie, not restricted to armodafinil and to modafinil). The drug-specific costs were restricted to pharmacy costs for armodafinil or for modafinil. The total healthcare costs included the sum of all medical and pharmacy costs. Because patients had varying lengths of follow-up, annualized costs were calculated by multiplying by 12 the average monthly cost for each patient. The costs in the analysis were adjusted to March 2012 US dollars using the Medical Consumer Price Index.20 The daily average consumption (DACON) for armodafinil and for modafinil was calculated by dividing the total tablets dispensed for each drug by the prescription days supplied.

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Statistical Methods Baseline characteristics were compared between the 2 cohorts using the chi-square tests for categorical variables (eg, sex, region, index payer, conditions of interest) and independent samples t-tests for continuous variables (eg, age, Charlson Comorbidity Index [CCI] score). The CCI score was used to represent the patientsâ&#x20AC;&#x2122; overall health status. It contains 19 categories of comorbidity and reflects the cumulative burden of comorbidity with higher scores indicating a more severe burden.21,22 (The categories of the CCI include myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, mild liver disease, diabetes, hemiplegia, moderate-to-severe renal disease, diabetes with end-organ damage, any tumor, leukemia, lymphoma, moderate-to-severe liver disease, metastatic solid tumor, and AIDS.21,22) The CCI scores were derived by evaluating the presence of various ICD-9 codes in the 6-month preindex period for each patient. To account for baseline differences between the 2 treatment cohorts, multivariate generalized linear models based on gamma distribution and log link function were used to compare postindex costs between the 2 cohorts; age, sex, CCI scores, region, index payer, and log-transformed preindex costs were used as covariates in the models. Paired t-tests were used to compare differences between the preindex and the postindex costs within each drug cohort. All analyses were conducted with SAS version 9.2 (SAS Institute; Cary, NC). A P value â&#x2030;¤.05 was considered significant. Results Patient Characteristics A total of 5693 patients receiving armodafinil and 9212 patients receiving modafinil met all of the inclusion criteria. The patients in the modafinil cohort were followed for an average of 19.35 months, and the patients in the armodafinil cohort were followed for an average of 13.95 months. At baseline, patients in the modafinil cohort were older (50.3 years vs 47.3 years; P <.001) and with a higher mean CCI score (0.81 vs 0.64; P <.001) compared with patients in the armodafinil cohort (Table). Relative to the modafinil cohort, the armodafinil cohort had higher percentages of patients with a diagnosis of OSA (84% vs 81.4%; P <.001) and SWD (7.7% vs 4.2%; P <.001), and a lower percentage of patients. Daily Average Consumption During the study period, 27,555 armodafinil prescriptions were filled by 5693 unique patients for an average of 4.8 armodafinil fills per patient. For modafinil, 57,196 prescriptions were filled by 9212 unique patients for an

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Healthcare Costs The postindex mean medical costs were significantly lower for the armodafinil cohort compared with the modafinil cohort after adjusting for baseline differences ($11,363 vs $13,775, respectively; P = .005 (Figure 3). Within each cohort, decreased medical costs were observed in the postindex period compared with the preindex period ($13,155 vs $11,363, respectively, for armodafinil; $15,323 vs $13,775, respectively, for modafinil; P <.001 for both). Of the postindex component medical costs, inpatient hospitalization costs ($3099 vs $4308, respectively; P = .014) and other costs ($643 vs $1035, respectively; P <.001) were significantly lower for the armodafinil cohort compared with the modafinil cohort.

This is the first large, real-world, retrospective, economic study to evaluate the cost differences between armodafinil and modafinil. The physician and outpatient costs were also lower for the armodafinil cohort; however, these differences did not reach significance. All-cause emergency department visits was the only cost category that was higher among patients receiving armodafinil than among patients receiving modafinil (P <.001). The postindex mean total healthcare costs were lower for the armodafinil cohort compared with the modafinil cohort after controlling for baseline differences ($18,309 vs $23,530, respectively; P <.001; Figure 4).

Discussion This is the first large, real-world, retrospective, economic study to evaluate the cost differences between armodafinil and modafinil. The results of this analysis indicate that after therapy initiation, the armodafinil cohort had lower total all-cause medical costs compared with the modafinil cohort. In addition, the armodafinil cohort had lower pharmacy costs than the modafinil cohort after therapy initiation. The differences in the pharmacy costs between the armodafinil and the modafinil cohorts were partly driven by the differences in the pharmacy cost between the 2 medications, with armodafinil having a lower price than modafinil on a per-tablet basis (approximately $10.44 vs $16.56, respectively, per tablet).

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Table Baseline Patient Characteristics Armodafinil Modafinil Baseline characteristics (N = 5693) (N = 9212) P value Female sex, %

49.5

51.5

.056

Male sex, %

50.5

49.5

.056

Mean age on index date (SD)

47.3 (13.4)

50.3 (13.5)

<.001

Mean Charlson Comorbidity Index score in the 6-month preindex period and on index date (SD)

0.64 (1.11)

0.81 (1.31)

<.001

13.95

19.35

<.001

Mean follow-up time, mo

Diagnoses for indications in the 6-month preindex period and on index datea Obstructive sleep apnea, %

84.0

81.4

<.001

Shift work disorder, %

7.7

4.2

<.001

Narcolepsy, %

20.3

22.8

<.001

Conditions are not mutually exclusive, and the total can sum to greater than 100%. SD indicates standard deviation.

Figure 2 DACON for Armodafinil versus Modafinil 1.6

1.47

1.4 1.2 1.04

DACON, mean

average of 6.2 modafinil fills per patient. A lower DACON was observed for armodafinil (1.04) compared with modafinil (1.47; Figure 2). The mean monthly drug-specific pharmacy costs were $166 for armodafinil and $326 for modafinil (P <.001).

1.0 0.8 0.6 0.4 0.2 0.0

Armodafinil

Modafinil

DACON indicates daily average consumption.

Furthermore, this analysis was conducted before the approval of generic modafinil in June 2012. When the armodafinil and modafinil pharmacy costs were subtracted from the total pharmacy costs, the remaining pharmacy costs were still lower for the armodafinil cohort compared with the modafinil cohort, suggesting that lower total pharmacy costs may be seen with armodafinil compared with generic modafinil. DACON is a technique used by managed care organizations to assess drug utilization and the associated eco-

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ean Annualized Medical Costs: Armodafinil Figure 3 M versus Modafinil 16,000

$15,323

Mean annualized medical costs, $

14,000

$13,775

$13,155

12,000

$11,363

10,000 8000 6000 4000 2000 0

Before armodafinil After armodafinil therapy initiation therapy initiation

Before modafinil therapy initiation

After modafinil therapy initiation

P = .005 for mean medical costs.a P values adjusted using a generalized linear model for preperiod differences between armodafinil and modafinil cohorts in age, sex, Charlson Comorbidity Index, region, index payer, and preindex costs.

Figure 4 P ostindex Mean Annualized Total Costs: Armodafinil versus Modafinil

Postindex mean annualized total costs, $

Total pharmacy costs Total medical costs

25,000 20,000

$23,530.42 $18,308.91 $13,775.43

15,000 $11,363.17

10,000 5000

$9754.99

$6945.74

0 Armodafinil therapy

Modafinil therapy

P <.001 for mean total costs.a P values adjusted using a generalized linear model for preperiod differences between armodafinil and modafinil cohorts in age, sex, Charlson Comorbidity Index, region, index payer, and preindex costs.

nomic implications between medications with similar therapeutic indications. Although armodafinil and modafinil are available for once-daily dosing in multiple tablet strengths, differences in the real-world utilization of these medications can be underscored in a DACON

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analysis. Armodafinil has a DACON of 1.04 compared with a DACON of 1.47 for modafinil. These results support true once-daily dosing for armodafinil and provide real-world support for the pharmacokinetic data showing that on a milligram-to-milligram basis, armodafinil sustains higher plasma concentrations versus modafinil during a 24-hour period.19 These pharmacokinetic advantages may have translated into DACON differences seen in this real-world analysis.

Limitations The findings of this study should be interpreted with the study limitations in mind. First, the results of this analysis are based on observational claims data and therefore cannot be interpreted as implying any difference in efficacy or other clinical outcome, such as disease progression or quality of life. As with all claims analyses, the data elements may be subject to coding irregularities and inaccuracies. For example, SWD is known to be undercoded in medical claims, and physicians may also classify patients presenting with excessive sleepiness associated with OSA or narcolepsy to a broader or different diagnosis. Because study eligibility required a coded indication, relevant patients might have been excluded from the analysis. Hence, the generalizability of the results is restricted to a population that is similar to the current study group. Second, the costs reported in this analysis are allcause pharmacy and medical costs and are not specific to OSA, SWD, and/or narcolepsy. Excessive sleepiness is a risk factor for comorbidities and can exacerbate several comorbidities, making all-cause medical resource utilization the most relevant costs for this analysis. Because patients in this analysis had multiple comorbidities, it was difficult to separate disease-specific costs. In addition, total costs, regardless of their origin, are the most relevant costs to a health plan. It is likely that an excessive sleepiness–specific cost analysis would underestimate the true costs associated with this condition because OSA, SWD, and narcolepsy––the underlying causes of excessive sleepiness––are often undercoded. Third, this analysis did not capture the time since diagnosis and did not correct for the potential increased cost of the initial diagnosis and treatment. This analysis included a 6-month preindex period to ensure a diagnosis for OSA, SWD, or narcolepsy, but patients were not required to be newly diagnosed. Previous research has shown that men and women with OSA have higher costs in the period immediately before disease diagnosis.23,24 Fourth, the study design and the analytic techniques contain some inherent limitations. Because of the intent-to-treat design, patients who switched therapies during follow-up were still considered members of the cohort to which they were originally assigned, and their

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costs were attributed to their index drug. Administrative claims do not provide information regarding reasons for treatment discontinuation or switching. Furthermore, the IMS database is fully de-identified and therefore does not contain information on the benefit design of payers. Finally, an observational retrospective cohort study design restricts the ability to draw direct causal inferences between treatments and outcomes. Although background characteristics, such as age, sex, CCI score, index payer, and preindex costs were controlled for in this analysis, residual confounding cannot be ruled out.

