May 2008, Vol 1, No 4

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ MAY 2008

VOLUME 1, NUMBER 4

EDITORIAL

Avoiding the Unthinkable: A Tale of 2 Triangles and the Process of Care They Govern Robert E. Henry

The Unbearable Lightness of Mental Health Alberto Colombi, MD, MPH CLINICAL

Schizophrenia: Current Concepts and Approaches to Patient Care ™

Peter F. Buckley, MD; Adriana Foster, MD BUSINESS

Trends in Pharmaceutical Expenditures: The Impact on Drug Benefit Design Joanne LaFleur, PharmD, MSPH; Leslie Fish, PharmD; Diana I. Brixner, RPh, PhD REGULATORY

Medicare Coverage for Erythropoiesis-Stimulating Agents: The Perfect Storm Interview (Part 1) with Samuel M. Silver, MD, PhD DEPARTMENTS

Generic Drug Trends AACR Meeting Highlights FDA Watch Industry Trends

©2008 Engage Healthcare Communications, LLC www.AHDBonline.com

CPAGE R AOMVE C

Help patients in your plan benefit from always-there patient care Indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes.

Important Safety Information Boxed Warning: Congestive Heart Failure • Thiazolidinediones (TZDs), including ACTOS, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of ACTOS and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered.1 • ACTOS is not recommended in patients with symptomatic heart failure.

Initiation of ACTOS in patients with established NYHA Class III or IV heart failure is contraindicated.1 Cardiac considerations: Like other TZDs, ACTOS can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate CHF. ACTOS should be used with caution in patients at risk for heart failure. Patients should be monitored for symptoms of heart failure or other adverse events related to fluid retention. In clinical trials, a small number of patients with a history of previously existing cardiac disease were reported to develop CHF when treated with ACTOS in combination with insulin. Reports of CHF have been received in postmarketing experience in patients with and without previously known heart disease.1 Hepatic safety: Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal (ULN) have been received in postmarketing experience with pioglitazone. Very rarely, these reports have involved hepatic failure with or without fatal outcome, although causality has not been established. Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with ACTOS, and periodically thereafter per the clinical judgment of the healthcare professional. If ALT >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with ACTOS.1 Other considerations: ACTOS may also be associated with hypoglycemia, edema, anemia, weight gain, and/or ovulation in premenopausal, anovulatory women. Adequate contraception should be recommended for premenopausal women. Macular edema has been reported in some diabetic patients receiving TZD therapy, although a causal relationship is unknown. Persons with diabetes should have routine eye exams and be instructed to immediately report any visual changes to their healthcare provider. An increased incidence of bone fracture was noted in female patients taking ACTOS. The risk of fracture should be considered in the care of patients treated with ACTOS, particularly females, and attention should be given to assessing and maintaining bone health according to current standards of care.1 Well-tolerated therapy: In US placebo-controlled ACTOS monotherapy clinical trials, the most common adverse events (e5%) were upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus, and pharyngitis.1 Indications and usage: ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. ACTOS is approved for use as monotherapy and in combination with sulfonylureas, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control.1 • ACTOS should not be used in patients with type 1 diabetes. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.1 • The major metabolic defects in type 2 diabetes are peripheral insulin resistance in muscle and fat, decreased pancreatic insulin secretion, and increased hepatic glucose output.2 Dyslipidemia in insulin resistance is represented by hypertriglyceridemia, decreased HDL levels, and increased small dense LDL particles.3 Renal and gastrointestinal function are also clinical considerations when prescribing an oral agent for type 2 diabetes.4 Please see Brief Summary of Prescribing Information on adjacent page.

References: 1. ACTOS package insert, Takeda Pharmaceuticals America, Inc. 2. Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674-682. 3. American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes Care. 2004;27(suppl 1):S68-S71. 4. American Diabetes Association. Standards of medical care in diabetes–2007. Diabetes Care. 2007;30(suppl 1):S4-S41.

ACTOS® (pioglitazone hydrochloride) Tablets Brief Summary of Prescribing Information. Please see package insert for Complete Prescribing Information.

WARNING: CONGESTIVE HEART FAILURE • Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients (see WARNINGS). After initiation of ACTOS, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered.

• ACTOS is not recommended in patients with symptomatic heart failure. Initiation of ACTOS in patients with established NYHA Class III or IV heart failure is contraindicated (see CONTRAINDICATIONS and WARNINGS).

INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control.

Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.

CONTRAINDICATIONS Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see BOXED WARNING).

ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components.

WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered (see BOXED WARNING). Patients with NYHA Class III and IV cardiac status were not studied during pre-approval clinical trials and ACTOS is not recommended in these patients (see BOXED WARNING and CONTRAINDICATIONS).

In one 16-week, U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%).

In this study, two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week, dose-controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0.9% (3/345) of patients on 45 mg reported CHF as a serious adverse event.

Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin.

In type 2 diabetes and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed.

ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation.

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive) In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg once daily, or placebo (n=2633) (see ADVERSE REACTIONS). The percentage of patients who had an event of serious heart failure was higher for patients treated with ACTOS (5.7%, n=149) than for patients treated with placebo (4.1%, n=108). The incidence of death subsequent to a report of serious heart failure was 1.5% (n=40) in patients treated with ACTOS and 1.4% (n=37) in placebotreated patients. In patients treated with an insulin-containing regimen at baseline, the incidence of serious heart failure was 6.3% (n=54/864) with ACTOS and 5.2% (n=47/896) with placebo. For those patients treated with a sulfonylurea-containing regimen at baseline, the incidence of serious heart failure was 5.8% (n=94/1624) with ACTOS and 4.4% (n=71/1626) with placebo.

PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo-treated patients. In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status.

In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease.

Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Since thiazolidinediones, including ACTOS, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOS should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see BOXED WARNING, WARNINGS, and PRECAUTIONS, Information for Patients).

Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 1). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 1 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS

Control Group (Placebo)

ACTOS 15 mg

ACTOS 30 mg

ACTOS 45 mg

Median (25th/75th percentile)

Median (25th/75th percentile)

Median (25th/75th percentile)

Median (25th/75th percentile)

-1.4 (-2.7/0.0) n=256

0.9 (-0.5/3.4) n=79

1.0 (-0.9/3.4) n=188

2.6 (0.2/5.4) n=79

-0.5 (-1.8/0.7) n=187

2.0 (0.2/3.2) n=183

3.1 (1.1/5.4) n=528

4.1 (1.8/7.3) n=333

Metformin

-1.4 (-3.2/0.3) n=160

N/A

0.9 (-0.3/3.2) n=567

1.8 (-0.9/5.0) n=407

Insulin

0.2 (-1.4/1.4) n=182

2.3 (0.5/4.3) n=190

3.3 (0.9/6.3) n=522

4.1 (1.4/6.8) n=338

Monotherapy Sulfonylurea Combination Therapy

Note: Trial durations of 16 to 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.

Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities).

Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies.

During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values e 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.

Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes.

Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the upper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued.

Macular Edema: Macular edema has been reported in post-marketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Some patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. It is unknown whether or not there is a causal relationship between pioglitazone and macular edema. Patients with diabetes should have regular eye examinations by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings (see ADVERSE REACTIONS).

Fractures: In a randomized trial (PROactive) in patients with type 2 diabetes (mean duration of diabetes 9.5 years), an increased incidence of bone fracture was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) versus placebo 2.1% (37/1728). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

Laboratory Tests FPG and HbA1c measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to initiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels).

Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.

Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician.

Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine.

Patients should be told to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day.

When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.

Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus,

adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.

Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate.

An enzyme inhibitor of CYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (such as rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response.

Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2).

No drug-induced tumors were observed in any organ.

During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors were identified. In two 3-year studies in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) on placebo.

Pioglitazone HCl was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCl daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m2).

Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCl (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).

Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2, respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m2). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2).

There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk.

Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman.

Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established.

Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.

ADVERSE REACTIONS Over 8500 patients with type 2 diabetes have been treated with ACTOS in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with ACTOS from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received ACTOS for at least 2 years.

The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 2.

Table 2

Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency e 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1

For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone.

In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema.

Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group.

The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%).

In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia).

In U.S. double-blind studies, anemia was reported in 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic).

In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for ©1999, 2008 Takeda Pharmaceuticals North America, Inc.

PIO-00538

7.2% of patients treated with ACTOS and sulfonylureas compared to 2.1% of patients on sulfonylureas alone.

In combination therapy studies with metformin, edema was reported in 6.0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7.0% of patients on insulin alone. Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema).

In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects).

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive) In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg daily or placebo (n=2633) in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean HbA1c 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in the cardiovascular composite endpoint (see Table 3 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS. Table 3 Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint Placebo N=2633 First Events Total Events (N) (N) 572 900 122 186 157 118 119 96 78 63 240 101 28 15 92 57

Cardiovascular Events Any event All-cause mortality Non-fatal MI Stroke ACS Cardiac intervention Major leg amputation Leg revascularization

ACTOS N=2605 First Events Total Events (N) (N) 514 803 110 177 105 131 76 92 42 65 101 195 9 28 71 115

Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, General, Macular Edema).

Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects.

Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values e 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, General, Hepatic Effects).

CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown.

OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to patient’s clinical signs and symptoms.

Rx only Manufactured by: Takeda Pharmaceutical Company Limited Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. One Takeda Parkway Deerfield, IL 60015 ACTOS® is a registered trademark of Takeda Pharmaceutical Company Limited and used under license by Takeda Pharmaceuticals America, Inc. © 1999, 2007 Takeda Pharmaceuticals America, Inc. 05-1141

September 2007

L-PIO-0907-4

1/08

Printed in U.S.A.

LETTER FROM THE EDITOR

Avoiding the Unthinkable: A Tale of 2 Triangles and the Process of Care They Govern

L

ast month, 2 back-to-back meetings brought out some of the leaders driving the transformation of healthcare into a value-based, patient-centered system. The Academy of Managed Care Pharmacy (AMCP) went first, celebrating its 20th anniversary, followed by the 5th Annual World Health Care Congress (WHCC). Both sessions revealed just how different, and better, healthcare is becoming. Even the warnings about the catastrophic consequences of not improving our healthcare system were accompanied by numerous remedies for it. Said one speaker, “If you can’t imagine things getting that bad, they probably won’t.”

There is some truth to this. In the face of improved evidence gathering, analysis, and application, it is getting harder to sit back and watch healthcare inefficiencies—clinical or economic—get bad. There are simply too many constructive remedies being proposed. We outline some of the advances proposed at the AMCP meeting in this issue of American Health & Drug Benefits (AHDB). Evidence-based medicine is finally making its appearance in value-based benefit designs.

Data-gathering techniques are improving to the point where healthcare providers and managers can track the effects of shifts in formularies and benefit designs.

Patient adherence is finally moving from a pipe dream to a hard metric, fortified by a dizzying array of payorgenerated tactics keeping patients connected with health “coaches.”

This is not your father’s healthcare system.

And so, because reasonable people are seeing real data showing what will happen to healthcare costs and outcomes if new efficiencies are not instilled into the practices of every stakeholder—from patient to provider, payor to purchaser, manufacturer to regulatory— it is becoming sensible to conclude that things are not going to get that bad. We are not going to spend an unsupportable proportion of the US gross national product on healthcare midway through the century.

We are not going to continue spending twice as much for identical healthcare outcomes in Miami as we do in Minnesota. And we will not apply population-based data on all patients as if everyone were an average patient. People are rational beings and, when con-

fronted by the unthinkable, will alter their course, not freeze like so many deer caught in the headlights of spiraling costs and intractable local customs.

As we witness the transformation of healthcare from expert-based opinion to evidence-based, value-based, patient-centered care, it becomes apparent that while processes are changing, the principles that support them are constant. The new research presented at the 2 conferences locks in on the eternal triangle of value: cost, quality, and access. So said Dr David Brailer, health information technology (HIT) expert, at his AMCP presentation. It is the balancing of these 3 interlocking forces that drives value.

AHDB organizes information on the basis of this and a second triangle: clinical, business, and regulatory. When value propositions are defined by a given healthcare intervention, that product or service must be delivered through formulary and benefit designs that satisfy a similar balance of clinical, business, and regulatory criteria. Circumstances and resources are in dynamic flux, but healthcare resource allocation is driven by these unchanging principles.

At these meetings, presentations revealed stunning new opportunities for value, with quality of research that was unthinkable even 5 years ago, and the trend can be expected to continue indefinitely. Observational data and HIT supplying it are bringing the promise of evidence-based medicine to formulary and benefit designs. Data were presented showing the differences in adherence rates across a range of medications used for the same condition, and the different overall healthcare resources consumed by the different patient groups. The ability to track patient adherence, outcomes, and healthcare resource allocation with such granularity is making health benefits able to serve the patient and the healthcare system alike, empowering all stakeholders to know exponentially more about the impact of healthcare interventions than was ever possible. This is good news for those caught in the glare of the headlights warning that spiraling healthcare costs were about to overrun the entire system and effectively wipe it out.

But back to that persistent value triangle of cost, quality, and access: the impending “collision” is not just with

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LETTER FROM THE EDITOR

undesirable healthcare costs, but also with substandard quality of care and access to it. The new systems for gathering and analyzing data on the quality of care and the adherence (access) to treatment regimens are integral for delivering best practices at best costs. Researchers are able to assign cost values to failing to provide optimal drugs or devices or to perform appropriate diagnostic tests. They can assess the impact on healthcare resource utilization of poor patient adherence to optimal treatment regimens. The sentiment is old—C. Everett Coop’s

The quality of evidence-based outcomes should help make meaningful transparency possible, along with the redefining of responsibilities of each stakeholder group to the others, always in support of the patient, the patient, the patient.

admonition that the least effective drug is the one never taken—but the ability to assign outcome metrics to it is new, empowering all stakeholders to do something about it. This technology is not getting rid of expert opinion but rather empowering experts to produce an evidencebased paradigm, armed with better facts than was ever possible before. Data are never self-explanatory, but expert analysis will help unravel the huge disparities in treatment costs and outcomes of patients in different parts of the United States—even in different areas of the state of New Jersey, as Dr Uwe Reinhardt reported at the recent WHCC. Thus, the quality of the Great Healthcare Debate on what benefits should be covered, and how, is increasing. Doomsday “chic” one hopes is on its way out, progress on its way in, as researchers replace a cost-centered approach to managing spiraling costs with a value-based approach: the cost-quality-access triangle.

By putting these elements first—by putting the patients’ needs, even the individual patient’s needs, first—costs will become manageable. Runaway healthcare costs back in the 1990s were addressed by the HMO strategy, “just say low.” This cost-minimization, race-to-the-bottom strategy did not resonate with patients or their providers. Evidence-based medicine

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then began to emerge, but only as a gauge of clinical quality. It became necessary to complete the triangulation of forces—cost, quality, access—by linking empirical quality care with access to care. This guides payors and purchasers alike on the truly acceptable opportunities to rein-in costs. Just how those models will take shape is yet unknown. What is likely is that they will be realistic, and that outcomes, health and economic, will be verifiable.

At the end of this scenario is the integration of stakeholder activities and agendas. Each party to the process of care is vitally interested in protecting its interests: patients, providers, payors, purchasers, manufacturers, regulatory, political, academia, evaluators, distributors, investors. Aligning the incentives of this multilateral group will require a collegial spirit currently absent from the Great Healthcare Debate. The quality of evidencebased outcomes should help make meaningful transparency possible, along with the redefining of responsibilities of each stakeholder group to the others, always in support of the patient, the patient, the patient. The fate of the 21st-century patient—which ultimately is us—will be determined in a more informed healthcare environment than ever existed.