Conclusions Based on this analysis, armodafinil provides real-world DACON advantages and may be associated with lower overall healthcare resource utilization and costs compared with modafinil. In light of these new comparative economic data, healthcare decision makers may have to consider DACON and real-world total cost differences in their formulary decision-making. Future studies are needed to explain the drivers of healthcare resource utilization and cost differences between patients receiving armodafinil and those receiving modafinil. ■ Funding Source This study was funded by Teva Pharmaceuticals. Author Disclosure Statement Dr Carlton, Dr Lunacsek, and Mr Regan are employees of Xcenda, which received funding from and provided consulting services to Teva Pharmaceuticals to conduct this analysis. Dr Carroll is a former employee of and had stocks in Teva Pharmaceuticals.

References

1. Janson C, Gislason T, De Backer W, et al. Daytime sleepiness, snoring and gastro-oesophageal reflux amongst young adults in three European countries. J Intern Med. 1995;237:277-285. 2. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

3. Schwartz JR, Roth T, Drake C. Armodafinil in the treatment of sleep/wake disorders. Neuropsychiatr Dis Treat. 2010;6:417-427. 4. National Sleep Foundation. State of the states report on drowsy driving. November 2007. Updated August 2008. http://drowsydriving.org/docs/2007%20State%20 of%20the%20States%20Report.pdf. Accessed August 9, 2013. 5. Drake CL, Roehrs T, Richardson G, et al. Shift work sleep disorder: prevalence and consequences beyond that of symptomatic day workers. Sleep. 2004;27:1453-1462. 6. Young T, Palta M, Dempsey J, et al. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort Study. WMJ. 2009;108:246-249. 7. Pagel JF. Excessive daytime sleepiness. Am Fam Physician. 2009;79:391-396. 8. Pépin J-L, Viot-Blanc V, Escourrou P, et al. Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study. Eur Respir J. 2009;33:1062-1067. 9. Longstreth WT Jr, Koepsell TD, Ton TG, et al. The epidemiology of narcolepsy. Sleep. 2007;30:13-26. 10. National Institute of Neurological Disorders and Stroke. Narcolepsy fact sheet. Updated April 16, 2014. www.ninds.nih.gov/disorders/narcolepsy/detail_narcolepsy. htm. Accessed August 9, 2013. 11. Czeisler CA, Walsh JK, Wesnes KA, et al. Armodafinil for treatment of excessive sleepiness associated with shift work disorder: a randomized controlled study. Mayo Clin Proc. 2009;84:958-972. 12. Czeisler CA, Walsh JK, Roth T, et al; for the U.S. Modafinil in Shift Work Sleep Disorder Study Group. Modafinil for excessive sleepiness associated with shiftwork sleep disorder. N Engl J Med. 2005;353:476-486. Erratum in: N Engl J Med. 2005;353:1078. 13. Harsh JR, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin. 2006;22:761-774. 14. Hirshkowitz M, Black JE, Wesnes K, et al. Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respir Med. 2007; 101:616-627. 15. Roth T, White D, Schmidt-Nowara W, et al. Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults. Clin Ther. 2006;28:689-706. 16. Schwartz JR. Modafinil in the treatment of excessive sleepiness. Drug Des Devel Ther. 2008;2:71-85. 17. Schwartz JR, Hirshkowitz M, Erman MK, Schmidt-Nowara W; for the United States Modafinil in OSA Study Group. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study. Chest. 2003;124: 2192-2199. 18. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol. 1998; 43:88-97. 19. Darwish M, Kirby M, D’Andrea DM, et al. Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: a randomized, open-label, crossover study. Clin Ther. 2010;32:2074-2087. 20. US Bureau of Labor Statistics. Consumer Price Index. Medical care component. http://data.bls.gov. Accessed August 9, 2013. 21. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383. 22. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613-619. 23. Albarrak M, Banno K, Sabbagh AA, et al. Utilization of healthcare resources in obstructive sleep apnea syndrome: a 5-year follow-up study in men using CPAP. Sleep. 2005;28:1306-1311. 24. Banno K, Manfreda J, Walld R, et al. Healthcare utilization in women with obstructive sleep apnea syndrome 2 years after diagnosis and treatment. Sleep. 2006;29: 1307-1311.

Stakeholder Perspective Out-of-Pocket Cost of Therapy Can Affect Patients’ Excessive Sleepiness and Daytime Functioning By Teresa M. DeLuca, MD, MBA Assistant Clinical Professor, Psychiatry, Mount Sinai School of Medicine, New York, NY, and former Chief Medical Officer–Pharmacy, Magellan Health Services, New York, NY

he article by Carlton and colleagues in this issue of American Health & Drug Benefits is the first large, real-world, retrospective, economic analysis

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comparing the differences in healthcare costs associated with armodafinil and modafinil for the treatment of excessive daytime sleepiness. The results indicate that ar-

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Stakeholder Perspective Continued modafinil has a lower daily average consumption compared with modafinil, as well as significantly lower medical costs, and lower total healthcare costs. These findings have obvious implications for provider prescribing and treatment planning, as well as for health plan formulary decision-making. They also provide useful consumer price information for patients to discuss with their physicians to arrive at a cost-effective treatment choice. PATIENTS: Excessive daytime sleepiness, the inability to maintain alertness while awake, is associated with medical conditions, including shift work disorder (SWD), obstructive sleep apnea (OSA), and narcolepsy. It is also associated with insufficient quality or quantity of sleep, either is a contributing factor likely to increase exponentially, based on studies showing that 65% of us sleep with our cell phones within reach.1 It is also well established in the scientific literature that people exposed to mobile radiation take longer to fall asleep and spend less time in deep sleep.2 Healthcare costs are not the only costs associated with excessive sleepiness. Lowered employee productivity affects not only the employer’s bottom line but also leads to workers’ frustration, as they struggle to stay awake and complete their tasks. Excessive daytime sleepiness also has consequences for society. Carlton and colleagues cite a National Highway Traffic Safety Administration estimate that in 2007, sleep problems contributed to more than 100,000 motor vehicle crashes in the United States, resulting in 1550 deaths; 71,000 injuries; and $12.5 billion in annual monetary loss.3 Those numbers alone should jolt us awake. Patient out-of-pocket spending is an increasingly important factor as health plan members are asked to take on a greater share of the cost of their care. The present study findings are particularly instructive here. The daily average consumption was lower for armodafinil (1.04) than for modafinil (1.47). This translated into mean monthly drug-specific pharmacy costs of $166 per patient for armodafinil and $326 per patient for modafinil. For health plan members responsible for coinsurance, the rates per prescription range from 32% to 36% (based on prescription drug coinsurance amounts for the metal plans available under the Affordable Care Act). This amount could result in out-of-pocket consumer savings of $60 to $117 monthly. As we know, out-of-pocket costs correlate with patient adherence to prescribed medica-

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tions; therefore, armodafinil could potentially be associated with a higher patient adherence rate than modafinil, leading to better-controlled daytime sleepiness. PAYERS: Total healthcare costs are the metric of most interest to payers, whether they are self-funded employers or fully insured health plans. Carlton and colleagues rightly note that patients in this analysis had multiple comorbidities, making it difficult to separate out disease-specific costs. The likelihood of undercoding OSA, SWD, and narcolepsy also make total costs, regardless of the origin, the most helpful metric for payers to weigh when evaluating these medications. Of note, all-cause emergency department visits were the only cost category that was higher among patients receiving armodafinil than among patients receiving modafinil. I would suspect this is because of the differences in a patient’s presenting symptoms or in the main complaint; however, without further research, this is a mere assumption. PROVIDERS: The majority of providers do not check the patient’s formulary before writing a prescription. Instead, they base prescribing decisions on their experience and on their comfort level with each drug. As a result, providers are not aware of the patient’s outof-pocket cost. Cost information from this study could arm providers with a resource to help them factor in the cost to the patient when writing a prescription, potentially increasing the likelihood that their patient will fill the prescription and will continue to use the prescribed treatment. Sleep is a natural process that enhances confidence, creativity, and cognitive function. The irony is that patients with excessive daytime sleepiness do not benefit from this sleep. Both armodafinil and modafinil have the potential to help patients achieve normal daily function in a safe environment. Based on this study’s analysis, armodafinil offers advantages over modafinil in lower overall healthcare resource utilization and cost. Such clear comparative economic data can, and should, be factored into decision-making by patients, providers, and payers. n 1. Hall K, Spurlock C. How mobile phones affect sleep (infographic). Huffington Post. February 15, 2013. Updated March 22, 2013. www.huffingtonpost.com/ 2013/02/15/phones-sleep-mobile-_n_2680805.html. Accessed September 10, 2014. 2. Arnetz B, Åkerstedt T, Hillert L, et al. The effects of 884 MHz GSM wireless communication signals on self-reported symptoms and sleep—an experimental provocation study. PIERS Online. 2007;3:1148-1150. 3. National Sleep Foundation. State of the states report on drowsy driving. November 2007. Updated August 2008. http://drowsydriving.org/docs/2007%20State%20of%20 the%20States%20Report.pdf. Accessed September 10, 2014.