The vitality of ideas expressed at this year’s healthcare meetings and in the pages of this journal provides evidence of a resourcefulness that has never left healthcare. For a time, the rush to progress seems drowned out by the glare of those frightful headlights warning of imminent doom. But the unthinkable is providing ample incentive to sidestep it. Experts are coming forward with propositions and systems for achieving healthcare progress never before imagined, and with results that are already taking root in our emerging new system of care. It is a good time to be alive, and because it is human nature not to accept the unthinkable, better times lie ahead.

Robert E. Henry Editor-in-Chief For editorial queries and submissions, please contact rhenry@AHDBonline.com.

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THE MEDICATION PRESCRIBED FOR LAURA MAY NOT WORK FOR SCOTT. Open Access.

Because different people have different needs.

Bristol-Myers Squibb supports open and unrestricted access to mental health medications. For people with mental illness, having access to newer and potentially more effective medications can be a crucial component of treatment.

1 in 4 adults suffer from a diagnosable mental disorder in any given year.1 Open access is especially important in the treatment of mental disorders because the response to therapy can vary greatly from individual to individual and from one medication to the next. Restrictions in the form of prior authorizations and preferred lists may have the unintended consequences of jeopardizing patient health while failing to reduce costs.

SUPPORT OPEN ACCESS AND GIVE PROVIDERS THE FREEDOM TO FIND THE MOST APPROPRIATE MEDICATION FOR EACH INDIVIDUAL. 1. National Institute of Mental Health. Available at: http://www.nimh.nih.gov/healthinformation/statisticsmenu.cfm. Accessed August 7, 2006.

D6-K0176Q October 2006 AA444678/10-06

MAY 2008

VOLUME 1, NUMBER 4

™

™

EDITORIAL

3

Avoiding the Unthinkable: A Tale of 2 Triangles and the Process of Care They Govern Robert E. Henry

10

Associate Publisher Maurice Nogueira maurice@engagehc.com

The Unbearable Lightness of Mental Health Alberto Colombi, MD, MPH

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Editorial Director Dalia Buffery dalia@AHDBonline.com

Correction

Contributing Editor Sandy Paton

CLINICAL

13 Schizophrenia: Current Concepts and Approaches to Patient Care Peter F. Buckley, MD; Adriana Foster, MD

Trends in Pharmaceutical Expenditures: The Impact on Drug Benefit Design Joanne LaFleur, PharmD, MSPH; Leslie Fish, PharmD; Diana I. Brixner, RPh, PhD

Medicare Coverage for Erythropoiesis-Stimulating Agents: The Perfect Storm Interview (Part 1) with Samuel M. Silver, MD, PhD

Economic Trends Influencing Healthcare Reform Keynote address delivered by Robert B. Reich

40

Technology in Healthcare: The Wave of the Future Presented by David Brailer, MD, PhD

42

Medication Therapy Management Project—The Latest Information for Managed Care Pharmacy Presented by Marissa Schlaifer, RPh; Linda Baggett, RPh, CGP; and Kimberly Vernachio, PharmD

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

AMCP COVERAGE

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President Brian F. Tyburski brian@engagehc.com Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com

REGULATORY

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Senior Production Manager Alaina Pede Director of Human Resources Blanche Marchitto

BUSINESS

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Publisher Nicholas Englezos nick@engagehc.com

Responding to FDA Alerts: How to Reduce Risks and Liability

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

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com

Presented by Kathleen Orrico, PharmD Continued on page 8

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AACR Meeting Highlights

Kip Piper, MA, CHE President, Health Results Group kpiper@AHDBonline.com

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Generic Drug Trends

By Caroline Helwick

Editorial Board

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Letter

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FDA Watch

Pharmacy Reimbursement Policy Michael R. Schaffer, PharmD, MBA Arthur F. Shinn, PharmD, FASCP Employers F. Randy Vogenberg, RPh, PhD Alberto M. Colombi, MD, MPH

Mark Senak, JD

56

Industry Trends

Specialty Pharmacy Rebecca M. Shanahan, Esq.

Gordon M. Cummins, MS

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Managed Care Pharmacy Policy Cynthia J. Pigg, BSPharm, MHA

Executive Summaries

Managed Markets Marketing Jeffrey A. Bourret, RPh, MS, FASHP Charles E. Collins, Jr, MS, MBA

UNMANAGED MOMENTS

Clinical Research Nirav R. Shah, MD, MPH Samuel M. Silver, MD, PhD Michael A. Weber, MD Managed Care & Government Affairs Sharad Mansukani, MD

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Research & Development Michael F. Murphy, MD, PhD Wayne A. Rosenkrans, Jr, PhD

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Healthcare Outcomes Gary M. Owens, MD Outcomes Research Gordon M. Cummins, MS Timothy S. Regan, BPharm, RPh American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205B, Jamesburg, NJ 08831. Copyright © 2008 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline.com, Telephone: 732-992-1889. Fax: 732-992-1881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205B, Jamesburg, NJ 08831.

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Pharmacy & Specialty Products James T. Kenney, RPh, MBA Pharmacy Benefit Design Joel V. Brill, MD Scott R. Taylor, RPh, MBA Pharmacoeconomics Jeff Jianfei Guo, BPharm, MS, PhD Policy & Public Health Alex Hathaway, MD, MPH, FACPM Joseph R. Antos, PhD Actuary David Williams

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GUEST EDITORIAL

The Unbearable Lightness of Mental Health Alberto Colombi, MD, MPH

I

s wellness just a physical matter? Is the burden of disease just a matter of costs?

These are obviously rhetorical questions. No one would challenge the notion that health is more than the absence of disease and is at the very least a state of mental and physical well-being. But how often do we try to understand “mental wellness”?

How often do we look into screening, diagnosis, intervention, and referral of mental issues in a fragmented mental healthcare system?

Similarly, no one would deny that the total burden of disease on work and on society is more than just its direct healthcare cost. Most of us recognize that indirect healthcare costs should be factored in, and these include absenteeism and presenteeism. Nevertheless, how often do we truly try to quantify health-related loss of function, hindered performance, and, ultimately, productivity loss? Compounding mental health and productivity loss, how well do we do in weighing in the intangible loss of function associated with mental stress and disease?

From prevention to treatment, there is an unintended but actual difference in how matters of physical and mental wellness are being addressed—one with empathy, the other with stigma. For instance, should an injury occur, a legion of good healthcare and safety colleagues will investigate, intervene, and discuss corrective actions. Should a heart attack happen—a personal matter, mind you—emergency response would be activated, people trained in CPR would come forward, defibrillators would be made available, and wellness teams would address risk prevention—from blood pressure to cholesterol level—and, in the back end, coronary artery disease claims utilization and costs would be analyzed.

But what about stress or depression, let alone a fatal case, as in suicide? A hallway murmur would follow perhaps, but no one will ask: • Could it have been prevented?

• Are our health programs adequate?

• Did our wellness team raise awareness?

Dr Colombi is Corporate Medical Director, PPG Industries, Inc, Pittsburgh, PA.

• Do we facilitate access to treatment and to prevention of mental discomfort and disease?

• Are our employee assistance programs proactive?

It is “personal,” we have no right “to interfere,” and we do not mean to. But would you let a personal heart attack take place without questioning if the ambulance arrives on time? Without activating the emergency response system, without even trying CPR, and without questioning if appropriate cardiovascular health-promotion programs are in place? Two personal matters that are nevertheless being treated very differently.

One argument for such disparity is that mental health is light, evanescent, elusive. Even excluding the personal suffering, if we look at economic figures only, that alone should be a compelling reason to better understand the whole “weight” of the issue.

Let us look at some preliminary figures. In our company, during a period of 7 years or so, some 28,000 employees filled out a self-reported Health Risk Assessment (HRA) Questionnaire online. Of these, about 19,000 were US employees, of whom about 1800 voluntarily filled out the validated depression screening instrument Patient Health Questionnaire (PHQ)-91 and responded to the Work Limitations Questionnaire (WLQ), which assesses limitations in performing normal job functions that result from physical or emotional matters.2 The WLQ calculates a Productivity Loss Index and a Time Loss Index. The approximately 1800 employees also completed a Stress Satisfaction Offset Score, which explores demand, control, effort, and reward of their job situation.3 Thus unassumingly, imperfectly, and while attending to the usual center-stage physical wellness characters—cardiovascular disease, diabetes, and metabolic syndrome prevention—we found ourselves looking at a respectable sample of our own employees who were sending us a message about mental wellness. Such a message cannot be ignored—our own people telling us that stress is the most important risk factor for them (69%), but the one which they are least ready to change (11%), either because they are not interested in Continued on page 12

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10

550

1

medicines for diabetes and mental health

thousand patients enrolled in pharmacy adherence programs

happier, healthier, more compliant patient

Healthcare may be a numbers game, but we’re only interested in one number.

At Lilly, helping you manage your patients requires a shared commitment to delivering initiatives, ideas, and positive outcomes. So we keep our focus on those who count on our medicines.

From diabetes and mental health education, to patient adherence efforts, to simply offering the best answers we can,

Lilly is working towards one focus... one patient at a time.

All numbers current as of December 2006. MG45572 COPYRIGHT Š 2007 ELI LILLY AND COMPANY.

GUEST EDITORIAL

Continued from page 10 change, or possibly because they do not believe that change is possible.

We are trained to interpret self-reported chronic conditions, predisease predictors, and lifestyle risk factor stratification, but we are unprepared to read through a message about stress, let alone depression.

We wonder what this all means: Is there an unrecognized issue of adapting organizations to human psychology—“orgonomics”—as much as there is a recognized need of adapting tools to human physiology, as in traditional ergonomics? While we wonder about organizational stressors and the possibility of prevention, we also ask ourselves what will be the treatment experience for those who might have screened positive for clinically relevant depression.

Keeping employees healthy, productive, and engaged is arguably a good business proposition. And although mental health seems “soft,” it does measure up in the ability of health to generate wealth.

Although their triage ends with the recommendation to consult with their personal physician—who is really taking care of them, and how? What will be their rehabilitation and early and safe return to work experience in a fragmented healthcare system, where stigma for mental disease does not facilitate early identification, screening, referral, and return to function?

Can we at least make the business case that mental wellness deserves as much attention as physical wellness does? Let us take another look at the productivity loss associated with these preliminary data.

Our company’s preliminary self-reported HRA data show that besides the expected impact of allergies and bronchitis, stress and depression are of utmost importance for preventing productivity loss.

Stress is one of the most relevant factors for loss of productivity on a population basis. According to our data, about $2 million are estimated lost per 1000 employees each year due to sub-par performance resulting from what is defined as “stress.” These data

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give equal importance to stress at work and at home, stress about parental care as much as about care for an elderly relative. Similarly, our data indicate that depression is another critical area for loss of engagement and productivity.

In addition, our data show that not only the few severe, untreated depression cases result in very high individual productivity loss, but that the moderate and mild depression cases, which are more common, add up to the overall population burden of disease when prevalence is considered. In fact, moderate and mild unaddressed depression may account for two thirds of the burden of depression on overall productivity loss.

This, in our data, is estimated to translate to about $1 million per 1000 employees annually. Accordingly, we would estimate that each year, for every 1000 employees, possibly $3 million is lost in absenteeism or presenteeism because of stress and depression combined.

Even if these estimates need further critical refinement, this entire issue carries substantial weight on financial grounds alone.

Let me conclude with the obvious: Economics is not the only consideration. In the initial days of occupational safety many decades ago, the seeds of good safety programs were rooted in the moral unwillingness to accept the “normalcy” of preventable disease, disability, and loss of life. Similarly, I am confident that mental well-being has to start with our nonacceptance of stigma and avoidable, crippling disability—let alone loss of life—from mental illness.

Although mental distress requires the respect that is due to personal matters, it also deserves supportive environments, relationships that respect employees’ dignity, and practical ways of balancing work and life.

Keeping employees healthy, productive, and engaged is arguably a good business proposition. And although mental health seems “soft,” its unbearable lightness does measure up in the ability of health to generate wealth.

References 1. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression measure. J Gen Intern Med. 2001;16:606-613.

2. Lerner D, Amick BC III, Rogers WH, et al. The Work Limitations Questionnaire. Med Care. 2001;39:72-85.

3. Shain M. Stress Satisfaction Offset Score (SSOS): best advice on stress risk management in the workplace. 2000. Publication prepared for Health Canada; available through Dr Martin Shain, at Martin_ Shain@camh.net.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The dose of BYSTOLIC may need to be reduced.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Body as a whole: asthenia.

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

Events Identified from Spontaneous Reports of BYSTOLIC Received Worldwide.

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

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

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

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

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

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

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

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

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

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

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

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

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

Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Licensed from Mylan Laboratories, Inc. Under license from Janssen Pharmaceutica N.V., Beerse, Belgium Rev. 12/07 © 2007 Forest Laboratories, Inc.

For the treatment of hypertension

Introducing BYSTOLIC. A novel beta blocker with efficacy and favorable tolerability across a broad range of patients.

1-3

n Unique mechanism of action includes cardioselective beta blockade and vasodilation1* n Once-daily antihypertensive, with efficacy maintained over 24 hours1

Please see brief summary of full Prescribing Information on adjacent page.

For full Prescribing Information visit www.BYSTOLIC.com.

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

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

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

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

BYSTOLIC should not be combined with other beta blockers.

The most common adverse events with BYSTOLIC versus placebo (approximately >1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. *In extensive metabolizers (most of the population) and at doses <10 mg, BYSTOLIC is preferentially â?¤1 selective. The mechanism of action of the antihypertensive response of BYSTOLIC has

not been definitively established. Possible factors that may be involved include: (1) decreased heart rate, (2) decreased myocardial contractility, (3) diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, (4) suppression of renin activity, and (5) vasodilation and decreased peripheral vascular resistance.

References: 1. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2007. 2. Data on file. Forest Laboratories, Inc. 3. Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens. 2007;9:866-875. Š2008 Forest Laboratories, Inc.

44-1012269R1

02/08

CLINICAL

Schizophrenia: Current Concepts and Approaches to Patient Care Peter F. Buckley, MD Adriana Foster, MD

Schizophrenia is the most serious of all mental conditions. It is typically a long-lasting condition characterized by repeated relapses and by marked functional impairment.

Genetic and environmental factors are important. Exactly which factors and how these combine to cause schizophrenia is still unclear. Antipsychotic medications form the bedrock for treatment. These drugs are effective, but not entirely so, and are associated with negative side effects. Individual differences among the available medications suggest that trials with a different medication may be appropriate when one agent fails or is not appropriate for the specific patient. Monitoring for side effects is important to ensure effiPeter F. Buckley, MD cacy and compliance. Often, patients choose to stop taking their medications for a variety of reasons, which invariably will lead most patients to a relapse of illness. Beyond medications, patients need considerable support and specialized services. Families are a key resource. The recent focus on personal determination has led to recovery-based services, including the incorporation of peer support into patient care. [AHDB. 2008;1(4):13-22.]

S

chizophrenia is a poorly understood condition.

Despite several recent documentaries and movies depicting the course and disability of this illness, the lay public remains largely confused about schizophrenia and continues to harbor notions that it is a “split personality” or a “Jekyll and Hyde” phenomenon.

Regrettably, efforts to articulate a clear account of what schizophrenia really is and what causes it have been hampered by a lack of compelling evidence as to its etiology. Despite the many clues to the cause(s) of schizophrenia, definitive evidence is still lacking. In many ways, we can be more dogmatic about what is not relevant to schizophrenia (Table 1). This is important because stigma, which is fueled by a lack of knowledge, is a major obstacle in managing schizophrenia. Several books provide comprehensive information about schizophrenia.1-4 This article offers a current overview of schizophrenia and its treatment.