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For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed on or after prior fluoropyrimidineor platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe

events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with ChildPugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly delayed disease progression1 MAJOR OUTCOME MEASURE

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)

1.0

Placebo

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.8

OS PROBABILITY

CYRAMZA

0.6

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

238 117

10 11 12 13

14 15 16 17 18 19

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

154 66

92 34

49 20

17 7

• The percentage of deaths at the time of analysis was 75% (179 patients) and 85% (99 patients) in the CYRAMZA and placebo arms, respectively1

7 4

3 2

37%

• Median progression-free survival (PFS) with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1 — The percentage of events at the time of analysis was 84% (199 patients) and 92% (108 patients), respectively The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measure was PFS. All patients were Eastern Cooperative Oncology Group Performance Status 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy. Patients were randomized 2:1 to CYRAMZA 8 mg/kg every 2 weeks + best supportive care (BSC) (n=238) or placebo + BSC (n=117).1 CI=confidence interval.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades; grade 3-4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%; 8% vs 3%), diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and hyponatremia (6% vs 2%; 3% vs 1%).

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

• The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZAtreated patients vs 8.7% of patients who received placebo. • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%). • Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZAtreated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. • As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZAtreated patients with post-baseline serum samples tested positive for anti-ramucirumab antibodies using an enzymelinked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant. • Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility. Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page. RB HCP ISI 21JUL2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

CYRAMZATM (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. INDICATIONS AND USAGE CYRAMZA as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single-agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of CYRAMZA as a single agent was evaluated in 570 patients, including patients in Study 1 who received CYRAMZA. Study 1 randomized patients (2:1) to receive CYRAMZA 8 mg/kg intravenously every two weeks (n=236) versus placebo every two weeks (n=115) in a double-blind, placebo-controlled trial in previously treated gastric cancer. In Study 1, patients with an ECOG performance status of 2 or greater, bilirubin greater than or equal to 1.5 mg/dL, uncontrolled hypertension, major surgery within 28 days, or receiving chronic anti-platelet therapy other than once daily aspirin were excluded. Patients received a median CYRAMZATM (ramucirumab) injection PA000IPAM00-BS 7x10

of 4 doses of CYRAMZA; the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received CYRAMZA for at least six months. In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo. Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 (MedDRA)a All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0. Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo). Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%. Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZA-treated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. The detection 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 incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal drug interaction studies have been conducted. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, CYRAMZATM (ramucirumab) injection PA000IPAM00-BS 7x10

anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single-agent. Geriatric Use Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over. Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab. Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab. Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus. Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment. Additional information can be found at www.CYRAMZAhcp.com.

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Original Research

Am Health Drug Benefits. 2014;7(6):346-358 www.AHDBonline.com Received July 14, 2014 Accepted in final form August 21, 2014

Disclosures are at end of text Supplemental material online

BACKGROUND: Previous studies have shown that there were greater racial and ethnic disparities among individuals who were ineligible for medication therapy management (MTM) services than among MTM-eligible individuals before the implementation of Medicare Part D in 2006. OBJECTIVE: To determine whether the implementation of Medicare Part D in 2006 correlates to changes in racial and ethnic disparities among MTM-ineligible and MTM-eligible beneficiaries. METHODS: Data from the Medicare Current Beneficiary Survey were analyzed in this retrospective observational analysis. To examine potential racial and ethnic disparities, non-Hispanic whites were compared with non-Hispanic blacks and Hispanics. Three aspects of disparities were analyzed, including health status, health services utilization and costs, and medication utilization patterns. A generalized difference-in-differences analysis was used to examine the changes in difference in disparities between MTM-ineligible and MTM-eligible individuals from 2004-2005 to 2007-2008 relative to changes from 2001-2002 and 2004-2005. Various multivariate regressions were used based on the types of dependent variables. A main analysis and several sensitivity analyses were conducted to represent the ranges of MTM eligibility thresholds used by Medicare Part D plans in 2010. RESULTS: The main analysis showed that Part D implementation was not associated with reductions in greater racial and ethnic disparities among MTM-ineligible than MTM-eligible Medicare beneficiaries. The main analysis suggests that after Part D implementation, Medicare MTM eligibility criteria may not consistently improve the existing racial and ethnic disparities in health status, health services utilization and costs, and medication utilization. By contrast, several sensitivity analyses showed that Part D implementation did correlate with a significant reduction in greater racial disparities among the MTM-ineligible group than the MTM-eligible group in activities of daily living and in instrumental activities of daily living. Part D implementation may be also associated with a reduction in greater ethnic disparities among the MTM-ineligible group than the MTM-eligible groups in the costs of physician visits. CONCLUSION: Part D implementation was not associated with consistent reductions in the disparity implications of the Medicare MTM eligibility criteria. The main analysis showed that Part D implementation was not associated with a reduction in disparities associated with MTM eligibility, although several sensitivity analyses did show reductions in disparities in specific aspects. Future research should explore alternative Medicare MTM eligibility criteria to eliminate racial and ethnic disparities among the Medicare population.

Dr Wang is Associate Professor, Department of Clinical Pharmacy, University of Tennessee College of Pharmacy, Memphis; Ms Qiao is Research Assistant, Department of Clinical Pharmacy, University of Tennessee College of Pharmacy, Memphis; Dr Shih is Associate Professor, Section of Hospital Medicine, Department of Medicine, and Director, Program in the Economics of Cancer, University of Chicago, IL; Ms Jamison is pharmacy student, University of Tennessee Health Science Center, College of Pharmacy, Memphis; Dr Spivey is Assistant Professor, Department of Clinical Pharmacy, University of Tennessee College of Pharmacy, Memphis; Dr Li is Postdoctoral Fellow, Department of Clinical Pharmacy, University of Tennessee College of Pharmacy, Memphis; Dr Wan is Professor, Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis; Dr White-Means is Professor and Director, Consortium for Health Education, Economic Empowerment and Research, Department of Clinical Pharmacy, University of Tennessee College of Pharmacy, Memphis; Dr Dagogo-Jack is Mullins Professor and Director, Division of Endocrinology, Diabetes and Metabolism, and Director, Clinical Research Center, University of Tennessee Health Science Center, Memphis; Dr Cushman is Professor, Departments of Preventive Medicine, Medicine, and Physiology, University of Tennessee College of Medicine, Memphis, and Chief, Preventive Medicine Section, Veterans Affairs Medical Center, Memphis, TN; Dr Chisholm-Burns is Dean and Professor, University of Tennessee College of Pharmacy, Memphis, Knoxville, and Nashville.

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he Medicare Part D program was implemented in 2006 according to the Medicare Prescription Drug, Improvement, and Modernization Act (MMA).1 Medication therapy management (MTM) services were established by the Centers for Medicare & Medicaid Services (CMS) as part of the Part D benefit. MTM services may be furnished by a pharmacist or by other healthcare providers to “ensure that covered Part D drugs prescribed to targeted beneficiaries…are appropriately used to optimize therapeutic outcomes.”1 The core components of MTM are the formulation of a medication treatment plan and integration of the plan with all health services provided to patients.2 In consideration of limited resources, the MMA restricted MTM services to Medicare beneficiaries meeting all 3 criteria, including (1) having multiple chronic conditions, (2) using multiple Part D drugs, and (3) being likely to exceed a drug cost threshold of $4000.1,3 For the year 2010 and onward, CMS required the eligibility thresholds to be lowered to no more than 3 chronic conditions, 8 drugs, and $3000 in annual drug costs.3 Of note, 2 of the 3 eligibility criteria depend significantly on the utilization of medications by the beneficiary, whereas multiple studies on medication use patterns have shown that racial and ethnic minorities use fewer medications and incur lower drug costs compared with nonminorities.4-9 Therefore, as Wang and colleagues have found, minorities may be less likely to meet the Medicare MTM eligibility criteria.10 Furthermore, in a recent study, Wang and colleagues found that non-Hispanic blacks and Hispanics were less likely than non-Hispanic whites to report self-perceived good health status, and that there were greater racial and ethnic disparities among the MTM-ineligible than MTM-eligible beneficiary population before the implementation of Part D based on the 2006 and 2010 MTM eligibility criteria.11 This suggests that MTM eligibility criteria perpetuate the existing racial and ethnic disparities in health status. The purpose of this present study was to determine the effects of Part D implementation on the health implications of Medicare MTM eligibility across racial and ethnic groups. If this study found that Part D implementation was not associated with reductions in greater racial and ethnic disparities in the MTM-ineligible than the MTM-eligible individuals, the urgency for modifying MTM eligibility criteria would be even greater than established by the previous studies by Wang and colleagues.10,11

Methods We conducted a retrospective observational analysis using data from the Medicare Current Beneficiary Survey (MCBS; study periods 2001-2002, 2004-2005, and 2007-

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Key Points The implementation of Medicare Part D established criteria for medication therapy management (MTM) services eligibility to improve beneficiaries’ health outcomes. ➤ Previous researchers found that racial and ethnic minorities may be less likely to meet the MTM eligibility criteria than non-Hispanic whites. ➤ Previous studies reported greater racial and ethnic disparities in self-perceived health status among MTM-ineligible than MTM-eligible populations. ➤ This suggests that the MTM eligibility criteria may perpetuate existing racial and ethnic disparities in health status of Medicare beneficiaries. ➤ This study investigated the effects of Part D implementation on the health implications of Medicare MTM eligibility across racial and ethnic groups. ➤ The main analysis found that Part D implementation was not associated with reductions in greater racial and ethnic disparities among MTM-ineligible than MTM-eligible beneficiaries. ➤ However, several sensitivity analyses showed a significant reduction in greater racial disparities among the MTM-ineligible group than the MTMeligible group in activities of daily living and in instrumental activities of daily living. ➤ Eliminating racial and ethnic disparities in healthcare has become an essential step to improving the healthcare system. ➤ Future research should explore alternative MTM eligibility criteria that would be value-based. ➤

2008).12 The MCBS, which is sponsored by CMS, includes a nationwide sample of Medicare beneficiaries linked to patients’ Medicare claims.12 This continuous, multipurpose survey provides information on Medicare beneficiaries’ health status, healthcare utilizations, health insurance coverage, and socioeconomic and demographic characteristics.12 The Electronic Orange Book Query data files (Orange Book) from the US Food and Drug Administration (FDA) were used to determine characteristics specific to prescription medications.13 These files provide comprehensive information for both brand-name and generic medications. To examine racial and ethnic disparities, 3 major groups were included—non-Hispanic whites, non-Hispanic blacks, and Hispanics. Racial disparities were examined by comparing whites and blacks, and ethnic disparities were examined by comparing whites and Hispanics. To reduce the heterogeneity of the study pop-

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ulation, the sample included only home-dwelling Medicare beneficiaries who were eligible for Medicare based on their age. Beneficiaries in a health maintenance organization with a closed network were excluded from the analysis, because not all claims for these individuals were included in the databases.

Theoretical Framework Andersen’s Behavioral Model for Health Services Utilization and Iezzoni’s Risk Adjustment Model were applied in this study.14,15 According to Andersen’s model, independent variables that govern prescription and health services utilization and costs were categorized into 3 groups: predisposing factors (race, ethnicity, age, sex, and marital status), enabling factors (socioeconomic status, education, health insurance, and region of residence), and need factors (self-perceived health status and a risk adjustment summary score).14 Iezzoni’s Risk Adjustment Model was used to analyze health status by categorizing risk dimensions into sociodemographic variables and health status measures.15 Disparity Measures The 3 aspects of disparities that were analyzed include health status, health services utilization and costs, and medication utilization patterns. To identify disparities in health status, the following measures were used: self-perceived good health status (classified as good [excellent, very good, or good] or poor [fair or poor]), number of chronic conditions, number of activities of daily living (ADLs), and number of instrumental ADLs (IADLs). To identify chronic conditions, a raw count among a list of 25 chronic conditions was obtained using the Clinical Classifications Software (Rockville, MD).16 This list was devised by Daniel and Malone and includes all major conditions that were specifically targeted by Medicare Part D.17 Disparities in health services utilization and costs were measured by number and cost of emergency department visits, physician visits, hospitalizations, and total healthcare costs. Medication utilization patterns were based on the generic-dispensing ratio.11,18 The generic-dispensing ratio was defined as the proportion of generic prescriptions among total prescriptions.11,18 The MCBS was linked to the FDA’s Orange Book to determine if the medications prescribed were generic or brand-name agents. A pharmacist manually determined if any unmatched medications were generic agents. Determining MTM Eligibility To determine MTM eligibility, the 2010 CMS criteria were applied.19 MTM eligibility thresholds used by Part D plans in 2010 included 2 to 8 Part D drugs (median, 5), 2 to 3 chronic conditions (median, 3), and at least

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$3000 in drug costs. Upper, median, and lower limits were used as representative values for the eligibility thresholds used by Part D plans based on the number of Part D drugs and chronic conditions for each beneficiary.19 The median and upper limits were the same for chronic conditions, thus 1 main analysis and 5 sensitivity analyses were conducted (3*2*1, representing the number of representative values for the thresholds based on the number of Part D drugs, number of chronic conditions, and the only drug cost threshold; 6 in total). The main analysis examined the combination of median threshold values for the number of chronic conditions (3 conditions), the number of Part D drugs (5 drugs), and the $3000 drug cost thresholds, whereas the other 5 of the 6 combinations of those thresholds were calculated as sensitivity analyses. The drug cost was converted to the study year dollars using the Consumer Price Index for medical care.20

Statistical Analysis A generalized difference-in-differences (DD) model, a difference-in-differences-in-differences-in-differences (DDDD) model was used. Specifically, differences in patterns of racial and ethnic disparities between MTM-ineligible and MTM-eligible beneficiaries between 2004-2005 and 2007-2008, relative to the changes from 2001-2002 and 2004-2005, were compared and are described in the Figure. (For example, when examining racial disparities, disparities between non-Hispanic whites and blacks were referred to as “difference,” whereas DD represented difference in disparities between the MTM-ineligible and MTM-eligible populations. There were 3 DDs in this study, one for each of the time periods—2007-2008, 2004-2005, and 2001-2002. Difference in differences in differences [DDD] in this study refers to changes in racial disparities from one period to the next. Specifically, there were 2 DDDs, one representing changes in DD from 2004-2005 to 2007-2008, the other for changes in DD from 2001-2002 to 2004-2005. DDDD in this study represents the difference in these 2 DDDs.) Racial and ethnic disparities were analyzed separately in regression models (see Appendix at www.AHDB online.com). The functional forms of the regression models varied according to the types of dependent variables. For example, a logistic regression was used when analyzing self-perceived good health status and high-risk medication use. A negative binomial model was used for count variables, including ADLs, IADLs, number of emergency department visits, number of physician visits, and number of hospitalizations. A Poisson regression was used for the number of chronic diseases, because a negative bino-

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Figure Research Design Difference in differences

DDD

DDDD

Disparity patterns between whites and blacks in 2001-2002 Disparity patterns between whites and blacks in 2004-2005

MTM-ineligible

Study outcomes among whites

Study outcomes among blacks

MTM-eligible

Study outcomes among whites Study outcomes among blacks

Racial disparities

Difference in differences in differences

Difference in differences (disparities) Difference in differences in differences

Racial disparities

Difference in differences in differences in differences

Disparity patterns between whites and blacks in 2007-2008

NOTE: This figure used the 2004-2005 period to illustrate difference in differences (disparities) between individuals eligible for MTM services and those ineligible for MTM. DDD indicates difference in differences in differences; DDDD, difference in differences in differences in differences; MTM, medication therapy management.

mial model would not converge. A generalized linear model was analyzed using log link and gamma distribution on all cost variables. An ordinary least squares regression was used for the generic-dispensing ratio. The highest levels of differences (ie, DDDD) calculated in this study were carried out with a creative programming method using STATA (StataCorp LP, College Station, TX) that is based on the interpretative method on the additive term (also called marginal effect). This method takes into account only the baseline effect among the reference group.21 The complex sampling structure of MCBS, including primary sampling units, strata, and cross-sectional full sample weights, was accounted for in all data analyses using SAS 9.3 (SAS Institute Inc, Cary, NC) and STATA 12.0. This study was deemed exempt from further Institutional Review Board review at the lead author’s institution.

Results The 2001-2002 study sample included a total of 15,787 (weighted to 54,259,004) Medicare beneficiaries. The sample included 13,299 whites (weighted to 45,997,416 or 84.77%), 1408 non-Hispanic blacks (weighted to 4,489,293 or 8.27%), and 1080 Hispanics (weighted to 3,772,315 or 6.95%).