Dr Buckley is Professor and Chair, and Dr Foster is Assistant Professor, Department of Psychiatry and Health Behavior, Medical College of Georgia, Atlanta.

Diagnosis Schizophrenia is a complicated diagnosis. The condition is characterized by delusions (fixed, false beliefs), hallucinations (typically “hearing voices” when no one is around), disturbances of speech (illogicality, nonlinearity of thought and conversation), restricted affect and emotionality, and impairments of thinking (memory, attention, reasoning, awareness).

Table 1 Dispelling Common Myths about Schizophrenia 1. Despite common belief, schizophrenia is NOT caused by: • “Difficult” parents • Diet • Stress • The left side of the brain dominating the right side 2. It is not a split personality 3. Not all patients are violent 4. Patients are not “inventing” unusual ideas or lying, they believe these

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KEY POINTS

Table 3 Risk of Developing Schizophrenia If Blood Relative Is Ill

Schizophrenia is the most serious of all mental conditions and is characterized by repeated relapses and significant functional impairment.

Diagnosis requires a psychotic episode that lasts at least 6 months.

Continuous use of antipsychotic medications is the mainstay of therapy.

Patient lack of compliance will inevitably lead to relapse and may have serious consequences.

The new-generation antipsychotics are slightly more effective but their metabolic side-effect profile is a serious concern, requiring ongoing monitoring by the treating physician.

Table 2 Diagnostic Features of Schizophrenia 1. Characteristics: • Cognitive impairment: poor attention, memory, abstract thinking • Delusions: bizarre; bodily; grandiose; jealousy; persecutory; religious • Hallucinations: auditory; gustatory; tactile; visual • Thought disorders: illogicality • Blunted affect and restricted emotionality, motivation, and enjoyment • Decline in social and/or occupational functioning 2. Features are NOT caused by: • Medical conditions • Mood disorder • Substance abuse 3. Features are present continuously for at least 6 months

Given the impact of such a constellation of symptoms, the condition is typically associated with a decline in social and/or occupational performance.

Indeed, this may be what parents, friends, or coworkers notice first—a withdrawal, dropping out of college, or inability to cope with the stress of work. For many patients, the onset of such “disintegration” is insidious.

Others have a florid presentation, manifest by prominent delusions, hallucinations, and bizarre behaviors, such as locking oneself in an elevator at a mall and shouting out, “Aliens, go away.”

Although such a presentation may lead some to wonder “how hard can it be to diagnose this person as psychotic,” the presentation could (and in fact is likely to)

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Relationship to relative Monozygotic (identical) twin Child of parent Sibling Parent

Rate, % 48 14 10 5

Source: Gottesman II, Shields J. Schizophrenia: The Epigenetic Puzzle. Cambridge University Press, Cambridge, UK; 1982.

be complicated by abuse of drugs. This complicates things considerably. Also, many people who develop schizophrenia become depressed as the illness evolves. It can be difficult to determine whether the person is suffering from major depression or is in the early stages of a psychotic illness. It is therefore best to wait and see how things play out definitively over months before making such a serious diagnosis as schizophrenia (Table 2).

Schizophrenia typically begins in adolescence or in early adulthood. It occurs equally in males and females, but the onset is on average 4 years later in females, and the illness tends to be milder in females. The reasons for these gender differences are not yet known.

Practically, the Diagnostic and Statistical Manual of Mental Disorders mandates that clinicians classify this illness as “schizophreniform disorder” if the duration is less than 6 months.5 This is because some patients have a single psychotic episode, which looks indistinguishable from schizophrenia, but they will regain normal functioning without any recurrence. Similarly, those who abuse drugs such as cannabis can have a psychotic break that appears like schizophrenia, but they, too, will regain normal functioning without further episodes once they quit taking the drugs. This latter condition is classified as a “drug-induced psychosis.”6

Causes(s) of Schizophrenia Ultimately, we do not know what causes schizophrenia,1,7,8 but we do know that it runs in families and is associated with birth complications, head injury, epilepsy, and drug abuse. Cannabis abuse raises one’s risk for schizophrenia by about 4.5-fold. Recent research suggests that people who have a genetic vulnerability are 16 times more likely to become psychotic when they abuse cannabis.

An ongoing debate about the causes of schizophrenia is whether any particular insult (eg, genetic defects, birth complications) leads to this condition (like the model of multiple causes of elevated blood pressure) or,

CLINICAL

alternatively, whether each of these insults can cause a psychotic condition that has a different cause but is similar in presentation and fits under the rubric of schizophrenia (as in pneumonia, whether caused by influenza virus or by bacteria).

Genetic component Whether schizophrenia is a single illness or multiple illnesses has not yet been teased out, but we do know it has a strong genetic basis, which puts blood relatives at risk (Table 3). Genetic studies have shown abnormalities on several chromosomes (eg, chromosome 5, 8, 11, 13, 22).9 However, as with many aspects of schizophrenia, the findings are inconclusive and do not point to a precise gene involved. More recent genetic studies have focused on the search for abnormalities in genes or their related proteins that are involved in neuronal development (eg, dysbindin, neuregulin, SNAP-25, brain-derived neurotrophic factor).10 Birth factors One of the most reproducible findings in schizophrenia is that affected patients are far more likely to have been born in the first 3 months of the year—the so-called season of birth effect.11 This curious, yet robust, association points to birth or to the time in utero as relevant to the development of schizophrenia.

Another reproducible finding is that about 20% of people who develop schizophrenia have had some sort of birth complication,12 such as a prenatal exposure to influenza, haemolytic anemia, severe malnutrition, preeclampsia, asphyxia, or fetal distress. This could, of course, have something to do with the pregnancy and with the delivery itself. For example, the fetus may experience hypoxia in the birth canal, which could result in minimal brain damage that manifests later in adolescence as schizophrenia. Alternatively, the birth complication may occur because the fetus itself is “defective.” Brain development in utero might have gone wrong in some way because of genetic misprogramming or because of some external injury (eg, a mother with an infection during the critical first 3 months of pregnancy).

Brain abnormalities There is evidence that brain development is disturbed in schizophrenia. The evidence comes from postmortem brain studies of people with schizophrenia who died from natural causes (eg, a heart attack, although this could also influence or bias postmortem brain findings) or from suicide (clearly, this could affect

Table 4 Abnormal Brain Structure Findings in Imaging Studies of Patients with Schizophrenia Brain area Whole brain gray matter Whole brain white matter Thalamus Globus pallidus Frontal lobe Temporal lobe Hippocampus Lateral ventricles Third ventricle Fourth ventricle

Percent change*: increased ( ) or decreased ( ), % 5 5 5 20 8 6 9 15 15 8

*These findings are (1) estimates from overall research literature; (2) not seen in all patients; (3) not seen all together; (4) not “diagnostic” of schizophrenia; (5) most often not noticeable on a clinical scan but are the result of research involving imaging scans from hundreds of patients.

Sources: References 13, 14.

the brain).10,13 Although this type of research has its own methodological problems, these studies have shown convincing evidence of abnormal (underdeveloped) cells and of cells that are misplaced or misaligned in the brains of people with schizophrenia.10,13 These subtle findings occur more often in the temporal lobes than in any other brain regions. Modern brain imaging techniques (eg, magnetic resonance imaging [MRI]) facilitate the study of live brains of people with schizophrenia, revealing fairly reproducible findings (Table 4).14,15 Some studies have also included relatives of patients with schizophrenia as a comparison group.16,17 These reveal much milder, but the same, findings in healthy relatives (who “do not have the illness” but may have genes susceptible to schizophrenia). This raises the question whether such brain abnormalities are present from birth or even before the onset of schizophrenia.

There have been efforts to tease this out. Studies of patients in their first episode of psychosis show the same patterns of abnormalities on brain imaging,18 but in a more attenuated form, as seen in first-episode patients with chronic schizophrenia. Other studies involve “prodromal” populations, namely, patients who have not had a psychotic episode yet but who show “mild” signs of schizophrenia (eg, oddities of thought and speech). These patients show even “milder,” barely detectable, brain abnormalities. In one such study,

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Table 5 Evidence for Schizophrenia as a Neurodevelopmental Disorder 1.

2.

3.

4.

Genes that code for neurodevelopment have been implicated High rates of birth complications Season of birth phenomenon Many patients have minor physical anomalies* • Abnormal or fused webs at toes • Abnormal palmar creases • Low-set ears • Shortened faces • Widened eyes 5. Many patients have abnormal fingerprints* 6. Type and pattern of structural brain abnormalities seen in brain-imaging studies 7. Type and pattern of brain changes in postmortem studies *Subtle skin “blemishes” that relate in timing to maturation of the skin and the central nervous system in utero.

Table 6 Elements of Comprehensive Care for Patients with Schizophrenia Access to coordinated substance abuse services Appropriate medication treatment Counseling: supportive psychotherapy Good medical care More specialized counseling/support: Cognitive behavioral therapy Peer support services Psychoeducation (illness education) Social skills training and community reintegration support services Financial aid Housing support Sheltered and “regular” employment opportunities Support and educational opportunities

the prodromal patients who went on to have a psychotic break had more temporal lobe abnormalities on MRI than patients who did not progress to psychosis.19 Collectively, these findings, which point to faulty early brain development, have led many to consider that schizophrenia may be a neurodevelopmental disorder (Table 5).1,7,20 That is, people with schizophrenia may have an aberrant development of brain “hardwire” (eg, misplaced, misaligned, or immature cells; faulty neural communication tracks). It is postulated that as time goes by, these cortical vulnerabilities become exposed as the patient progresses toward psychosis. Some have suggest-

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ed that the reason for the onset of psychosis at adolescence is a clue. This is a time of brain “rewiring” and plasticity. With these changes, the otherwise “dormant” brain abnormalities are now exposed. Others have postulated that given this brain vulnerability from birth, other events (eg, drug abuse, stress) during adolescence may also push the person (ie, brain) “over the edge” to cause psychosis. This “2-hit” notion is also an intuitively appealing hypothesis. All these reflect the notion that schizophrenia is a neurodevelopmental disorder, and as with other such disorders (eg, cerebral palsy), the causes may be genetic, environmental, or both.

Kraepelin, the German psychiatrist who first described schizophrenia in 1896, considers this to be a dementing condition. He describes how schizophrenia evolves in adolescence and progresses inexorably into a chronic state (which he called “dementia praecox,” dementia of youth).

Seemingly in direct opposition to the brain-imaging evidence that supports the neurodevelopmental hypothesis in schizophrenia, other, long-term imaging studies report a progressive loss of brain tissue.21,22 This would favor a neurodegenerative hypothesis of schizophrenia (like Huntington’s disease). Some have suggested that schizophrenia may have both neurodevelopmental and neurodegenerative processes at work.

Under such a parsimonious scheme, it is proposed that the underlying neurodevelopmental brain vulnerability predisposes to a more progressive brain loss.23 A precedent for this viewpoint is Down syndrome (DS), which is a prototypical neurodevelopmental disorder caused by chromosomal abnormalities. Patients with DS show a variety of neurodevelopmental features clinically (see Table 5), and they also have mental retardation.

Patients with DS develop Alzheimer’s-like dementia very early on, typically in their 40s. Therefore, some have suggested that a 2-process model may also explain schizophrenia. But as elegant as each of these hypotheses are, they are also very difficult to prove or refute.

The weight of evidence currently favors a neurodevelopmental basis for schizophrenia. It is plausible that some patients could have a neurodevelopmental form of schizophrenia, while others may have a neurodegenerative schizophrenia.20 The complexity of the process involved and the lack of a clear understanding lessen our ability to give a clear picture about schizophrenia to the public.

Brain Chemistry and Schizophrenia Overactivity of the dopamine neurotransmitter system is the most compelling neurochemical abnormality in schizophrenia.24 This is also the most easily explained

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Table 7 Selected First- and Second-Generation Antipsychotic Medications: General Information*

Drug class

Generic available?

Initial dose†

Haldol (haloperidol) Haldol long-acting injection

Yes No

1-5 mg 25-50 mg IM

Trilafon (perphenazine) Melleril (thioridazine) Stelazine (trifluoperazine) Loxitane (loxapine) Moban (molindone hydrochloride)

No Yes Yes Yes No

4-8 mg 50-100 mg 2-5 mg 20 mg 20 mg

Clozaril (clozapine)

Yes

12.5-25 mg

Abilify (aripiprazole) Abilify injection acute acting

No No

Geodon (ziprasidone) Geodon injection acute acting

No No

10-15 mg 5.25-9.75 mg IM 40-80 mg 10-20 mg/d IM

Invega XR extended release (paliperidone)

No

3-6 mg

Risperdal (risperidone) Risperdal long-acting injection

No No

Seroquel (quetiapine)

No

Seroquel XR extended release Zyprexa (olanzapine) Zyprexa injection acute acting

No No No

Drug name

Maintenance dose†

Maximum dose‡

5-25 mg/d 50-200 mg IM, for 2-4 wks 16-56 mg/d 300-800 mg/d 2-20 mg/d 50-100 mg/d 50-100 mg/d

60 mg/d 300 mg IM, for 3-4 wks 64 mg/d 800 mg/d 20 mg/d 150 mg/d 150 mg/d

150-600 mg/d in 2-3 divided doses 10-30 mg/d 5.25-15 mg IM 40-160 mg/d 10-20 mg/d IM

900 in 2-3 divided doses 30 mg/d 30 mg IM, 10 hrs 160 mg/d 40 mg/d IM (not studied for >3 days) 12 mg/d

Cost of 30-day supply of oral drugs§

First-generation (typical) agents $

$$ $$ $$ $$$ $$$$

Second-generation (atypical) agents

3-12 mg/d; titrate up in 3-mg increments 1-2 mg 3-6 mg 25 mg IM 25 mg IM (w/ oral Risperdal) every 2 wks 50-100 mg 300-600 mg/d in 2-3 divided doses 50-100 mg 300-800 mg/d 5-15 mg 10-40 mg/d 2.5-10 mg IM 5-10 mg/d IM

16 mg/d 50 mg IM every 2 wks 800 mg/d in 2-3 divided doses 800 mg/d 40 mg/d 30 mg/d IM in 3 mg 2-3 hrs apart

IM indicates intramuscular. *This is not an exhaustive list of the first-generation antipsychotics and is not intended to be used as a guide for dosing decisions. † The dosing profiles for initial and maintenance treatments represent reasonable clinical practice; however, clinicians should consult the current Physicians’ Desk Reference (PDR) and related regulatory sources for specific recommendations. ‡ These doses represent current clinical practice, meaning that in some cases the dose is above the US Food and Drug Administration (FDA)-recommended upper-limit dose for that agent. Please also consult the FDA, other regulatory sources, and PDR. Dosing profiles tend to change over time as more information and research results become available. § Cost estimates vary considerably. Please consult formulary information and/or the local pharmacy.

$$$$

$$$$$

$$$$$

$$$$$

$$$$$

$$$$$

$$$$$ $$$$$

Cost key: $ 0-25 $$ 26-50 $$$ 51-100 $$$$ 101-200 $$$$$ >200 Source for cost: Lexi-Comp, at www.drugstore.com.