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Significant differences were noted between whites and minorities on several demographic characteristics (Table 1). In comparison to whites, minorities were less likely to be married, and were more likely to have lower levels of education, belong to poorer income categories, have Medicaid, and have reported poorer health status (P <.05). The 2004-2005 and 2007-2008 samples had similar characteristics. Based on unadjusted and adjusted multivariate regression models in the DDDD part of the analyses, the main analysis (representing the combination of 5 Part D drugs, 3 chronic conditions, and $3000 in drug costs) did not find any significant DDDD (Table 2, Panel 1). However, significant findings were seen in other levels of differences and in some variables’ sensitivity analyses. For example, the marginal effects were higher among whites than among blacks in the model (Table 3, Panel 1). In the DD part of the analysis, the difference was calculated for the differences between whites and blacks among the MTM-ineligible and the MTM- eligible beneficiaries. This study found significant differences for every individual time period in the unadjusted model for the self-perceived good health status, including 2001-2002 (difference in odds, 2.49; P <.001; 95% confidence interval [CI], 1.96-3.02); 2004-2005 (difference in odds, 2.51;

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Table 1 Sociodemographic Characteristics across Racial and Ethnic Groups in the Medicare Population, 2001-2002 Non-Hispanic Non-Hispanic Hispanics, Variables Groups whites, N (%) blacks, N (%) N (%) Age, yrsa

65-74

5787 (51.52)

635 (53.93)

536 (57.46)

75-84

5361 (37.00)

512 (33.45)

368 (31.17)

≥85

2151 (11.47)

261 (12.62)

176 (11.37)

Female

7563 (56.80)

867 (60.71)

634 (59.51)

Male

5736 (43.20)

541 (39.29)

446 (40.49)

Not married

5931 (42.06)

945 (65.11)

547 (47.48)

Married

7362 (57.94)

461 (34.89)

530 (52.52)

Lower than high school

3657 (30.91)

895 (64.78)

666 (66.04)

High school

4086 (38.12)

266 (22.31)

183 (19.91)

Higher than high school

3293 (30.97)

141 (12.91)

129 (14.05)

100% FPL

1272 (11.36)

528 (37.71)

367 (35.13)

100%-149% FPL

1949 (17.61)

328 (24.98)

253 (24.92)

150%-199% FPL

1621 (14.73)

175 (13.70)

134 (13.90)

200%-300% FPL

3045 (29.12)

184 (14.83)

161 (16.70)

>300% FPL

2704 (27.18)

89 (8.79)

84 (9.36)

12,291 (92.95)

885 (66.09)

654 (62.55)

Yes

1008 (7.05)

523 (33.91)

426 (37.45)

Northeast

2607 (20.51)

216 (18.21)

119 (16.32)

Midwest

3519 (26.44)

203 (15.51)

86 (10.42)

South

4876 (36.70)

896 (58.47)

338 (40.81)

West

2282 (16.34)

90 (7.81)

245 (32.45)

4395 (27.98)

405 (21.88)

154 (11.66)

Yes

8899 (72.02)

1002 (78.12)

926 (88.34)

Excellent

2189 (17.48)

142 (10.88)

137 (14.02)

Very good

3961 (30.58)

293 (22.91)

227 (21.80)

Good

4234 (31.68)

477 (33.38)

352 (33.25)

Fair

2095 (14.79)

372 (25.37)

280 (24.44)

Poor

750 (5.47)

120 (7.46)

79 (6.50)

Sex Marital statusa,b Education

a,b

Poverty status

a,b

Medicaid

a,b

US Census region

a,b

Metropolitan statistical area

Self-perceived health statusa,b

P <.05 for the difference between non-Hispanic whites and Hispanics. P <.05 for the difference between non-Hispanic whites and non-Hispanic blacks. FPL indicates federal poverty level. a

P <.001; 95% CI, 1.77-3.25); and 2007-2008 (difference in odds, 2.24; P <.001; 95% CI, 1.17-3.3). These results suggest that racial disparities may be greater among MTM-ineligible beneficiaries than among MTM-eligible beneficiaries. Similar patterns were found in the adjusted model (Table 2, Panel 1). Nonetheless, neither the difference-in-differences-indifferences (DDD) nor the DDDD part of the analyses revealed significant findings, which indicates that Part D was not associated with significant changes in pat-

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terns of disparities (DDDD in the unadjusted model = –0.30; P = .72; 95% CI, –1.97 to 1.37; DDDD in the adjusted model = –0.56; P = .63; 95% CI, –2.82 to 1.71). The sensitivity analyses for self-perceived good health status had similar findings. For a few variables, however, when examining racial disparities, some sensitivity analyses did produce significant findings for the DDDD part of the analysis, suggesting that Part D may be associated with significant changes in disparities in some situations. Specifically, in the

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September 2014

Vol 7, No 6

Effects of Part D on Disparity Implications of MTM Eligibility Criteria

Implications of MTM Eligibility Criteria across Table 2, Panel 1 Unadjusted and Adjusted Estimates of Part D Effect on Health Groups, based on 2010 Eligibility Criteria: Main Analysisa Outcomes

2001-2002 (DD)b

2004-2005

(DD)b

2007-2008 (DD)b

2001-2002 vs 2004-2005

2007-2008 vs 2004-2005

(DDD)c

Part D effect (DDDD)d –0.30

(DDD)c

Health status Self-perceived good health status

Unadjusted

2.49e

2.51e

2.24e

Adjusted

2.26

Chronic diseases, N

Unadjusted

–0.26

Adjusted Activities of daily living, N Instrumental activities of daily living, N

–0.02

–0.28

2.37

1.92

–0.10

–0.45

–0.56

–0.19

–0.14

–0.07

0.05

–0.02

–0.25

–0.17

–0.22

–0.08

–0.05

–0.12

Unadjusted

–0.14

–0.05

0.22

–0.09

0.27

0.18

Adjusted

–0.14

0.63

–0.001

0.77

0.76

Unadjusted

–0.15

–0.04

0.27

–0.10

0.31

0.21

Adjusted

–0.17

–0.06

0.58e

–0.11

0.64

0.53

–0.18

–0.07

–0.25

Health services utilization/costs Emergency department visits, N

Unadjusted

–0.04

0.14e

0.07

Adjusted

–0.03

0.09

0.13

–0.12

0.04

–0.08

Emergency department cost, $

Unadjusted

–13.95

31.61

21.11

–45.56

–10.50

–56.06

Adjusted

–35.77

–25.53

93.77

–10.24

119.31

109.06

Physician visits, N

Unadjusted

–4.28

–1.90

0.04

–2.38

1.95

–0.43

Adjusted

–6.27

–0.83

–3.82

–5.44

–2.99

–8.43

Cost of physician visits, $

Unadjusted

–48.08

–725.43

510.70

677.35

1236.13

1913.47

Adjusted

–125.77

–738.56

–736.69

612.80

1.87

614.67

Hospitalizations, N

Unadjusted

–0.08

–0.09

–0.003

0.002

0.08

0.09

Adjusted

–0.07

–0.11

–0.05

0.03

0.06

0.09

Unadjusted

–901.71

–918.14

–792.26

16.43

125.89

142.32

Adjusted

–891.81

–598.73

–975.07

–293.08

–376.34

–669.42

Unadjusted

–1462.66

–2793.35

164.90

1330.69

2958.25

4288.93

Adjusted

–1485.44

–2190.91

–905.71

705.47

1285.20

1990.67

–0.01

0.02

0.03

–0.03

0.01

–0.01

0.02

0.05

–0.04

0.02

–0.01

Hospitalization cost, $ Total cost, $ Medication utilization

Generic-dispensing ratio Unadjusted Adjusted

Eligibility thresholds examined 5 Part D drugs, 3 chronic conditions, and $3000 in drug costs. DD (Difference in differences [disparities]) = (MTM-ineligible whites – MTM-ineligible blacks) – (MTM-eligible whites – MTMeligible blacks). c DDD (Difference in differences in differences [disparities]) = DD for (2007-2008) – DD for (2004-2005) or DD for (2004-2005) – DD for (2004-2005) – DD for (2001-2002). d DDDD (Difference in differences in differences in differences [disparities]) = DDD for ([2007-2008] vs [2004-2005]) – DDD for ([2004-2005] vs [2001-2002]). e P <.05. DD indicates difference in differences; DDD, difference in differences in differences; DDDD, difference in differences in differences in differences; MTM, medication therapy management. a

analysis of ADLs, only sensitivity analysis 5 (thresholds of ≥8 drugs, ≥2 chronic conditions, and >$3000 in drug costs) produced a significant DDDD estimate of 1.13 in the adjusted model (P = .03; 95% CI, 0.09-2.17).

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The interpretation of this estimate requires an examination of all levels of differences involved. The marginal effects were typically lower among whites than blacks (Table 3, Panel 1). The same patterns predominantly

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ifferences between Non-Hispanic Whites and Non-Hispanic Blacks, Measured by Marginal Effects Table 3, Panel 1 D for Select Variables and Analyses 95% Differences between MTM Marginal Standard confidence non-Hispanic whites Time period eligibility Group effect error interval & blacks Self-perceived health status (unadjusted main analysis) 2001-2002

Ineligible Eligible

2004-2005

Ineligible Eligible

2007-2008

Ineligible Eligible

Whites

5.12

0.19

4.76-5.49

Blacks

2.28

0.18

1.92-2.64

Whites

1.53

0.07

1.39-1.66

Blacks

1.17

0.19

0.80-1.54

Whites

5.86

0.22

5.43-6.28

Blacks

2.61

0.25

2.11-3.11

Whites

1.81

0.08

1.66-1.97

Blacks

1.08

0.16

0.77-1.39

Whites

6.47

0.27

5.94-7.01

Blacks

3.53

0.43

2.69-4.38

Whites

1.71

0.08

1.56-1.87

Blacks

1.01

0.18

0.66-1.36

Whites

0.56

0.02

0.52-0.59

Blacks

0.88

0.07

0.73-1.02

Whites

1.44

0.07

1.30-1.58

Blacks

1.74

0.22

1.30-2.18

Whites

0.48

0.02

0.44-0.51

Blacks

0.76

0.06

0.64-0.88

Whites

1.32

0.06

1.21-1.43

Blacks

1.29

0.18

0.93-1.65

Whites

0.44

0.02

0.40-0.49

Blacks

0.61

0.05

0.51-0.71

Whites

1.16

0.06

1.04-1.27

Blacks

1.85

0.30

1.26-2.45

2.84

0.36

3.24

0.73

2.94

0.71

Activities of daily living (adjusted sensitivity analysis 5) 2001-2002

Ineligible Eligible

2004-2005

Ineligible Eligible

2007-2008

Ineligible Eligible

–0.32

–0.30

–0.28

0.02

–0.16

–0.70

Instrumental activities of daily living (adjusted sensitivity analysis 4) 2001-2002

Ineligible Eligible

2004-2005

Ineligible Eligible

2007-2008

Ineligible Eligible

Whites

0.48

0.01

0.45-0.50

Blacks

0.71

0.05

0.60-0.81

Whites

0.94

0.04

0.86-1.02

Blacks

1.05

0.14

0.78-1.32

Whites

0.63

0.02

0.60-0.67

Blacks

1.00

0.07

0.87-1.13

Whites

1.64

0.06

1.53-1.76

Blacks

1.66

0.18

1.30-2.02

Whites

0.61

0.02

0.57-0.64

Blacks

0.84

0.07

0.70-0.97

Whites

1.40

0.06

1.27-1.52

Blacks

1.99

0.25

1.51-2.47

–0.23

–0.11

–0.37

–0.02

–0.23

–0.60

MTM indicates medication therapy management.