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CLINICAL

Table 8 Safety and Tolerability of First- and Second-Generation Antipsychotics Effect

Typical agents

Aripiprazole (Abilify)

Clozapine (Clozaril)

Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Risperidone (Risperdal)

Ziprasidone (Geodon)

Extrapyramidal syndrome Tardive dykinesia Somnolence Prolactin Weight gain Dyslipidemia Diabetes QTc interval prolongation Orthostatic blood pressure

+-+++

++

±

±-+1

±

±-+++1

±-+1

+++ ±-+++ +++ ± ± ± ±

± (?) ++ – ± ± ± ±

± +++ ± ++++ ++++ ++++ ++

± (?) ++ + +++ +++ +++ +

± (?) +++ ± ++ ++ ++ +

±-+ ± +++ + + + +

± (?) ± ± ± ± ± ++

±

+

+++

+

±

++

±

1. Indicates dose-related; –, none; ±, none/minimal; +, mild; ++, moderate; +++/++++, marked compared with placebo.

Note: This table gives an overall impression of the side-effect profile. For individual drugs, clinicians should consult the approved product labeling and/or the most current Physicians’ Desk Reference manual.

theory for the public—people become psychotic because their dopamine is overactive. There is certainly evidence for this, including functional brain-imaging studies that show excess of dopamine in the brain of patients when they are acutely psychotic. But like all the other explanations of schizophrenia, it is not quite as simple as “too much dopamine.” Some researchers have suggested there is overactivity of dopamine in one brain region (eg, temporal lobes), concomitant with underactivity in another area (eg, frontal lobes). Also, the fault may not be across all dopamine receptors but perhaps selectively in some of the subclasses of dopamine receptors or beyond the actual receptors, even as a subsequent maleffect in cell-signaling.

It is clear that other neurotransmitter systems are affected in schizophrenia. The neurotransmitter systems implicated in this disease are: • Cholinergic • Dopamine • Glutamatergic • Noradrenergic • Serotonin.

Deficits in other neurotransmitter systems (eg, glutamate receptors) may underlie schizophrenia directly and/or indirectly through their interrelated effects on the dopamine system.25 Thus far, the dopamine system has been the most pronounced neurochemical abnormality and, significantly, appears to be related to how patients respond to treatment.

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Treatment of Schizophrenia It is hardly surprising, given the complexity of the condition, that effective treatment of schizophrenia requires attention to multiple components of care. It is true that medications form the bedrock of treatment, but medications alone are not enough to keep people stable and/or to achieve recovery.1,3,26,27 Elements of comprehensive care for patients with schizophrenia are listed in Table 6.

Antipsychotic medications Antipsychotic medications are the mainstay of treatment (Table 7). Although all currently available antipsychotics act on the dopamine system (invariably to block dopamine D2 receptors and are therefore considered to work by “turning off” the overactive dopamine receptors), this is likely to be too simplistic.

Antipsychotic medications also have a variety of agonist (activating) and antagonist (deactivating) effects on several other neurotransmitters. Pharmaceutical companies have targeted the development of highly selective drugs (eg, a dopamine D4 antagonist) or more “gunshot” drugs that have effects at multiple receptors (“pleomorphic” antipsychotics, such as clozapine [Clozaril] or olanzapine [Zyprexa]). The exact “magic potion” for treating schizophrenia remains a mystery.

For now, the available medications are effective, but with limitations (Table 8).

A thorough account of the psychopharmacology of schizophrenia is beyond the scope of this article. Some

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general comments on the treatment of schizophrenia are more appropriate.

1. With the exception of clozapine, the other antipsychotics are more similar than different in their ability to control the symptoms of schizophrenia.28,29 All of them are effective in relieving acute symptoms— anxiety, agitation, delusions, and hallucinations. Some may act a bit quicker (or perhaps are easier to get quicker to an effective dose) and some may be more powerful in their effect on symptoms (again, dosing may play a big role here).

The older (also known as conventional, typical, or first-generation) antipsychotic medications have proved efficacy and work best against positive symptoms, with little benefit for negative, depressive, or cognitive symptoms (they may even worsen these aspects of the illness). Their major adverse side effects are related to their antagonism of the dopamine system.

These drugs cause acute and chronic muscle (extrapyramidal) side effects that are distressing and disfiguring. Because they have been around for a long time, they are relatively inexpensive.

The new antipsychotics, also known as atypical or second-generation antipsychotics, show similar or slightly better efficacy compared with the first-generation agents in treating positive symptoms. They have variable, but generally only modest, benefits in treating negative, depressive, and cognitive symptoms.

Although these medications generally have a lower risk for extrapyramidal side effects than the first-generation agents, they have other serious side effects, as reflected in Table 8.

More so than the first-generation antipsychotics, the newer agents cause weight gain and metabolic disturbances of glucose, insulin, cholesterol, and lipids.29,30 This is a major drawback, which has substantially complicated the treatment of schizophrenia and is currently the number-one issue in the psychopharmacology of schizophrenia. Treating physicians are monitoring patients carefully to detect such disturbances and are also concerned about switching medications and seeking relief in another antipsychotic when these problems emerge.

These drugs are also remarkably expensive, which limits access and imposes high financial burden on an already overburdened mental healthcare system. In contrast, if these (or any particular) drugs keep a patient from relapsing and avoiding hospitalization, then the medication is cost-effective.

2. Although antipsychotics are generally effective (better in acute care and for positive symptoms), a substantial group of patients remains unwell. Some

patients relapse frequently over time; some are chronically psychotic, and the medications barely work for them. Efforts to help these patients include: • Trials of high doses of an antipsychotic • A trial of 2 antipsychotics together • Trials of add-on drugs (eg, antidepressants, stimulants) that may boost the effect of the antipsychotics • Use of clozapine (the most powerful of all antipsychotics but with a high side-effect burden) • For intractable situations, as well as for severe depression or catatonia, a trial of electroconvulsive therapy.

There is also a particular interest at present in finding ways to reduce the cognitive deficits of schizophrenia, which are rate-limiting obstacles to recovery.31 3. The side-effects burden of the antipsychotics is substantial. Clinicians engage in a trial-and-error process with patients in an effort to find the drug that will work best and will result in fewer side effects. The sensitivity of each patient is unique—both in terms of the ability to respond to one drug (but perhaps not to another) as well as to experience the side effects.

The response and tolerability of each patient is individualized. We can make general predictions about the overall risk-benefit profile of any given drug, but how a patient will fare in practice is the true test. In addition, the dose of the medication strongly influences both response and tolerability. At present, the selection, dosing, and use of antipsychotics in clinical practice are more art than science. Efforts toward personalized medicine and toward the emergent strategy of pharmacogenetics (the genetics of medication response and sideeffect prediction) offer future hope.

4. Regardless of the benefits and drawbacks of the medications themselves, our ability to treat schizophrenia is curtailed even more by the patient’s reluctance to take antipsychotic drugs and to continue using medications.32 Estimates differ by each study, but approximately 50% of patients are noncompliant with their prescribed antipsychotic medication regimen.33 Most are partially noncompliant, missing medications “here and there.” Some patients are noncompliant and “learn the hard way,” by having recurrent relapses of illness. Some patients remain noncompliant with treatment and, as a result, are extremely difficult to treat.

When at imminent risk to themselves or others, patients can be hospitalized against their will and be forcibly medicated until their illness is stabilized. The problem then recurs, however, when they are discharged from the hospital. To combat medication noncompliance, patients can receive their antipsychotic medication in an injectable form that provides contin-

www.AHDBonline.com

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CLINICAL

Table 9 Psychiatric and Medical Conditions Associated with Schizophrenia Anxiety and (less commonly) obsessions/compulsion Cardiovascular disorders Depression Metabolic disturbances Obesity Sexual behavior associated with HIV, hepatitis C infection Smoking Substance abuse Suicidality Violence

uous treatment over weeks, usually 2 to 4 weeks. Some clinicians believe that this strategy is underutilized and should become more mainstream rather than be confined to patients who refuse their medications.

Comorbidities complicate treatment In addition to the complexity of the illness itself, patients with schizophrenia are likely to have other psychiatric and/or medical comorbidities over the course of their illness, as outlined in Table 9.

Social aspects of treating mental illness Beyond medications, patients need a huge amount of support.34 The greatest support patients can get—and do get—is from their families. Relatives provide love, emotional support, housing, and financial assistance. They are also the people who know the patient best and can be watchful for signs of relapse. However, the emotional strain of caring and living with someone who is suffering from schizophrenia can be overwhelming.

Relatives also need support. They need education on the latest treatments, as well as tips on how to manage difficult situations. Organizations such as the National Alliance for Mental Illness are an invaluable resource.

Patients also need psychological support from mental health professionals. Patients benefit from counseling and supportive psychotherapy. There are also programs that focus on social skills training, helping patients to make friends and to reintegrate into the community. Most patients do not work; if they do, it is often at a low-paying job. Although it is clear that active psychosis and cognitive deficits reduce the capacity of people to hold down jobs (especially stressful jobs), it is also evident that having a job is a powerful motivator for healthy living and boosts self-esteem.

There are now efforts to train people and to enhance

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AMERICAN HEALTH & DRUG BENEFITS

May 2008

their cognitive abilities so that they will be able to sustain in employment.35 Our system is poorly constructed to help people get, and hold jobs. Sometimes patients are faced with the painful decision of taking a job and losing their Medicaid support, because they now earn a wage. These situations expose some of the many ways that our society discriminates against people with mental illness.

Similar to the role of sponsors in Alcoholics Anonymous, patients with serious mental illness are now also helping other patients to recover.36 These “peer-support specialists” can be powerful catalysts for change, for individual patients and for systems of care through their roles as advocates. This is a powerful approach that broadens the focus of care toward more meaningful, life-attainment goals. It also instills personal responsibility and hope in patients.

Hope is a powerful catalyst in coping with illness.

The notion that some people can recover from serious illnesses like schizophrenia is powerful.37 Important components of recovery for people with serious mental illness include hope, spirituality, and empowerment.37 Patients with more severe illness require continuous support to help them live in the community. This service is delivered by a community psychiatric team comprised of case managers, with each team serving just a few patients. This labor-intensive approach, called “assertive community treatment” (ACT), works well to maintain patients in the community. Although its staffing costs are high, it is still cost-effective, because ACT dramatically reduces days spent in a hospital.

Conclusion Schizophrenia is a challenging condition to diagnose and to treat. The lack of insight that is so common with the condition could undermine (through treatment nonadherence) the efforts of family and mental health professionals to provide comprehensive care.

The potential for comorbidities further adds to the complexity of the illness and will require additional psychiatric and/or medical treatment. These further complicate already arduous clinical circumstances.

Patients with schizophrenia need comprehensive care, compassion, and support. They deserve this.

Disclosure Statement Dr Buckley receives grant/research support from AstraZeneca, National Institute of Mental Health, Pfizer, Solvay, and Wyeth; is a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceutica, Lundbeck, Pfizer, Solvay, and Wyeth; and receives honoraria from Bristol-Myers Squibb, Janssen Pharmaceutica, Lundbeck, and Pfizer.

CLINICAL

References 1. Lieberman J, Stoup S, Perkins DO. Textbook of Schizophrenia.

Washington, DC: American Psychiatric Press; 2006.

2. Jones PB, Buckley PF. Schizophrenia. London: Elsevier; 2006.

3. Castle DJ, Copolov D, Wykes T, Mueser K, eds. Pharmacological and Psychosocial Treatments for Schizophrenia. 2nd ed. London: Informa; 2008.

4. Torrey EF. Surviving Schizophrenia: A Manual for Families, Patients, and Providers. Collins: New York; 2006 [1983].

5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised. Washington, DC: American Psychiatric Association; 2000.

6. Castle DJ, Murray RM, eds. Marijuana and Madness. Cambridge, England: Cambridge University Press; 2004.

7. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculation on the pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50:884-897.

8. Buckley PF. Update on the treatment of schizophrenia and bipolar disorder. CNS Spectr. 2008;13(suppl):1-10.

9. McClellan JM, Susser E, King MC. Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry. 2007;190:194-199.

10. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry.

2005;10(1):40-68.

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

Oxford: Blackwell Press; 2003.

12. Cannon M, Clarke MC. Risk for schizophrenia—broadening the concepts, pushing back the boundaries. Schizophr Res. 2005;79:5-13.

13. Iritani S. Neuropathology of schizophrenia: a mini review.

Neuropathology. 2007;27(6):604-608.

14. Pearlson GD, Calhoun V. Structural and functional magnetic resonance imaging in psychiatric disorders. Can J Psychiatry. 2007;52:158-166.

15. Wright IC, Rabe-Hesketh S, Woodruff PW, et al. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry. 2000;57:16-25.

16. Boos HB, Aleman A, Cahn W, et al. Brain volumes in relatives of patients with schizophrenia: a meta-analysis. Arch Gen Psychiatry.

2007;64:297-304.

17. Harms MP, Wang L, Mamah D, et al Thalamic shape abnormalities in individuals with schizophrenia and their nonpsychotic siblings. J Neuroscie. 2007;27:13835-13842.

18. Weiden PJ, Buckley PF, Grody M. Understanding and treating “firstepisode” schizophrenia. Psychiatr Clin North Am. 2007;30:481-510.

19. Pantelis C, Velakoulis D, McGorry PD. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet. 2003;361:281-288.

20. Murray RM, O’Callaghan E, Castle DJ, Lewis SW. A neurodevelopmental approach to the classification of schizophrenia. Schizophr Bull.

1992;18:319-332.

21. Malaspina D. Schizophrenia: a neurodevelopmental or a neurodegenerative disorder. J Clin Psychiatry. 2006;67:e07.

22. Molina V, Reig S, Sanz J, et al. Association between relative temporal and prefrontal sulcal cerebrospinal fluid and illness duration in schizophrenia. Schizophr Res. 2002;58:305-312.

23. Waddington JL. Neuroimaging and other neurobiological indices in schizophrenia: relationship to measurement of functional outcome. Br J Psychiatry. 2007;50(suppl):s52-s57.

24. Kapur S, Remmington G. Dopamine D2 receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient.

Biol Psychiatry. 2001;50:873-883.

25. Meador-Woodruff J, Klienman J. Neurochemistry of schizophrenia: glutamate abnormalities. In: Davis KL, Charey D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: Fifth Generation of Progress. Lippincott, Williams and Wilkins: Philadelphia, PA; 2002.

26. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guidelines for the management of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 suppl):1-56.

27. Buckley PF. Factors that influence treatment success in schizophrenia. J Clin Psychiatry. 2008;69:4-10 (in press).

28. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.

29. Meyer JM. Cardiovascular illness and hyperlipidemia in patients with schizophrenia. In: Meyer JM, Nasrallah HA, eds. Medical Illness and Schizophrenia. Washington, DC: American Psychiatric Publishing; 2003:53-80.

30. Newcomer JW. Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry. 2007;68(suppl 4):8-13.

31. Moore TA, Buchanan B, Buckley P, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. 2007;68:1751-1762.

32. Harvey PD, Cornblatt B. Pharmacological treatment of cognition in schizophrenia: an idea whose time has come. Am J Psychiatry.

2008;165:163-165.

33. Dolder CR, Lacro JP, Dunn LB, Jeste DV. Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry. 2002;159:103-108.

34. Lacro JP, Dunn LB, Dolder CR, et al. Prevalence of and risk factors for medication non-adherence in patients with schizophrenia. J Clin Psychiatry. 2002;63:892-909.

35. Lauriello J, Bustillo J, Keith SJ. A critical review of research on psychosocial treatment of schizophrenia. Biol Psychiatry. 1999;46:1409-1417.

36. Davidson L, Chinman M, Sells D, et al. Peer support among adults with mental illness: a report from the field. Schizophr Bull. 2006;32:443-450.

37. Substance Abuse and Mental Health Services Administration.

National consensus statement on mental health recovery. Rockville, MD: US Department of Health and Human Services; 2006. http:// mentalhealth.samhsa.gov/publications/allpubs/sma05-4129/. Accessed December 20, 2006.

AHDB Stakeholder Perspective The Approach to Schizophrenia PAYORS: Payors have had a difficult time understanding how to approach schizophrenia. In the private sector, payors are accustomed to taking action when possible. Employers expect contracted insurance companies to take action on their behalf whenever it makes sense. This disease state, however, does not lend itself to such a direct treatment approach. Patients with schizophrenia-related disorders are often reluctant to adhere to medication regimens. The results are often viewed in one of two ways: The sick member who avoids medication, or the sick member who takes expensive medications in a nonadherent manner—both of which result in less-than-optimal health.

The major payors in this arena are state Medicaid agencies. Medicaid dollars pay for a substantial amount, perhaps half, of all prescriptions for schizophrenia, and must then pay for all related healthcare Continued on page 22 www.AHDBonline.com

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CLINICAL

AHDB Stakeholder Perspective Continued from page 21 costs. So what are the goals of these state agencies? The states seek to ensure that people have access to care.

Unfortunately, effectiveness is secondary to access.

This theme seems to be consistent regardless of who the payor is—private or public. As we do for other disease states, the payor community should push for a metric that demonstrates effective care for the patient with schizophrenia. Granting access to a random assortment of nonadherent monotherapies and combination therapies is not the answer. We should strive to ensure that patients and their providers make valiant attempts at treatment protocols before abandoning them in favor of the next horse on the schizophrenia drug carousel.

In the 1970s, advocates fought against the use of “depo-products” (eg, injected haloperidol) on the basis that some patients were overmedicated, and that one did not have the ability to immediately

reverse the course of treatment if desired when using such extended-release products. Over the past 35 years, reverting to daily oral medications as standard treatment has witnessed the reemergence of patient nonadherence. A call for a return to forced medication has now been heard to redress the situation.

Where shall it go from here?

PATIENTS: Ultimately, the direction should be determined by what is best for the patient. Neither legal advocates interested in outlawing extendedrelease medications as a civil rights infringement, nor state agencies willing to throw the entire medicine cabinet at patients without regard to medication effectiveness, should be making this decision.

Prior Authorization for Antipsychotics Complicates Adherence

a strong predictor of acute psychotic episode, hospitalization, and other negative clinical and economic outcomes. Pharmacy savings were minimal.”2 They admit that restrictive policies may control costs when applied to more homogeneous drug classes (eg, nonsteroidal anti-inflammatory drugs or angiotensinconverting enzyme inhibitors), but because of marked differences in patients’ response to antipsychotics, such tools are not productive and can be harmful when used for antipsychotics the authors say. In an interview with Newswire, Dr Soumerai said, “Given the tremendous variation in individual responses to these drugs as well as the devastating impact of treatment disruption on schizophrenic patients, a policy that pushes all patients toward a limited number of preferred drugs may do more harm than good.”3 More than 30% of Medicare Part D and Medicaid programs have PA policies for antipsychotics.1,2

BENEFIT MANAGERS: The question of open versus restrictive access to the newer (atypical) antipsychotic medications lingers, as prior authorization (PA) and step-edit policies are being used to control costs,1 and nonadherence remains a major concern. In his article, Dr Buckley notes that schizophrenia is the most serious mental condition, which requires optimal therapy.

Findings from a study just published in Health Affairs and led by Dr Steven B. Soumerai of Harvard Medical School’s Department of Ambulatory Care and Prevention “provide strong evidence of both intended and unintended consequences of the Maine PA policy”2 implemented in a Medicaid program from July 2003 through March 2004. Dr Soumerai and colleagues compared antipsychotics use in the Maine program pre- and postimplementation of the PA policy; an open access Medicaid program in New Hampshire was used as control. The Maine PA policy resulted in a 29% greater risk of treatment discontinuation compared with the period before implementing the PA policy.2 No differences in discontinuation risk were found in the New Hampshire program.

The authors concluded that “the most adverse clinical outcome was treatment discontinuation, which is

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Michael Schaffer, PharmD Director of Pharmacy HealthMarkets, Philadelphia, PA

References 1. Polinki JM, Wang PS, Fischer MA. Medicaid’s prior authorization program and access to atypical antipsychotic medications. Health Aff. 2007;26:750-760.

2. Soumerai SB, Zhang F, Ross-Deganan D, et al. Use of atypical antipsychotic drugs for schizophrenia in Maine Medicaid following a policy change. Health Aff. 2008;27:w185-w195; DOI 10.1377/hlthaff.

27.3.w185.

3. Plasso A. Restrictive drug policies often cause schizophrenic patients to discontinue medications. Newswire; April 1, 2008. www.

PharmExec.findpharma.com. Accessed April 6, 2008.

3RD Law of Healthonomics:

Soaring healthcare costs are only the symptoms.

Youâ&#x20AC;&#x2122;ve got to start treating the disease.

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www.CenterVBHM.com

Reference: 1.

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GENERIC DRUG TRENDS

Managed Care and Medicare Use of Generics: Seizing the Opportunity, Part 2 Gary M. Owens, MD

L

ast month I discussed the unprecedented share of generic drugs in the total prescriptions that were dispensed in the United States in the past year. In 2004 and 2005, managed care organizations began to recognize the potential value of the very robust pipeline of generic products that were to be launched over the next 5 years. They recognized the significant impact this could have on their pharmacy cost and, ultimately, on the premium structure of the benefit.

Therefore, managed care organizations have embraced the concept of generic drugs openly. They have long recognized the value that these lower-cost versions of pharmaceuticals can bring to their members.

Strategic initiatives—such as waiving copayments, moving drugs with generic equivalents to higher formulary tiers, or in some cases off the formulary altogether—have since been implemented. Genericbefore-brand step-edits are commonplace in today’s benefit plans and have successfully improved generic utilization in key therapeutic classes.1

The Payoff The payoff for promoting increased utilization of generic drugs is rapid, according to health plan standards. The savings include a one-time savings in the year of the generic launch, followed by ongoing savings

Average relative price per dose, %

Figure Generic Competition and Drug Pricing 100

94%

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Source: FDA analysis of retail sales data from IMS Health, MS National Sales Perspective, 1999-2004, extracted February 2005. http://www.fda.gov/cder/ogd/ generic_competition.htm.

each year thereafter. Because of the significant upside potential, health plans and pharmacy benefit management (PBM) organizations often actively promote the use of generics by such things as: • Mailings to members • Communications to pharmacists and doctors • Adjustments to formularies.

These efforts, coupled with generic substitution legislation in many states, often result in rapid conversion of the branded product to the generic. It is now commonplace to see a generic achieve as much as 85% to 95% of the market share within 30 days of its launch.2 At some mail order fulfillment facilities, the generic market share can exceed 95% within the first month.2 For health plans, employers, and PBMs, the economic power of generics is based on several factors.

First, generics often cost 30% to 80% less than their branded counterparts. As seen in the Figure, this level of savings is directly related to market competitive forces, with the price dropping rapidly, as more manufacturers enter the market. Second, generic drugs are generally not subject to the same price inflation as branded products. In its 2007 Drug Trend Report, Medco reported that in 2006, the price inflation for generics was 0.2% compared with 6.9% for branded drugs.2

Medicare Benefits For Medicare members who are in Medicare Advantage plans or prescription drug plans (PDPs), the opportunities are also significant. Medicare members immediately benefit from generic drugs by the lower out-of-pocket cost, since these agents are typically on the lowest formulary copayment tier, or the copayment that is based on the percentage of drug cost is lower.

The second benefit to Medicare beneficiaries comes from the lower acquisition cost of a generic. Since generics cost less, the total spending on behalf of the beneficiary is lower and, therefore, reaching the spending level to put them in what is known as Medicare’s “donut hole” takes longer.

The third benefit is in the period of coverage gap, when the member pays the cost of the drug. The lower cost of a generic, coupled with deeper discounts, result in lower spending by the beneficiary in the period of self-coverage. Many Medicare drug plans also offer enhanced coverage of generics through the socalled donut hole, thereby creating another benefit for the beneficiaries.

In testimony to the Senate Special Committee on Aging on September 21, 2006, then-Centers for MediContinued on page 26

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As we expand beyond our shores, we take with us knowledge and expertise gained for more than 45 years. We recognize the trust that pharmacists place in Mylan Products, that’s why we will continue to do what we do best . . . make proven medicine more affordable for the patients who need them.

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GENERIC DRUG TRENDS

Continued from page 24 care & Medicaid Administrator, Mark B. McClellan, MD, PhD, testified that, “There are early indications that Medicare beneficiaries enrolled in Part D are relying on generics to a greater extent than the U.S. population as a whole. We would expect this utilization trend to continue, as more and more beneficiaries realize the significant savings available by switching to generic drugs.”3 Dr McClellan added, “The Consumers Union found that beneficiaries with common chronic conditions who switch to generic or other therapeutically equivalent medications can save between $2300 and $5300 a year.”3

Generics in Benefit Design: Potential Consequences Less than 25 years ago the use of generic drugs was relatively uncommon, with fewer than 20% of all prescriptions being filled with a generic product.4 Barriers to entry of the generic market were significantly altered in 1984, with the passage of the Hatch-Waxman Act (see AHDB, April 2008, pages 52-55). The past 10 years have seen significant realization of the benefits of this legislation, as billions of dollars in sales of branded drugs have been converted to generics. The public has benefited from more availability of these low-cost alternatives to branded drugs by seeing a significant decrease in the rate of pharmaceutical-spending increase. In addition, Medicare beneficiaries who are enrolled in Medicare Advantage plans or PDPs have taken full advantage of the savings that generics have to offer. One potential consequence of this, however, may have been the demise of the blockbuster small-molecule model in the pharmaceutical industry.

The consequences of this development are still unclear, but 2007 did witness the fewest US Food and Drug Administration approvals of new drugs since 1983. In contrast, consumers in both commercial and Medicare plans have seen significant savings accrue to them by switching to lower-cost generics. As noted last month, in 2007 generic drugs accounted for 63% of all prescriptions written in this country.4 But this represents only about 20% of the total pharmacy spending on drugs5; therefore, there are still many opportunities for savings using generic medications.

It is reasonable to expect continued emphasis, educational efforts, and PBMs designed to encourage the use of generic drugs in 2008 and beyond as a growing portion of the pharmacy market converts to generics. It is also reasonable to expect continued pressure on pharmacy cost and continued efforts to help control this cost by the use of generics.

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Conclusion: Specialty Pharmacy One large, untapped area of generic potential is the biologic and specialty pharmacy area. The debate over this issue will certainly intensify in the future. In the meantime, we can expect continued emphasis by health plans, PBMs, and benefit managers on the value of generic medications in the pharmacy benefit.

Disclosure Statement Dr Owens is a consultant to Amgen, Genzyme, Novartis, and Wyeth, and received an honorarium from Encysive.

References 1. Atlantic Information Services [AIS]. Health plans try new tactics to spur generic drug utilization. Reprinted from the August 7, 2006, issue of Health Plan Week. http://www.aishealth.com/ManagedCare/GenBus/MCW_health_plans_ tactics_generics.html. Accesssed January 21, 2008.

2. Medco Health Solutions. 2007 Drug Trend Report. 2007, vol 9. http:// www.medco.com/art/pdf/Drug_Trend_2007.pdf. Accessed February 3, 2008.

3. McClellan MB. Generic drug utilization in the Medicare prescription drug benefit. Senate Special Committee on Aging, Washington, DC. September 21, 2006. http://www.hhs.gov/asl/testify/t060921.html.

Accessed March 18, 2008.

4. Frank RG. The ongoing regulation of generic drugs. N Engl J Med. 2007;357(20):1993-1996.

5. IMS Health. Generics market expected to soar to $80 billion by 2008. http://www.imshealth.com/ims/portal/front/articleC/0,2777,6599_4018 3881_52651243,00.html. Accessed February 3, 2008.

Dr Owens is President, Gary Owens Associates and former chair of Pharmacy & Therapeutic Committees, Independence Blue Cross.

Unmanaged Moment

“He’s losing it. He just told the truth, the whole truth and nothing but the truth.”

BUSINESS

Trends in Pharmaceutical Expenditures: The Impact on Drug Benefit Design Joanne LaFleur, PharmD, MSPH Leslie Fish, PharmD Diana I. Brixner, RPh, PhD

Annual national spending for pharmaceutical agents was increasing at a rapid pace during the late 1990s and early part of the 21st century, outpacing increases in spending on hospital care and on physician services, which had dominated the industry in the 1970s. In the past few years, however, this trend has shifted, resulting in a lower growth rate in 2005. The reasons for these trends of increases and subsequent declines are explained in this article, including the slower pace of increase in generics and the increasing role of biologic agents in the rate of pharmaceutical price inflation. The sharp increases in drug spending led to changes in prescription drug benefit designs that have not been Joanne LaFleur, PharmD, fully tested. The recent decline creates an opportunity for health plans to evaluate the MSPH value of current and new strategies and implement value-based benefit designs in accordance with the shifting focus in healthcare toward value-based patient care. [AHDB, 2008;1(4):29-34.]

I

n the latter part of the 1990s, the annual increase rate in national spending for pharmaceutical medications ranged from 11% to 17%, overtaking the growth rates for hospital care (3%-6%) and physician services (4%-7%), which had dominated the healthcare industry in the 1970s.1 At the turn of the 21st century, this rate was expected to continue to climb but instead had reached a peak by 2001-2002. And by 2005, the increased spending rate fell to 6%—the lowest it had been since the 1970s.2 For the first 9 months of 2007, the increase rate was only 4.7%—slightly lower than the expected range between 5% and 7%.3 Current projections of increased prescription drug spending rate for 2008 are3:

Dr LaFleur is Research Assistant Professor, University of Utah Pharmacotherapy Outcomes Research Center, Salt Lake City, UT; Dr Fish is Senior Director of Pharmacy Services, Fallon Community Health Plan, Worcester, MA; and Dr Brixner is Associate Professor and Director, University of Utah Pharmacotherapy Outcomes Research Center, Salt Lake City, UT.

• 5% to 7% in the outpatient setting • 12% to 14% in clinic-administered drugs • 4% to 6% for hospital drug expenditures.

This recent leveling-off can be attributed to several factors (many of them a direct result of opposite trends in the previous decade), including4,5: • A smaller number of new drugs entering the market • Expirations of patents for several blockbuster drugs in 2002-2003 • Reductions in the use of several high-cost agents because of safety concerns • Switching to nonprescription status for some frequently used drugs • Lower price inflation for prescription drugs • Higher cost-sharing by consumers • The introduction of a Medicare prescription drug benefit (Part D) in 2005.

Reasons for Shift in Prescription Drug Spending Trends The high rates of growth in the late 1990s are attributed to 3 main factors—(1) increased overall utilization,

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BUSINESS

KEY POINTS The annual increase rate in drug spending has been declining since 2005. Current projections suggest this trend will continue in 2008.

People older than 65 are the largest consumers of prescription drugs—spending 2.7% of their income compared with 1% in the general population.

The growing use of biologics has contributed to pharmaceutical price inflation; biologics are used by 0.2% of patients but account for 8% of total medical costs in an insured population.

The increase in prescription drug spending by private insurance in the late 1990s led to the targeting of prescription drugs for managed plans to rein in costs, primarily by shifting costs to the patient.

The decreased pressure on health plans to contain costs in the coming years provides a great opportunity to evaluate for the first time the impact of cost-saving strategies on patient outcomes and long-term costs.

Value-based drug benefit design should lead to overall cost-efficiencies.

(2) increased prescription drug prices, and (3) increased use of new and expensive drugs. The first factor, increased overall utilization, reflects both an increase in the total US population and an increase in the per-capita number of prescriptions consumed on an annual basis.