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Vol 7, No 6

Effects of Part D on Disparity Implications of MTM Eligibility Criteria

nadjusted and Adjusted Estimates of Part D Effect on Health Implications of MTM-Eligibility Criteria across Table 2, Panel 2 U Ethnic Groups, based on 2010 Eligibility Criteria (Main Analysis)a 2001-2002

2004-2005

2007-2008

2001-2002 vs 2004-2005

2004-2005 vs 2007-2008

(DDD)c

Part D effect (DDDD)d

Unadjusted

2.06e

1.95e

3.13e

0.10

1.18

1.29

Adjusted

1.85

1.77

2.83

0.08

1.06

1.14

Unadjusted

0.26

0.07

0.29

0.19

0.22

0.40

Adjusted

0.24

0.03

0.26

0.21

0.23

0.44

Unadjusted

0.26

–0.04

–0.02

0.30

0.02

0.31

Adjusted

0.30

–0.21

–0.08

0.51

–0.13

0.64

Unadjusted

0.34

0.08

0.05

0.26

–0.03

0.23

Adjusted

0.28

–0.06

0.07

0.34

0.13

0.47

Unadjusted

–0.002

0.06

0.01

–0.07

–0.05

–0.12

Adjusted

–0.05

0.04

0.02

–0.09

–0.02

0.10

Unadjusted

–22.48

–11.79

–15.07

–10.69

–3.28

–13.97

Adjusted

–65.23

–61.86

–32.59

–3.37

29.27

25.89

Unadjusted

–3.85

4.57

9.70e

–8.43

5.13

–3.30

Adjusted

–1.04

5.97

4.43

–7.01

–1.54

–8.54

Unadjusted

–946.22

1793.64

–136.80

–2739.87

–1930.45

–4670.31

Adjusted

–834.08

2311.65

320.71

–3145.73

–1990.94

–5136.67

Unadjusted

–0.16

0.03

0.02

–0.19

–0.01

–0.20

Adjusted

–0.23

–0.003

0.01

–0.22

0.01

–0.21

Unadjusted

–498.20

453.10

762.66

–951.31

309.55

–641.76

Adjusted

–1756.59

–135.06

–445.20

–1621.53

–310.14

–1931.67

Unadjusted

–1309.96

2369.43

3150.54

–3679.38

781.11

–2898.27

Adjusted

–2198.01

2821.89

2172.83

–5019.90

–649.06

–5658.95

Unadjusted

–0.001

–0.002

0.02

0.001

0.03

Adjusted

0.001

0.0003

0.03

0.0003

0.03

Outcomes

(DD)b

(DDD)c

Health status Self-perceived good health status Chronic diseases, N Activities of daily living Instrumental activities of daily living

Health services utilization/costs Emergency department visits, N Emergency department cost, $ Physician visits, N Cost of physician visits, $ Hospitalizations, N Hospitalization cost, $ Total costs, $

Medication utilization Generic dispensing ratio

Eligibility thresholds examined 5 Part D drugs, 3 chronic conditions, and $3000 in drug costs. DD (Difference in differences) = (MTM-ineligible whites – MTM-ineligible blacks) – (MTM-eligible whites – MTM-eligible blacks). c DDD (Difference in differences in differences) = DD for (2007-2008) – DD for (2004-2005) or DD for (2004-2005) – DD for (2004-2005) – DD for (2001-2002). d DDDD (Difference in differences in differences in differences) = DDD for ([2007-2008] vs [2004-2005]) – DDD for ([2004-2005] vs [2001-2002]). e P <.05. DD indicates difference in differences; DDD, difference in differences in differences; DDDD, difference in differences in differences in differences; MTM, medication therapy management. a

held for 2004-2005 and 2007-2008 (Table 3, Panel 1). The DD between the MTM-ineligible group and the MTM-eligible group was –0.02 (P = .94) for 2001-2002; –0.31 for 2004-2005 (P = .09); and 0.54 (P = .09) for 2007-2008, suggesting there may not be significant difference in the abovementioned disparity patterns be-

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tween the MTM-ineligible and MTM-eligible groups for any time periods examined. Furthermore, the DDD was found to be –0.29 (P = .36) for 2004-2005 versus 2001-2002 and 0.84 (P = .01) for 2007-2008 versus 2004-2005, indicating that there may be a decrease in the greater racial disparity among the

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Table 3, Panel 2 Differences between Non-Hispanic Whites and Hispanics, Measured by Marginal Effects on Non-Hispanic Whites and Hispanics for Select Variables and Analyses 95% Differences between MTM Marginal Standard confidence non-Hispanic whites Time period eligibility Group effect error interval & Hispanics Self-perceived good health status (unadjusted main analysis) 2001-2002

Ineligible Eligible

2004-2005

Ineligible Eligible

2007-2008

Ineligible Eligible

Whites

5.12

0.19

4.76-5.49

Hispanics

2.53

0.21

2.11-2.95

Whites

1.53

0.07

1.39-1.66

Hispanics

0.99

0.17

0.65-1.32

Whites

5.86

0.22

5.43-6.28

Hispanics

3.12

0.37

2.39-3.85

Whites

1.81

0.08

1.66-1.97

Hispanics

1.02

0.18

0.67-1.38

Whites

6.47

0.27

5.94-7.01

Hispanics

2.84

0.37

2.13-3.56

Whites

1.71

0.08

1.56-1.87

Hispanics

1.22

0.24

0.74-1.70

Whites

2177.49

60.36

2059.19-2295.79

Hispanics

2553.77

611.89

1354.49-3753.05

Whites

4747.57

183.95

4387.02-5108.11

Hispanics

4058.99

415.98

3243.69-4874.29

Whites

2716.63

81.63

2556.65-2876.62

Hispanics

2213.53

128.99

1960.71-2466.35

Whites

5507.98

283.04

4953.24-6062.72

Hispanics

6914.15

983.19

4987.14-8841.16

Whites

2985.01

137.39

2715.73-3254.29

Hispanics

1897.42

195.87

1513.52-2281.32

Whites

6184.31

236.85

5720.10-6648.52

Hispanics

5366.42

452.90

4478.75-6254.08

2.60

0.54

2.74

0.79

3.63

0.50

Costs of physician visits (adjusted sensitivity analysis 1) 2001-2002

Ineligible Eligible

2004-2005

Ineligible Eligible

2007-2008

Ineligible Eligible

–376.28

688.58

503.10

–1406.17

1087.59

817.90

MTM indicates medication therapy management.

MTM-ineligible than in the MTM-eligible populations when comparing 2007-2008 and 2004-2005, but there may not be significant changes when comparing 20012002 and 2004-2005. These findings, combined with the significant DDDD value of 1.13, suggest that Part D implementation may be associated with a decrease in any racial disparities in ADLs among the MTM-ineligible group versus the MTM-eligible group using the combinations of eligibility thresholds for sensitivity analysis 5. For the variable IADLs, the same patterns as ADLs were found in sensi-

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tivity analysis 4 (for thresholds of ≥8 drugs, ≥3 chronic conditions, and >$3000 in drug costs) and sensitivity analysis 5. This suggests that Part D implementation may be also associated with a greater decrease in any racial disparities in IADLs among the MTM-ineligible group than among the MTM-eligible group. With regard to racial disparities, no other variables were found to be associated with significant results in the DDDD part of the analysis. Concerning the comparison between whites and Hispanics, the main analysis did not find significant DDDD

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Vol 7, No 6

Effects of Part D on Disparity Implications of MTM Eligibility Criteria

for any variable (Table 2, Panel 2). However, the analy sis of costs of physician visits did show significant findings for some sensitivity analyses. For costs of physician visits, the DDDD was found to be significant in the adjusted models for sensitivity analysis 1 (thresholds of ≥2 drugs, ≥2 chronic conditions, and >$3000 in drug costs) and analysis 3 (thresholds of ≥5 drugs, ≥2 chronic conditions, and >$3000 in drug costs). The DDDD estimate was –4613.71 (P = .04; 95% CI, –8907.29 to –320.13) for sensitivity analysis 1. The marginal effects were quantitatively higher among whites than among Hispanics under most situations, although the CIs did not overlap for the MTM-ineligible groups in 2004-2005 and in 2007-2008 (Table 3, Panel 2). The DD estimates were –1064.86 (P = .17) for 2001-2002; 1909.27 (P = .06) for 2004-2005; and 269.69 (P = .63) for 2007-2008, suggesting that disparities between whites and Hispanics were similar between MTM-ineligible and MTM-eligible populations for all time periods. The DDD values were 2974.13 (P = .02) when comparing 2004-2005 and 2001-2002, and –1639.58 when comparing 2007-2008 and 2004-2005 (P = .15). When combined with the DDDD value of –4613.71 (P = .04), these findings suggest that Part D implementation was associated with a reduction in greater ethnic disparities in the costs of physician visits for the MTM-ineligible than for the MTM-eligible groups. Sensitivity analysis 3 had similar results, showing a DDDD estimate of –5094.36 (P = .03). No other variables were found to be associated with significant findings in the DDDD part of the analysis.