From 1993 to 2000, the US population increased from 256 million to 276 million.1 This population expansion has continued and, according to the most recent Census estimates, has just crossed the 300-million mark.6 Figure 1 Average Retail Prescription Drug Prices, 1990-2000 70 60

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1997

Used with permission from Kaiser Family Foundation.1,2 All rights reserved.

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1998

During the same period, the average number of prescriptions per person also rose—from 7.3 to 10.4.1 This increase in utilization per capita is the result of several factors, including an average annual increase of 14% in promotional spending by pharmaceutical manufacturers between 1996 and 2000, as well as an increase in the proportion of all consumers who are older than age 65 years.1 The elderly are by far the largest consumers of prescription drugs, spending 2.7% of their income on prescriptions, compared to only 1% for the general population.1 This may also be partly explained by a lower overall income for the elderly. Nonetheless, for the period from 1993 to 2000, utilization changes accounted for about one half of the overall increase in pharmaceutical spending.1 A second contributor to the high rates of increase in pharmaceutical spending has been the increase in prices for prescription drugs, which was clearly evident throughout the 1990s (Figure 1) and continued into the new century. In 1990, the average price for a prescription drug at a retail pharmacy was $22; by 2000 it had increased to $46.1 Hidden in this number is a striking increase in retail prices for brand-name drugs. The average retail price for generic drugs increased from $10 in 1990 to $19 in 1999, roughly a 90% increase, compared with the average increase in the retail price for brand-name drugs from $27 in 1990 to $65 in 1999—an increase of 140%.1 From 1994 to 2005, prices increased by an average of 8.3% annually—more than triple the average annual inflation rate of 2.5% during that period.1 Over the past several years, the increased availability and use of biologic drugs has been one cause of pharmaceutical price inflation; biologics are used by only 0.2% of patients in the United States but account for 8% of total medical costs in an insured population.4 More recently, since the introduction of Medicare Part D, the 65 cost of medications used by the 61 Medicare population has increased faster than inflation and cost-of-liv46 42 ing adjustment for social security—by 9.2%, which is nearly 4 times higher than the average inflation rate over 19 18 past years.7 Between April 2006 and April 2007, the cost increases for some of 1999 2000 the most frequently prescribed Part D drugs were1: • 15% for escitalopram (Lexapro) • 5% for calcipotriene ointment (Dovonex)

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Approvals, N

14% for eszopiclone (Lunesta) Figure 2 Number of FDA Approvals for Pharmaceuticals and Biologics, 1995-2005 9.2% for celecoxib (Celebrex) 9.2% for atorvastatin (Lipitor) 60 9% for zolpidem (Ambien) 53 7.5% for fluticasone (Flovent) 50 7% for valsartan (Diovan) 39 40 36 35 35 6% for quetiapine (Seroquel).

30 30 29 27 30 Although price increases within a 24 21 21 20 18 18 19 1-year time frame may only represent 19 20 17 17 16 16 15 15 14 a snapshot in time, the more relevant 12 10 10 9 9 9 10 7 7 issue is that price increases are rarely 5 associated with the incremental bene0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 fit of the drug therapy from previous All approvals Expedited review Standard review years, and disproportionate price increases to any specific population, such as the elderly, are rarely justified FDA indicates US Food and Drug Administration. or accommodated through pharmacy Source: Reference 5. benefit design. For the period between 1993 and 2000, price inflation for prescription drugs accounted for 19% to Figure 3 Percentage of Total National Drug Expenditures by Type of Payor, 1990-2006 24% of the overall increases in expenditures for prescription drugs.8 56 60 50 A third contributor to the high 49 49 48 47 47 50 43 43 42 rates of increase in drug spending 40 36 35 during that period was an increase in 31 39 31 28 26 27 27 30 26 the use of newer and more expensive 22 22 21 20 19 18 25 25 25 agents in general (Figure 2). The 20 23 approval of new drugs and biologics 10 by the US Food and Drug Admin0 istration (FDA) fluctuates from year 1990 1992 1994 1996 1998 2000 2002 2004 2005 2006 Projected to year, but in the late 1990s, when Government programs Private insurance Out-of-pocket annual increases in expenditures were high, the number of drugs and biologics approved annually averaged Used with permission from Kaiser Family Foundation. All rights reserved.

37.5 Between 2001 and 2005, when annual increases in spending began to decline, the number of new FDA approvals also fell Second, new drugs increase overall spending because to an annual average of 24.5 new drugs are often used as add-on therapy rather than A number of variables can affect how new drugs a replacement for existing treatments, as in the case of increase overall spending. First, new drugs may be used new treatments for Alzheimer’s disease or diabetes. in place of older, and less costly, drugs. For example, with Finally, new drugs increase spending because they may the introduction of oral antidiabetic agents, the use of treat a condition not previously treated with drug therrelatively inexpensive insulin in the mid-1990s was apy, such as for the treatment of obesity, erectile dysreduced.9 More recently, Brixner and colleagues showed function, or irritable bowel syndrome. Therefore, that the market share of angiotensin receptor blockers between 1993 and 2000, the increased use of new agents continues to grow,10 despite the publication of the contributed to about one third of the overall increase in Antihypertensive and Lipid-Lowering Treatment to spending on prescription drugs.1 11 Prevent Heart Attack Trial (ALLHAT) in 2007, which Change in Health Plan Reimbursement Strategies indicated that older antihypertensive medications were Shifting Drug Cost to Private Insurers the preferred first-line agents for the reduction of cardioAs spending on pharmaceuticals increased in past vascular mortality in patients with hypertension.

Percentage

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Figure 4 Projected Pharmaceutical Cost Trend, 2002-2017 14

600

12

500

8 300 6 200

4

100

2 0

0 2002

2004

Rx cost

2006

2008

2010

2012

2014

2016

Rx cost as % of total healthcare cost

Source: Reference 19.

years, there was also an accompanying transition of private insurance expenditures over time (Figure 3). In the early 1990s, consumer out-of-pocket spending was the number-one source of payment for prescription drugs, accounting for 56% of all expenditures in 1990.2 During the next few years, the proportion of total outof-pocket prescription drug spending by consumers began to decline, with an associated increase in the proportion of spending by private insurance. By 1997, the private insurance sector overtook consumer out-ofpocket spending as the top payor, and by 2000, private insurance paid for 50% of all prescription drugs.2 This shift in spending to private insurance did not reflect a decrease in out-of-pocket spending for consumers as one might conclude; rather, it resulted from the increase in overall spending on prescription drugs in the US market. For example, in 1980 consumer out-of-pocket spending on prescription drugs represented 5.6% of total consumer out-of-pocket expenditures on healthcare; by 1999 it had increased to 10.2%.1 This represented 1.0% of all consumer expenditures, including housing (32.6%), food (13.6%), and transportation (18.9%). Nonetheless, the increase in prescription drug spending by private insurance led to the targeting of prescription drugs for managed plans to rein-in costs, primarily by costshifting to the patient.

In a recent review, the Kaiser Family Foundation identified nearly 30 strategies used by health plans to decrease spending on pharmaceuticals, including efforts to directly limit the availability of drugs, to increase cost-sharing for patients, or to decrease pre-

32

Percentage

In $ billions

10 400

scribing of drugs through educational efforts targeted toward providers.12 Methods used to increase cost-sharing include copayments, particularly when associated with a tiered formulary. A formulary is a list of preferred drugs developed by healthcare systems to identify the most useful drugs.13 Tiered benefit designs are a mechanism used to allow open formularies, while simultaneously limiting the utilization of nonpreferred agents with increased cost-shifting to the patient.

AMERICAN HEALTH & DRUG BENEFITS

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Tiered Benefit Design Tiered benefit designs range in complexity from the simplest formâ&#x20AC;&#x201D;2 different copayments for branded drugs and generic drugsâ&#x20AC;&#x201D;to a design with 4 or more tiers for generics, preferred brand-name drugs, nonpreferred brand-name drugs, and specialty or biologic drugs.12 The tiered benefit design has become prevalent in health plans. By 2004, 90% of covered workers had tiered benefit designsâ&#x20AC;&#x201D;65% with 3 tiers, 20% with 2 tiers, and 3% with 4 tiers.12 Studies of these benefit designs generally show a decrease in short-term spending on pharmaceuticals.14-18 However, the overall value of these designs in terms of their impact on patient outcomes and long-term costs has not yet been evaluated.12 Projections for Drug Expenditures Prescription drug spending is expected to continue to increase for the next 4 years, although at a lower rate than was seen a decade ago.19 Projections for prescription drug expenditures in the coming years are outlined in Figure 4. The increase is expected to accompany a decreasing proportion of overall healthcare spending in other healthcare markets.19 The reason for this is that pharmaceuticals tend to be a very cost-effective option compared with other types of healthcare spending. A heuristic frequently cited in the popular press states that every dollar spent on prescription drugs saves $3.50 in other healthcare expenditures.20 With decreased rates of inflation for prescription drugs, the resultant decreased pressure on health plans to contain costs should be viewed as an opportunity to evaluate the impact of cost-saving strategies on patient outcomes and long-term costs, which has not heretofore been done.

Conclusions As healthcare costs continue to rise and pharmaceutical expenditures continue to show value in the treat-

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ment and prevention of disease, drug benefit design should be expected to transition from a cost-management approach to a value-based approach. Patients should be expected to pay more when preference drives their decision. However, when legitimate health concerns, such as lack of efficacy or adverse events, can be documented, that evidence should support access to alternative medication choice, without financial burden to the patient. If access to drugs is determined by the drugs’ value to defined populations, then valuebased drug benefit design should lead to overall costefficiencies, by defining patient-target populations for drug access and not by defining this access by cost.

Disclosure Statement Dr Brixner received honoraria from Pfizer for the preparation of this article.

14. Huskamp HA, Deverka PA, Epstein AM, et al. The effect of incentive-based formularies on prescription-drug utilization and spending. N Engl J Med. 2003;349:2224-2232.

15. Joyce GF, Escarce JJ, Solomon MD, Goldman DP. Employer drug benefit plans and spending on prescription drugs. JAMA. 2002; 288:1733-1739.

16. Kamal-Bahl S, Briesacher B. How do incentive-based formularies influence drug selection and spending for hypertension? Health Aff (Millwood). 2004;23:227-236.

17. Motheral B, Fairman KA. Effect of a three-tier prescription copay on pharmaceutical and other medical utilization. Med Care. 2001;39:1293-1304.

18. Rector TS, Finch MD, Danzon PM, et al. Effect of tiered prescription copayments on the use of preferred brand medications. Med Care.

2003;41:398-406.

19. Keehan S, Sisko A, Truffer C, et al. Health spending projections through 2017: the baby boom generation is coming to Medicare. Health Aff. 2008;27:w145-w155.

20. Pear R. Future bleak for bill to keep health records confidential. New York Times; 1999:A12.

For inquiries or comments, please contact editorial@AHDBonline.com.

References 1. Henry J. Kaiser Family Foundation. Prescription Drug Trends—A Chartbook Update. Kaiser Family Foundation. http://www.kff.org/ rxdrugs/loader.cfm?url=/commonspot/security/getfile.cfm&PageID=137 96. November 2001. Accessed March 22, 2008.

2. Henry J. Kaiser Family Foundation. Prescription Drug Trends. Kaiser Family Foundation. http://www.kff.org/rxdrugs/upload/3057_06.pdf.

Updated May 2007. Accessed March 22, 2008.

3. Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures—2008. Am J Health Syst Pharm. 2008;65:234-253.

4. Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures—2006. Am J Health-Syst Pharm. 2006;63:123-138.

5. US Food and Drug Administration. Center for Drug Evaluation and Research Report to the Nation: 2005. Improving Public Health Through Human Drugs. http://www.fda.gov/cder/reports/rtn/2005/rtn2005.PPT. Updated August 2006. Accessed March 22, 2008.

6. CNN.com. US population now 300 million and growing. CNN.com. http://www.cnn.com/2006/US/10/17/300.million.over/index.html.

Updated October 17, 2006. Accessed March 22, 2008.

7. Families USA. No Bargain: Medicare Drug Plans Deliver High Prices.

Families USA Publication No. 07-101. http://www.familiesusa.org/ assets/pdfs/no-bargain-medicare-drug.pdf. Accessed April 25, 2008.

8. Hoffman JM, Shah ND, Vermeaulen LC, et al. Projecting future drug expenditures—2007. Am J Health Syst Pharm. 2007;64:298-314.

9. Hauber A, Gale EA. The market in diabetes. Diabetologia.

2006;49:247-252.

10. Brixner DI, Ghate SR, McAdam-Marx C, Maio V. Analysis of primary care prescribing patterns of antihypertensive agents (AAs) before and after publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Poster presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 9th Annual European Congress, October 28-31, 2006, Copenhagen, Denmark.

11. Einhorn PT, Davis BR, Massie BM, et al, for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) heart failure validation study: diagnosis and prognosis. Am Heart J. 2007;153:42-53.

12. Henry J. Kaiser Family Foundation. Cost-containment strategies for prescription drugs: assessing the evidence in the literature. http://www.kff.org/rxdrugs/upload/Cost-Containment-Strategies-forPrescription-Drugs-Assessing-The-Evidence-in-the-Literature-Report.pdf.

Updated March, 2005. Accessed March 22, 2008.

13. American Society of Health-System Pharmacists. ASHP guidelines on formulary system management. Am J Health Syst Pharm. 1992;49:648-652.

AHDB Stakeholder Perspective Drug Expenditures’ Impact on Benefit Design HEALTH PLANS: Commercially sponsored health plans remain focused on aggressive costmanagement strategies for healthcare services that make sense to all stakeholders. As a premise for facilitating change, the authors may be naïve about the window of opportunity to introduce new solutions for healthcare expenditures, including pharmaceuticals. Although there may some respite in cost escalation as a result of brand blockbusters going generic, overall costs have not truly flattened from a health plan sponsor’s perspective.

Current drug trends remain a concern, and alternatives, such as value-based strategies, are increasing from an interest perspective but not from the perspective of adoption across the greater marketplace. Some of the many issues associated with the concept of value-based benefit design is a lack of consensus on what constitutes such value, as well as what works for both the employee and the employer; how to implement a value-based plan; and what program design is the best for optimal economic outcomes for any specific plan sponsor.

Employers and other plan sponsors are facing a recessionlike economy in the United States, along Continued on page 34 www.AHDBonline.com

33

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AHDB Stakeholder Perspective Continued from page 33 with a multivariate set of factors that affect healthcare costs, including the presidential election cycle.

Furthermore, the impact of biologic drugs followed by nanotechnology will likely exert greater pressure on an existing pharmacy benefit system that does not appear to work for drug products, with cost of product expenditures 10- to 100-fold greater than the traditional oral or topical pharmaceuticals used in the market today.

BENEFIT MANAGERS: It is important for all stakeholders to address fundamental issues in the healthcare market. A review of value-based drug benefit design is reasonable and needs to be replicated beyond a few success stories. Furthermore, the basic premise of increased cost-efficiency through efforts such as value-based plans or patient-segment targeting needs to be better understood. For example, some believe that patient segmentation through medical/scientific means, such as personalized

healthcare, could increase health spending and exacerbate drug trends for the short-term, which can threaten business survival. Another question is how can we achieve appropriate patient segmentation through existing benefit programs or designs to provide the needed cost-efficiencies in health plans that will include the value of pharmaceuticals?

Commenting or reporting on current trends and benefit design can be a challenge for academic researchers, as well as for healthcare benefit managers. Being aware of all the information and perspectives available about medical or pharmacy program benefit performance, however, can only help all decision makers in making better informed health benefit plan decisions.