Discussion This study sought to determine the effects of Part D implementation, based on the 2010 MTM eligibility criteria, on differences in racial and ethnic disparities in health status, health services utilization and costs, and medication utilization between the MTM-ineligible group and the MTM-eligible group. Although several sensitivity analyses for a few variables showed significant association between Part D implementation and MTM disparities, the results of the main analysis did not show a significant association between Part D implementation and MTM disparities. This suggests that after Part D implementation, the Medicare MTM eligibility criteria did not mitigate the majority of variables related to existing racial and ethnic disparities in health status, health services utilization and costs, and medication utilization. However, it is important to note that in some situations, Part D did correlate with a significant reduction in racial disparities, specifically among the MTM-ineligible

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l September 2014

group versus the MTM-eligible groups in relation to ADLs (sensitivity analysis 5) and IADLs (sensitivity analyses 4 and 5). Furthermore, Part D implementation also may be associated with a greater reduction in ethnic disparities, if any, among the MTM-ineligible group versus the MTM-eligible groups in the costs of physician visits (sensitivity analyses 1 and 3). However, these findings are not comforting, because the combinations of the thresholds in the sensitivity analyses were used by Part D plans less frequently than the combination of the thresholds in the main analysis.

This suggests that after Part D implementation, the Medicare MTM eligibility criteria did not mitigate the majority of variables related to existing racial and ethnic disparities in health status, health services utilization and costs, and medication utilization. These findings are not surprising. Previous literature has reported that Part D implementation led to higher medication utilization, but also had mixed effects on patient health status and the use of healthcare resources other than prescription medications.22-24 In addition, Part D has been found to have mixed effects on racial and ethnic disparities in prescription utilization.25,26 This present study did reveal significant differences in several variables. For example, the self-perceived health status measured by marginal effects was higher among non-Hispanic whites than among non-Hispanic blacks and Hispanics. In addition, this study found that there were greater disparities in self-perceived good health status in MTM-ineligible than in the MTM-eligible population. Both results are consistent with previous research.11 The reasons for the absence of consistent and significant effects of Part D implementation on racial and ethnic disparities may be complex. For example, various barriers hinder appropriate medication utilization among minorities, including patients’ lack of accurate knowledge about medications. Omojasola and colleagues found that blacks and Hispanics were 10 times as likely as whites to believe that generic drugs had more side effects.27 Blacks and Hispanics were also 4 times as likely to agree that generic drugs were inferior to brand-name drugs when compared with their white counterparts. However, respondents who found generic drugs comparable with brand-name drugs were 3 times more likely to

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use generic drug discount programs.27 The negative perceptions regarding generic drugs among minority patients likely prevent these patients from enjoying the benefits of generic prescriptions, such as decreased total out-of-pocket expenses and a reduction of cost-related barriers to medication adherence. One additional cause for the limited effects of Part D may be that blacks and Hispanics are more likely to have lower income and education levels and poorer health status, which are associated with problems related to healthcare coverage and access.28,29 Socioeconomic status is a particularly serious challenge to reducing racial and ethnic disparities in health outcomes and can also hinder the potential benefits of MTM services. For example, Cook and colleagues assessed patient behaviors after MTM services and found that poverty status was associated with participants taking less action after a medication review, even after adjusting for factors such as insurance.30 Therefore, even if MTM services are available to eligible minorities, socioeconomic factors have a substantial impact on whether health disparity patterns improve as a result of these services. Reducing disparity implications of MTM services, therefore, may have to take a multipronged approach.

Prioritization of value-based healthcare (where costs and benefits are balanced) rather than cost-based healthcare represents a key strategy in combating racial and ethnic disparities. This study is important also because eliminating racial and ethnic disparities in healthcare has become an essential step to improving the healthcare system. Since the first report about racial and ethnic disparities was issued in the 1980s,31 bridging the gap between minorities and nonminorities has become a primary goal of government agencies, such as the US Department of Health and Human Services (HHS).32 The HHS initiative Healthy People 2010/2020 set the elimination of disparities as one of its goals.33 In addition, the National Institute on Minority Health and Health Disparities pursues the mission “to lead scientific research to improve minority health and eliminate health disparities.”34 Its research aims for an “America in which all populations will have an equal opportunity to live long, healthy, and productive lives.”34 Prioritization of value-based healthcare (where costs and benefits are balanced) rather than cost-based healthcare represents a key strategy in combating racial and ethnic disparities. Given the same health status, minori-

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ties tend to use fewer prescription medications and incur lower drug costs than do whites, and thus are less likely to be eligible for MTM services.10 According to Porter, within a value-based system, good health is ultimately less costly than poor health, so the best way to contain cost may be to improve the health of the population.35 Future research should explore alternative MTM eligibility criteria that would be value-based.

Limitations This study has limitations. Because of the unavailability to the research community of MTM claims databases suitable for this study, the analyses conducted were based on policy scenarios rather than on actual beneficiary enrollment data for MTM services. Similarly, disparities in MTM eligibility were examined rather than actual receipt of services. However, it is necessary to examine eligibility criteria to ensure that awareness is raised among policymakers regarding the disparity effects of these criteria. In addition, the main analysis did not show significant differences; however, several scenarios in the sensitivity analyses did find that the Part D implementation was associated with significant reduction in greater racial and ethnic disparities among the MTM-ineligible population compared with the MTM-eligible population in measures of health status, health services utilization and services, and medication utilization patterns. Furthermore, the categorization of the study sample into 3 racial and ethnic groups may not accurately reflect variation in biology, culture, or preferences, although data from the MCBS have been considered authoritative for the reported information on race and ethnicity when compared with other databases.4,36,37 Conclusion The results of this study indicate that the greater racial and ethnic disparities seen among the Medicare MTM-ineligible population than the MTM-eligible population in measures related to health status, health services utilization and services, and medication utilization patterns may not have been significantly reduced after the implementation of Medicare Part D. These results highlight a need for the US healthcare system to develop strategies to address these health inequalities and/or gaps between nonminority and minority Medicare beneficiaries to improve the health of the population. Future studies should explore strategies to eliminate the disparity implications related to the MTM eligibility as reflected in health status, health services utilizations and costs, and medication utilization patterns. n

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Effects of Part D on Disparity Implications of MTM Eligibility Criteria

Acknowledgments The authors would like to acknowledge the research assistance from Kiraat D. Munshi, MS, Caroline Clark, and Yuewen Deng. Funding Source This study was funded by grant R01AG040146 from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. Author Disclosure Statement Dr Wang has received grant support from Pfizer Inc. and from Eli Lilly and Company; Dr Dagogo-Jack has received research support from AstraZeneca, Novo Nordisk, and Boehringer-Ingelheim, and is a consultant to Merck, Novo Nordisk, and Eli Lilly and Company; Dr Cushman has received an institutional research grant from Merck and from Eli Lilly and Company; Ms Qiao, Dr Shih, Ms Jamison, Dr Spivey, Dr Li, Dr Wan, Dr White-Means, and Dr Chisholm-Burns reported no real or potential conflicts of interest.