F. Randy Vogenberg, RPh, PhD Chief Strategic Officer Employer-based Pharmaceutical Strategies, LLC

Information for Authors Manuscripts submitted to American Health & Drug Benefits (AHDB) must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by AHDB. To be considered for publication, manuscripts must adhere to the format described in this document. All manuscripts are subject to peer review, and acceptance is based on that review. If accepted, authors will be notified of any recommended revisions. The revised manuscript should be resubmitted in its entirety, with all changes made.

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address, telephone number, and e-mail address of the corresponding author A 200-word Abstract Conclusion Double space the entire manuscript and number pages Cite all Tables and Figures in the text, but place the actual graphic elements at the end of the article; type all figure heads and captions in a Word format References: use 25-30 current, post-1990 references, cited in the text but listed at the end of the manuscript. Avoid automatic numbering or footnote/endnote features Length of article: 2500-3000 words, plus tables and figures Save all Figures or images as individual files, at high resolution (300 dpi), as jpg, tiff, or eps. Images not saved appropriately or saved within the Word document will delay the peer-review process significantly.

Routine editorial changes will be made to conform to house style, following the AMA Manual of Style, 10th ed. (New York, NY: Oxford University Press, 2007). The edited manuscript is sent to the author for a final review and approval. Time from submission to publication is generally 3 to 5 months.

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COPYRIGHT/DISCLOSURE Authors are required to sign a Copyright Transfer Form, assigning all copyrights to Engage Healthcare Communications, LLC, publisher of AHDB, as well as a Financial Disclosure Form, disclosing any financial interests or potential conflict of interest involving the materials discussed in the manuscript.

PERMISSIONS Authors must secure a written permission from the original publisher for any previously published (online or in print) Table or Figure. Provide the source with each element.

MANUSCRIPT FORMAT • Title page should have a proper title for the article and list the names, titles, and affiliations of all authors. Also list the name,

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HOW TO SUBMIT Save the manuscripts as a Word file and attach individual files for each image used in the article, saved as an image file (eg, jpeg, tif, eps).

Submit the manuscript electronically to: editorial@AHDB online.com. For assistance with submission, call 732-992-1892.

For many patients with schizophrenia

Gaps in medication can compromise their progress…

RISPERDAL CONSTA helps to keep them on solid footing RISPERDAL CONSTA, while not guaranteeing adherence, allows you to recognize and intervene when a patient misses a dose

Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo.

Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen 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 either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

RISPERDAL® CONSTA® (risperidone) is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including RISPERDAL CONSTA. Clinical manifestations include muscle rigidity, fever, altered mental status and evidence of autonomic instability (see full Prescribing Information).

Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.

Hyperglycemia and Diabetes: Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death has been reported in patients treated with atypical antipsychotics (APS), including RISPERDAL CONSTA. Patients starting treatment with APS who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of

Extrapyramidal Symptoms (EPS): The overall incidence of EPS-related adverse events in patients treated with 25 mg and 50 mg of RISPERDAL CONSTA and placebo, respectively, were akathisia (2%, 9%, 4%), Parkinsonism* (4%, 10%, 3%) and tremor (0%, 3%, 0%). *Bradykinesia, extrapyramidal disorder, and hypokinesia.

01CS921

Maintenance Treatment: Patients should be periodically reassessed to determine the need for continued treatment.

Please see accompanying brief summary of full Prescribing Information, including Boxed Warning, for RISPERDAL CONSTA. Visit our Web site at risperdalconsta.com

ATING 50 Y E BR

S AR

Cerebrovascular Adverse Events (CAEs): CAEs, including fatalities, have been reported in elderly patients with dementia-related psychosis taking oral risperidone in clinical trials. The incidence of CAEs with risperidone was significantly higher than with placebo.

RISPERDAL CONSTA is not approved for treating these patients.

Potential for Cognitive and Motor Impairment: RISPERDAL CONSTA has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that RISPERDAL CONSTA does not affect them adversely.

TM

IN

Commonly Observed Adverse Events for RISPERDAL CONSTA: Treatment-emergent adverse events with an incidence of 5% or greater in at least one of the RISPERDAL CONSTA groups (25 mg or 50 mg) and at least twice that of placebo were: somnolence, akathisia, Parkinsonism, dyspepsia, constipation, dry mouth, fatigue, and weight increase.

Orthostatic Hypotension: RISPERDAL CONSTA may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period. Monitoring should be considered in patients for whom this may be of concern. RISPERDAL CONSTA should be used with caution in patients with known cardiovascular disease, and conditions that would predispose patients to hypotension.

M

H

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose. Elderly patients appeared to be at increased risk for TD. Prescribing should be consistent with the need to minimize the risk of TD. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

EN

LT

IMPORTANT SAFETY INFORMATION FOR RISPERDAL CONSTA

of patients experiencing weight gain (>7% of baseline body weight) was 6% placebo versus 9% RISPERDAL CONSTA.

E

hyperglycemia should also undergo fasting blood glucose testing.

CE L

RISPERDAL® CONSTA® (risperidone) long-acting injection is indicated for the treatment of schizophrenia.

TA L H E

A

Weight Gain: In a 12-week trial, the percentage © Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2008 March 2008 01CS851R1

BEFORE PRESCRIBING, PLEASE CONSULT COMPLETE PRESCRIBING INFORMATION OF WHICH THE FOLLOWING IS A BRIEF SUMMARY. Increased Mortality in Elderly Patients with Dementia–Related Psychosis Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen 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 either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. RISPERDAL® CONSTA® (risperidone) is not approved for the treatment of patients with Dementia-Related Psychosis.

INDICATIONS AND USAGE: RISPERDAL® CONSTA® (risperidone) is indicated for the treatment of schizophrenia.

CONTRAINDICATIONS: RISPERDAL® CONSTA® (risperidone) is contraindicated in patients with a known hypersensitivity to the product or any of its components.

WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. RISPERDAL® CONSTA® (risperidone) is not approved for the treatment of dementia-related psychosis (see Boxed Warning). Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Other signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include: discontinuation of the antipsychotic and other drugs not essential to therapy; intensive symptomatic treatment and medical monitoring; and treatment of other serious medical problems. If a patient requires antipsychotic drugs after recovery from NMS, the reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences have been reported. Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. The risk of developing and likelihood that it will become irreversible are believed to increase with the duration of treatment and the total cumulative dose. However, tardive dyskinesia can develop, after brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although it may remit, partially or completely, if the antipsychotic is withdrawn. Prescribing should be in a manner to minimize the occurrence. In patients who require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms should appear drug discontinuation should be considered. Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis: Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with oral risperidone compared to patients treated with placebo. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementia-related psychosis. (See also Boxed WARNING, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.) Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including RISPERDAL®. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.

PRECAUTIONS: General: Administration: RISPERDAL® CONSTA® should be injected into the gluteal muscle, and care must be taken to avoid inadvertent injection into a blood vessel. (See DOSAGE AND ADMINISTRATION in full PI, and ADVERSE REACTIONS – Postintroduction Reports [retinal artery occlusion].) Orthostatic Hypotension: RISPERDAL® CONSTA® (risperidone) may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.8% (12/1499 patients) of patients treated with RISPERDAL® CONSTA® in multiple-dose studies. Patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). RISPERDAL® CONSTA® should be used with particular caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia, and (2) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral RISPERDAL® and antihypertensive medication. Seizures: During premarketing testing, seizures occurred in 0.3% (5/1499 patients) of patients treated with RISPERDAL® CONSTA®. Therefore, RISPERDAL® CONSTA® should be used cautiously in patients with a history of seizures. Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. RISPERDAL® CONSTA® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. (See also Boxed WARNING, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.) Osteodystrophy and Tumors in Animals: RISPERDAL® CONSTA® produced osteodystrophy in male and female rats in a 1-year toxicity study and a 2-year carcinogenicity study at a dose of 40 mg/kg administered IM every 2 weeks. RISPERDAL® CONSTA® produced renal tubular tumors (adenoma, adenocarcinoma) and adrenomedullary pheochromocytomas in male rats in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks. In addition, RISPERDAL® CONSTA® produced an increase in a marker of cellular proliferation in renal tissue in males in the 1-year toxicity study and in renal tumorbearing males in the 2-year carcinogenicity study at 40 mg/kg administered IM every 2 weeks.

Neither the renal or adrenal tumors, nor osteodystrophy, were seen in studies of orally administered risperidone. Osteodystrophy was not observed in dogs at doses up to 14 times (based on AUC) the IM MRHD in a 1-year toxicity study. The renal tubular and adrenomedullary tumors in male rats and other tumor findings are described in more detail under PRECAUTIONS, Carcinogenicity, Mutagenesis, Impairment of Fertility. The relevance of these findings to human risk is unknown. Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. Potential for Cognitive and Motor Impairment: Somnolence was reported by 5% of patients treated with RISPERDAL® CONSTA® in multiple-dose trials. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that treatment with RISPERDAL® CONSTA® does not affect them

adversely. Priapism: Rare cases of priapism have been reported in patients treated with RISPERDAL® CONSTA®. Thrombotic Thrombocytopenic Purpura (TTP): A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to RISPERDAL® therapy is unknown. Antiemetic Effect: Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumor. Body Temperature Regulation: Disruption of body temperature regulation has been attributed to antipsychotic agents.

Suicide: The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy. Use in Patients with Concomitant Illness: Clinical experience with RISPERDAL® CONSTA® in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL® CONSTA®, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome. Caution is advisable when using RISPERDAL® CONSTA® in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Increased plasma concentrations of risperidone and 9–hydroxyrisperidone occur in patients with severe renal impairment. Patients with renal or hepatic impairment should be carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with renal or hepatic impairment (see DOSAGE AND ADMINISTRATION – Dosage in Special Populations in full PI). Information for Patients: Physicians are advised to discuss the following issues with patients for whom they prescribe RISPERDAL® CONSTA®.

Orthostatic Hypotension: Patients should be advised of the risk of orthostatic hypotension and instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). Interference With Cognitive and Motor Performance: Because RISPERDAL® CONSTA® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that treatment with RISPERDAL® CONSTA® does not affect them adversely. Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy and for at least 12 weeks after the last injection of RISPERDAL® CONSTA®. Nursing: Patients should be advised not to breast-feed an infant during treatment and for at least 12 weeks after the last injection of RISPERDAL® CONSTA®. Concomitant Medication: Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol: Patients should be advised to avoid alcohol during treatment with RISPERDAL ® CONSTA ® . Drug Interactions: The interactions of RISPERDAL ® CONSTA ® and other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® CONSTA® is administered in combination with other centrally-acting drugs or alcohol.

Because of its potential for inducing hypotension, RISPERDAL® CONSTA® may enhance the hypotensive effects of other therapeutic agents with this potential. RISPERDAL® CONSTA® may antagonize the effects of levodopa and dopamine agonists. Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety. Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of the active moiety, whereas ranitidine increased the AUC of the active moiety by 20%. Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

Carbamazepine and Other CYP 3A4 Enzyme Inducers: In a drug interaction study in schizophrenic patients, 11 subjects received oral risperidone titrated to 6 mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3 weeks. During co-administration, the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Coadministration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL® CONSTA® treatment. At the initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers, patients should be closely monitored during the first 4-8 weeks, since the dose of RISPERDAL® CONSTA® may need to be adjusted. A dose increase, or additional oral RISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL ® CONSTA ® should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL® CONSTA® and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. (See also DOSAGE AND ADMINISTRATION in full PI.) The efficacy of the 12.5 mg dose has not been investigated in clinical trials. Fluoxetine and Paroxetine: Fluoxetine (20 mg QD) and paroxetine (20 mg QD), CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone.

Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA® dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. When RISPERDAL® CONSTA® is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. (See also DOSAGE AND ADMINISTRATION in full PI.) The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.

Lithium: Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13). Valproate: Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (C max) after concomitant administration of risperidone. Digoxin: RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Drugs that Inhibit CYP 2D6 and Other CYP Isozymes: Risperidone is metabolized to 9–hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs (see CLINICAL PHARMACOLOGY in full PI). Drug interactions that reduce the metabolism of risperidone to 9–hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9–hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n; 70 patients) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made. In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. There were no significant interactions between risperidone and erythromycin (see CLINICAL PHARMACOLOGY in full PI). Drugs Metabolized by CYP 2D6: In vitro studies indicate that risperidone is a relatively weak inhibitor of

CYP 2D6. Therefore, RISPERDAL® CONSTA® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis - Oral: Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the oral maximum recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis, or 0.2, 0.75, and 3 times the oral MRHD (mice) or 0.4, 1.5, and 6 times the oral MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There was a significant increase in pituitary gland adenomas in female mice at doses 0.75 and 3 times the oral MRHD on a mg/m2 basis. There was a significant increase in endocrine pancreatic adenomas in male rats at doses 1.5 and 6 times the oral MRHD on a mg/m2 basis. Mammary gland adenocarcinomas were significantly increased in female mice at all doses tested (0.2, 0.75, and 3 times the oral MRHD on a mg/m2 basis), in female rats at all doses tested (0.4, 1.5, and 6 times the oral MRHD on a mg/m2 basis), and in male rats at a dose 6 times the oral MRHD on a mg/m2 basis. Carcinogenesis - IM: RISPERDAL® CONSTA® was evaluated in a 24-month carcinogenicity study in which SPF Wistar rats were treated every 2 weeks with IM injections of either 5 mg/kg or 40 mg/kg of risperidone. These doses are 1 and 8 times the MRHD (50 mg) on a mg/m2 basis. A control group received injections of 0.9% NaCl, and a vehicle control group was injected with placebo microspheres. There was a significant increase in pituitary gland adenomas, endocrine pancreas adenomas, and adrenomedullary pheochromocytomas at 8 times the IM MRHD on a mg/m2 basis. The incidence of mammary gland adenocarcinomas was significantly increased in female rats at both doses (1 and 8 times the IM MRHD on a mg/m2 basis). A significant increase in renal tubular tumors (adenoma, adenocarcinomas) was observed in male rats at 8 times the IM MRHD on a mg/m2 basis. Plasma exposures (AUC) in rats were 0.3 and 2 times (at 5 and 40 mg/kg, respectively) the expected plasma exposure (AUC) at the IM MRHD. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown (see PRECAUTIONS - Hyperprolactinemia). Mutagenesis: No evidence of mutagenic potential for oral risperidone was found. In addition, no evidence of mutagenic potential was found in the in vitro Ames reverse mutation test for RISPERDAL® CONSTA®. Impairment of Fertility: Oral risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies at doses 0.1 to 3 times the oral maximum recommended human dose. No mating and fertility studies were conducted with RISPERDAL® CONSTA®. Pregnancy: Pregnancy Category C: The teratogenic potential of oral risperidone was studied in three embryofetal development studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the oral maximum recommended human dose [MRHD] on a mg/m2 basis) and in one embryofetal development study in New Zealand rabbits (0.315 mg/kg or 0.4 to 6 times the oral MRHD on a mg/m2 basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the oral MRHD on a mg/m2 basis. In three reproductive studies in rats (two peri/post-natal development studies and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times the oral MRHD on a mg/m2 basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams. There was no no-effect dose for increased rat pup mortality. In one peri/post-natal development study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the oral MRHD on a mg/m2 basis.

In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Days 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the oral MRHD on a mg/m2 basis. No studies were conducted with RISPERDAL® CONSTA®.

Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to oral RISPERDAL® therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of risperidone during the last trimester of pregnancy. RISPERDAL® CONSTA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery: The effect of RISPERDAL® CONSTA® on labor and delivery in humans is unknown.

Nursing Mothers: In animal studies, risperidone and 9–hydroxyrisperidone are excreted in milk.