References

1. Centers for Medicare & Medicaid Services (CMS), HHS. Medicare program; Medicare prescription drug benefit. Final rule. Fed Regist. 2005;70:4193-4585. 2. American Pharmacists Association, National Association of Chain Drug Stores Foundation. Medication Therapy Management in community pharmacy practice: core elements of an MTM service (version 1.0). J Am Pharm Assoc (2003). 2005;45: 573-579. 3. Centers for Medicare & Medicaid Services. 2011 Medicare Part D Medication Therapy Management (MTM) programs. June 30, 2011. www.cms.gov/Medicare/ Prescription-Drug-Coverage/PrescriptionDrugCovContra/downloads/mtmfactsheet 2011063011final.pdf. Accessed July 6, 2014. 4. Briesacher B, Limcangco R, Gaskin D. Racial and ethnic disparities in prescription coverage and medication use. Health Care Financ Rev. Winter 2003-2004;25:63-76. 5. Schore J, Brown R, Lavin B. Racial disparities in prescription drug use among dually eligible beneficiaries. Health Care Financ Rev. Winter 2003-2004;25:77-90. 6. Wang J, Noel JM, Zuckerman IH, et al. Disparities in access to essential new prescription drugs between non-Hispanic whites, non-Hispanic blacks, and Hispanic whites. Med Care Res Rev. 2006;63:742-763. 7. Wang J, Dong Z, Hong SH, Suda KJ. A comparison of direct medical costs across racial and ethnic groups among children with cancer. Curr Med Res Opin. 2008;24: 847-858. 8. Wang J, White-Means SI, Hufstader MA, Walker GD. The economic implications of the racial and ethnic disparities in the use of selective serotonin reuptake inhibitors. Curr Med Res Opin. 2007;23:853-863. 9. Wang J, Zuckerman IH, Miller NA, et al. Utilizing new prescription drugs: disparities among non-Hispanic whites, non-Hispanic blacks, and Hispanic whites. Health Serv Res. 2007;42:1499-1519. 10. Wang J, Mullins CD, Brown LM, et al. Disparity implications of Medicare eligibility criteria for medication therapy management services. Health Serv Res. 2010;45: 1061-1082. 11. Wang J, Qiao Y, Tina Shih YC, et al. Potential health implications of racial and

ethnic disparities in meeting MTM eligibility criteria. Res Social Adm Pharm. 2014; 10:106-125. 12. Centers for Medicare & Medicaid Services. Medicare Current Beneficiary Survey (MCBS). Updated July 24, 2014. www.cms.gov/Research-Statistics-Data-and-Systems/ Research/MCBS/index.html?redirect=/mcbs/. Accessed July 24, 2014. 13. US Food and Drug Administration. Orange Book data files. Updated July 18, 2014. www.fda.gov/drugs/informationondrugs/ucm129689.htm. Accessed July 24, 2014. 14. Andersen RM, Rice TH, Kominski GF, eds. Changing the U.S. Health Care System: Key Issues in Health Services Policy and Management. 3rd ed. San Francisco, CA: Jossey-Bass; 2007. 15. Iezzoni LI, ed. Risk Adjustment for Measuring Healthcare Outcomes. 2nd ed. Chicago, IL: Health Administration Press; 1997. 16. Agency for Healthcare Research and Quality. Clinical Classifications Software (CCS) for ICD-9-CM. July 2014. Updated July 29, 2014. www.hcup-us.ahrq.gov/ toolssoftware/ccs/ccsfactsheet.jsp. Accessed July 6, 2014. 17. Daniel GW, Malone DC. Characteristics of older adults who meet the annual prescription drug expenditure threshold for Medicare medication therapy management programs. J Manag Care Pharm. 2007;13:142-154. 18. Pharmacy Quality Alliance. PQA performance measures. http://pqaalliance.org/ measures/default.asp. Accessed July 6, 2014. 19. Centers for Medicare & Medicaid Services. 2010 Medicare Part D Medication Therapy Management (MTM) programs. June 8, 2010. www.cms.gov/Medicare/ Prescription-Drug-Coverage/PrescriptionDrugCovContra/downloads/MTMFact Sheet_2010_06-2010_final.pdf. Accessed July 6, 2014. 20. Bureau of Labor Statistics. Consumer Price Index. www.bls.gov/cpi/. Accessed July 6, 2014. 21. Buis ML. Stata tip 87: interpretation of interactions in nonlinear models. Stata J. 2010;10:305-308. 22. Liu FX, Alexander GC, Crawford SY, et al. The impact of Medicare Part D on out-of-pocket costs for prescription drugs, medication utilization, health resource utilization, and preference-based health utility. Health Serv Res. 2011;46:1104-1123. 23. Afendulis CC, He Y, Zaslavsky AM, et al. The impact of Medicare Part D on hospitalization rates. Health Serv Res. 2011;46:1022-1038. 24. Kaestner R, Khan N. Medicare Part D and its effect on the use of prescription drugs, use of other health care services and health of the elderly. The National Bureau of Economic Research Working Paper. www.nber.org/papers/w16011. Accessed September 5, 2014. 25. Chen J, Rizzo JA, Ortega AN. Racial and ethnic differences in drug expenditures and access under Medicare Part D. J Health Care Poor Underserved. 2011;22:1059-1074. 26. Mahmoudi E, Jensen GA. Has Medicare Part D reduced racial/ethnic disparities in prescription drug use and spending? Health Serv Res. 2014;49:502-525. 27. Omojasola A, Hernandez M, Sansgiry S, Jones L. Perception of generic prescription drugs and utilization of generic drug discount programs. Ethn Dis. 2012;22:479-485. 28. Shi L. Vulnerable populations and health insurance. Med Care Res Rev. 2000;57: 110-134. 29. Trivedi AN, Zaslavsky AM, Schneider EC, Ayanian JZ. Relationship between quality of care and racial disparities in Medicare health plans. JAMA. 2006;296:1998-2004. 30. Cook DM, Moulton PV, Sacks TM, Yang W. Self-reported responses to medication therapy management services for older adults: analysis of a 5-year program. Res Social Adm Pharm. 2012;8:217-227. 31. Heckler MM. Report of the Secretaryâ&#x20AC;&#x2122;s Task Force on Black and Minority Health, Department of Health and Human Services, 1985. http://minorityhealth. hhs.gov/assets/pdf/checked/1/ANDERSON.pdf. Accessed September 5, 2014. 32. US Department of Health and Human Services. HHS action plan to reduce racial and ethnic health disparities: a nation free of disparities in health and health care. http://minorityhealth.hhs.gov/npa/files/Plans/HHS/HHS_Plan_complete.pdf. Accessed July 6, 2014. 33. Koh HK. A 2020 vision for healthy people. N Engl J Med. 2010;362:1653-1656. 34. National Institute on Minority Health and Health Disparities. About NIMHD: vision & mission. www.nimhd.nih.gov/about/visionMission.html. Accessed July 6, 2014. 35. Porter ME. A strategy for health care reformâ&#x20AC;&#x201D;toward a value-based system. N Engl J Med. 2009;361:109-112. 36. LaVeist TA. Beyond dummy variables and sample selection: what health services researchers ought to know about race as a variable. Health Serv Res. 1994;29:1-16. 37. Waldo DR. Accuracy and bias of race/ethnicity codes in the Medicare enrollment database. Health Care Financ Rev. Winter 2004-2005;26:61-72.

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Stakeholder Perspective Medication Therapy Management, Medicare, and Disparities in Population Health By Dima M. Qato, PharmD, MPH, PhD Assistant Professor, Department of Pharmacy Systems, Outcomes, and Policy, University of Illinois College of Pharmacy, Chicago

acial and ethnic disparities in health and healthcare among older adults, including Medicare beneficiaries, have been long-standing public health concerns in the United States. The study by Wang and colleagues in this issue of the journal is yet another reminder that the current Medicare program, specifically Medicare Part D, needs to better prioritize the unmet healthcare needs of minority populations. PATIENTS: The findings in the study by Wang and colleagues have important health implications for minority patients, particularly black and Hispanic Medicare beneficiaries with Part D coverage. Black and Hispanic patients are more likely than nonminority patients to underuse prescription medications, which are often critical for improving their health. Consequently, they are also less likely to qualify for or to meet the eligibility criteria for medication therapy management (MTM), which is largely based on the number, types, and costs of medications prescribed. MTM programs have important health benefits and are often associated with improved medication adherence and health outcomes. Therefore, as the results of this study suggest, current Medicare Part D MTM programs may be perpetuating existing disparities in health status, considering that nonminority patients are more likely to be eligible for and to benefit from these programs. The current Medicare Part D MTM program requirements ignore the problem of the persistent underuse of prescription medications among chronically ill minority patients with Medicare coverage. POLICYMAKERS: This study has important implications for Medicare policy and reiterates that Medicare programs, such as MTM, should focus more on improving population health. Programs such as Medicare Part D

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need to target the unmet health and healthcare needs of the minority Medicare population. The current MTM program structure is poorly designed, because it disproportionately excludes the patients who are most at risk for poor health outcomesâ&#x20AC;&#x201D;low-income minority Medicare beneficiaries with multiple chronic conditions who are prescribed multiple medications but are often not using them. These are the patients who are less likely to adhere to prescription medications and the most likely to benefit from an MTM program. Alongside health reform efforts to improve population health and reduce health disparities through the provision of population-based healthcare, Medicare Part D should also adopt a similar mechanism in identifying MTM-eligible Medicare enrollees. Such an alternative strategy should be designed to target patients and not numbers; the number of prescription medications (from a predetermined list of eligible medications) is currently a criterion for MTM eligibility. For example, all Medicare beneficiaries with specific chronic conditions for which medications are critical in improving health outcomes should be eligible. Targeting patients with conditions that are major contributors to health disparities (eg, hypertension, diabetes, and cardiovascular disease) should also be prioritized. This population-based approach may not only improve health outcomes for minority patients but may also get us closer to reducing the gap in health outcomes between minority and nonminority older adults. Ultimately, efforts to reduce disparities in population health, whether through the implementation of MTM or the reduction of the costs of prescription medications, will result in considerable cost-savings to the US healthcare system. n

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REFERENCES: 1. Chambers SA, Allen E, Rahman A, Isenberg D. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford). 2009;48(6):673-675. 2. Urowitz MB, Gladman DD, Ibañez D, et al. Evolution of disease burden over five years in a multicenter inception systemic lupus erythematosus cohort. Arthritis Care Res (Hoboken). 2012;64(1):132-137. 3. Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford). 2012;51(3):491-498. ©2014 GSK group of companies. All rights reserved. Printed in USA. BN2670R0 April 2014