Risperidone and 9–hydroxyrisperidone are also excreted in human breast milk. Therefore, women should not breast-feed during treatment with RISPERDAL® CONSTA® and for at least 12 weeks after the last injection. Pediatric Use: RISPERDAL® CONSTA® has not been studied in children younger than 18 years old. Geriatric Use: In an open-label study, 57 clinically stable, elderly patients (e 65 years old) with schizophrenia or schizoaffective disorder received RISPERDAL® CONSTA® every 2 weeks for up to 12 months. In general, no differences in the tolerability of RISPERDAL® CONSTA® were observed between otherwise healthy elderly and nonelderly patients. Therefore, dosing recommendations for otherwise healthy elderly patients are the same as for nonelderly patients.

Because elderly patients exhibit a greater tendency to orthostatic hypotension than nonelderly patients, elderly patients should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). In addition, monitoring of orthostatic vital signs should be considered in elderly patients for whom orthostatic hypotension is of concern (see PRECAUTIONS, DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY in full PI). Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis: In placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated with oral risperidone alone or with oral placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementiarelated psychosis was seen with the use of oral risperidone regardless of concomitant use with furosemide. RISPERDAL® CONSTA® is not approved for the treatment of patients with dementiarelated psychosis. (See Boxed WARNING, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)

ADVERSE REACTIONS: Associated with Discontinuation of Treatment: In the 12-week, placebocontrolled trial, the incidence of schizophrenic patients who discontinued treatment due to an adverse event was lower with RISPERDAL® CONSTA® (11%; 22/202 patients) than with placebo (13%; 13/98 patients). Incidence in Controlled Trials: Commonly Observed Adverse Events in Controlled Clinical Trials: Spontaneously reported, treatment-emergent adverse events with an incidence of 5% or greater in at least one of the RISPERDAL® CONSTA® groups (25 mg or 50 mg) and at least twice that of placebo were: somnolence, akathisia, parkinsonism, dyspepsia, constipation, dry mouth, fatigue, weight increase. Dose Dependency of Adverse Events: Extrapyramidal Symptoms: The overall incidence of EPS-related adverse events (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL® CONSTA® was comparable to that of patients treated with placebo; the incidence of EPS-related adverse events was higher in patients treated with 50 mg RISPERDAL® CONSTA®. 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. Vital Sign Changes: RISPERDAL® is associated with orthostatic hypotension and tachycardia (see PRECAUTIONS). In the placebo-controlled

trial, orthostatic hypotension was observed in 2% of patients treated with 25 mg or 50 mg RISPERDAL® CONSTA® (see PRECAUTIONS). Weight Changes: In the 12-week, placebo-controlled trial, 9% of patients treated with RISPERDAL® CONSTA®, compared with 6% of patients treated with placebo, experienced a weight gain of >7% of body weight at endpoint. Laboratory Changes: The percentage of patients treated with RISPERDAL® CONSTA® who experienced potentially important changes in routine serum chemistry, hematology, or urinalysis parameters was similar to or less than that of placebo patients. Additionally, no patients discontinued treatment due to changes in serum chemistry, hematology, or urinalysis parameters. ECG Changes: The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg RISPERDAL® CONSTA® and 98 schizophrenic patients treated with placebo in a 12-week, double-blind, placebo-controlled trial were evaluated.

Compared with placebo, there were no statistically significant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with RISPERDAL® CONSTA®. Pain Assessment and Local Injection Site Reactions: The mean intensity of injection pain reported by patients using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL® CONSTA® experienced redness, swelling, or induration at the injection site. Other Events Observed During the Premarketing Evaluation of RISPERDAL® CONSTA®: During its premarketing assessment, RISPERDAL ® CONSTA® was administered to 1499 patients in multiple-dose studies. The conditions and duration of exposure to RISPERDAL® CONSTA® varied greatly, and included (in overlapping categories) open-label and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and short-term and long-term exposure studies. The following reactions were reported: (Note: frequent adverse events are those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. It is important to emphasize that, although the reported events occurred during treatment with RISPERDAL® CONSTA®, they were not necessarily caused by it.) Psychiatric Disorders: Frequent: anxiety, psychosis, depression, agitation, nervousness, paranoid reaction, delusion, apathy. Infrequent: anorexia, impaired concentration, impotence, emotional lability, manic reaction, decreased libido, increased appetite, amnesia, confusion, euphoria, depersonalization, paroniria, delirium, psychotic depression. Central and Peripheral Nervous System Disorders: Frequent: hypertonia, dystonia. Infrequent: dyskinesia, vertigo, leg cramps, tardive dyskinesiaa, involuntary muscle contractions, paraesthesia, abnormal gait, bradykinesia, convulsions, hypokinesia, ataxia, fecal incontinence, oculogyric crisis, tetany, apraxia, dementia, migraine. Rare: neuroleptic malignant syndrome. aIn the integrated database of multiple-dose studies (1499 patients with schizophrenia or schizoaffective disorder), 9 patients (0.6%) treated with RISPERDAL® CONSTA® (all dosages combined) experienced an adverse event of tardive dyskinesia. Body as a Whole/General Disorders: Frequent: back pain, chest pain, asthenia. Infrequent: malaise, choking. Gastrointestinal Disorders: Frequent: nausea, vomiting, abdominal pain. Infrequent: gastritis, gastroesophageal reflux, flatulence, hemorrhoids, melena, dysphagia, rectal hemorrhage, stomatitis, colitis, gastric ulcer, gingivitis, irritable bowel syndrome, ulcerative stomatitis. Respiratory System Disorders: Frequent: dyspnea. Infrequent: pneumonia, stridor, hemoptysis. Rare: pulmonary edema. Skin and Appendage Disorders: Frequent: rash. Infrequent: eczema, pruritus, erythematous rash, dermatitis, alopecia, seborrhea, photosensitivity reaction, increased sweating. Metabolic and Nutritional Disorders: Infrequent: hyperuricemia, hyperglycemia, hyperlipemia, hypokalemia, glycosuria, hypercholesterolemia, obesity, dehydration, diabetes mellitus, hyponatremia. Musculo-Skeletal System Disorders: Frequent: arthralgia, skeletal pain. Infrequent: torticollis, arthrosis, muscle weakness, tendinitis, arthritis, arthropathy. Heart Rate and Rhythm Disorders: Frequent: tachycardia. Infrequent: bradycardia, AV block, palpitation, bundle branch block. Rare: T-wave inversion. Cardiovascular Disorders: Frequent: hypotension. Infrequent: postural hypotension.

Urinary System Disorders: Frequent: urinary incontinence. Infrequent: hematuria, micturition frequency, renal pain, urinary retention. Vision Disorders: Infrequent: conjunctivitis, eye pain, abnormal accommodation. Reproductive Disorders, Female: Frequent: amenorrhea. Infrequent: nonpuerperal lactation, vaginitis, dysmenorrhea, breast pain, leukorrhea. Resistance Mechanism Disorders: Infrequent: abscess. Liver and Biliary System Disorders: Frequent: increased hepatic enzymes. Infrequent: hepatomegaly, increased SGPT. Rare: bilirubinemia, increased GGT, hepatitis, hepatocellular damage, jaundice, fatty liver, increased SGOT. Reproductive Disorders, Male: Infrequent: ejaculation failure. Application Site Disorders: Frequent: injection site pain. Infrequent: injection site reaction. Hearing and Vestibular Disorders: Infrequent: earache, deafness, hearing decreased. Red Blood Cell Disorders: Frequent: anemia. White Cell and Resistance Disorders: Infrequent: lymphadenopathy, leucopenia, cervical lymphadenopathy. Rare: granulocytopenia, leukocytosis, lymphopenia. Endocrine Disorders: Infrequent: hyperprolactinemia, gynecomastia, hypothyroidism. Platelet, Bleeding and Clotting Disorders: Infrequent: purpura, epistaxis. Rare: pulmonary embolism, hematoma, thrombocytopenia. Myo-, Endo-, and Pericardial and Valve Disorders: Infrequent: myocardial ischemia, angina pectoris, myocardial infarction. Vascular (Extracardiac) Disorders: Infrequent: phlebitis. Rare: intermittent claudication, flushing, thrombophlebitis. Postintroduction Reports: The following adverse drug reactions have been identified during postapproval use of risperidone: agranulocytosis, anaphylactic reaction, angioedema, atrial fibrillation, diabetic ketoacidosis in patients with impaired glucose metabolism, hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, and water intoxication. Adverse events reported since market introduction which were temporally (but not necessarily causally) related to oral RISPERDAL ® therapy include the following: apnea, cerebrovascular disorder, including cerebrovascular accident, diabetes mellitus aggravated, hyperglycemia, Parkinson’s disease aggravated, and pituitary adenomas. There have been rare reports of sudden death and/or cardiopulmonary arrest in patients receiving oral RISPERDAL®. A causal relationship with oral RISPERDAL® has not been established. It is important to note that sudden and unexpected death may occur in psychotic patients whether they remain untreated or whether they are treated with other antipsychotic drugs. Retinal artery occlusion after injection of RISPERDAL® CONSTA® has been reported during postmarketing surveillance. This has been reported in the presence of abnormal arteriovenous anastomosis.

DRUG ABUSE AND DEPENDENCE Controlled Substance Class: RISPERDAL® CONSTA® (risperidone) is not a controlled substance.

For more information on symptoms and treatment of overdosage, see full Prescribing Information.

7519511B - US Patent 4,804,663 Revised February 2008

©Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2008 01CS947B

AMCP HIGHLIGHTS

Economic Trends Influencing Healthcare Reform

By Maude Campbell

Based on a keynote address by Robert B. Reich delivered at the Academy of Managed Care Pharmacy, April 17, 2008, San Francisco, CA.

T

he US economy is in a consumer-driven recession that is likely to be long and deep and that is ushering in dramatic changes in consumer spending patterns. This will inevitably translate into healthcare changes as well, according to Robert B. Reich. The 3 major trends underlying current economic changes are demographics, globalization, and technology.

“There is a grave, grave necessity and a groundswell for some kind of reform.”

Economic Trends Demographics The changing demographics of the US population influence our healthcare. “The biggest problem we face in terms of the demographic time bomb is healthcare.

Healthcare expenses are going up by double digits… and there is a grave, grave necessity and a groundswell for some kind of reform,” Mr Reich points out. Unlike in 1994, when the Clinton administration attempted to gain support for universal healthcare, health-related expenditures are now rising faster with increasing copayments and deductibles, and a much larger percentage of the population is without health insurance.

“This is the time, this is the hour, that people are really ready for healthcare reform,” he says.

Changing demographics and healthcare costs comprise only a portion of the set of circumstances leading to the current recession, which is making the economy the number one issue in the upcoming presidential election. The previous 3 recessions were brought about because the Federal Reserve Board raised interest rates too high in an effort to fight inflation or because investors and businesses had overinvested in equipment and then pulled back on their spending.

Robert B. Reich is Professor of Public Policy at the University of California at Berkeley, CA, and former Secretary of Labor under President Clinton.

38

AMERICAN HEALTH & DRUG BENEFITS

May 2008

In contrast, this recession is led by consumers who are pulling back on spending. “The economy requires people to spend money to buy all the goods and services that the economy produces,” Mr Reich notes. “And American consumers are deep in debt, deeper in debt than we have ever seen before in the history of keeping data on debt. They had been getting money out of their homes, treating their homes as piggy banks, refinancing through home equity loans. They can’t do that anymore” because of declining home prices and rising fuel and food prices, as well as continued job loss.

The current median wage adjusted for inflation is just slightly above where it was in 1970. The average American is already working 450 hours annually more than the average European. All of the coping mechanisms to deal with low median wages have disappeared.

“There really is no way in which people can keep on spending at the rate at which we are producing goods and services,” Mr Reich explains. And healthcare costs are increasing.

The impending retirement of the baby boomers poses great challenges to social security, retirement plans, and to Medicare. Demographics interlock with globalization and technology to shape the current economy and our future healthcare.

Globalization “When most people think about globalization, they think about trade, they think about ‘our’ companies versus ‘their’ companies,” Mr Reich says. “Every big company is becoming a global company, with suppliers coming from all over the world. American companies and even American products have dissolved.” Even products with an American nameplate are global products.

“Where things are made in the supply chain, where components come from, and where particular things are done” depend more and more on worldwide wages and expertise. His own hip replacements were designed in France, manufactured in Germany, and installed with the expertise of American physicians.

Expertise is crucial, and this is what Americans need to worry about.

Americans are very concerned that globalization is directing jobs to China, Southeast Asia, and other low-

AMCP HIGHLIGHTS

wage nations, but in reality “jobs are not all going to the low-wage nations. If that is where jobs were going, Bangladesh would be the center of the world economy and it is not.” High-wage nations such as Germany continue to be major exporters even though their wages are high. This is because “they have expertise, they have knowledge, they have skills. If we want to remain a high-wage economy, we have to educate ourselves, our children, and our grandchildren to make sure they have the productivity and the skill and the innovative potential to actually justify a high standard of living in this global economy,” he emphasizes.

Technology Technology is responsible for displacing more Americans than globalization, according to Mr Reich.

“The reason we are losing all the manufacturing jobs, the primary reason, is not because they are going to China. The primary reason is that manufacturing is becoming so efficient. In a factory in the United States there are no people.” Although governors like to attract factories to their states, with tax abatements and subsidies, the old assembly lines are gone. “The factories are full to capacity, they are humming, but there are only 10 people in the factory and they are technicians behind computer consoles controlling the machine tools and robots. We are not going to get a lot of new jobs out of factories.”

In the early 1900s more than half of Americans worked in agriculture; today, only 5% of Americans do.

Mr Reich explains that this is “not because farming was a big disaster, but because farming was a big success. It is the same with manufacturing…. Even in China, the factories that used to be inefficient—the state-run factories are getting new technologies and they need fewer people.”

Most Americans are not unemployed, but their jobs do not pay well. Jobs are in the local service economy and are sheltered from globalization, because they must be done in person. Again, the solution is education.

“Globalization and technology are your friends if you are well educated, because globalization means you have a greater and greater market for your insights, for your knowledge, for your applications…. Globalization and technology are your enemies if you don’t have adequate education,” Mr Reich suggests.

“Companies are going to be even more intensely competing for talented people and there is going to be even greater pressure for immigration,” Mr Reich points out. “A debate on immigration has already occurred and it is only going to get louder.”

Healthcare Reform Healthcare consumers are experiencing dramatic changes in the economy that present growing challenges to delivering quality healthcare and pharmaceuticals. “There is going to be a change, and it won’t be dramatic, it will be incremental,” Mr Reich predicts.

“The question is, will it be sensible?”

Because the aging population and rising healthcare costs will put substantial change on Medicare, it is predicted that there will be a change in law affecting Medicare and other health programs. “There is going to be a change in law that enables government to use this leverage with pharmaceutical companies to reduce the price in bulk discounts of pharmaceuticals,” Mr Reich says, adding that this will reduce the research and development incentives to the pharmaceutical industry. “Behind a lot of reform in healthcare are these kinds of diabolical trade-offs in terms of how much we are, as a society, prepared to pay for new drugs, new procedures, new equipment, and life-saving advances.”

“The American healthcare system is the only healthcare system in the world...designed to avoid sick people.”

Healthcare reform will also have to address prevention. “Prevention is a big part of it. Disease management is a big part of it. Using information technology better than we are using it to cut down on paperwork today is a big part of it,” Mr Reich notes.

“The American healthcare system is the only healthcare system in the world that I know of designed to avoid sick people.” He notes the pressure on some insurers to cover only people who are low risk and low expense “and to try and avoid people with preexisting conditions or who are more expensive. There is also a great deal spent on advertising, marketing, and on contesting claims.” The question is how to get rid of all these “reverse incentives,” he adds.

Mr Reich suggests that, “We are not going to go to single payer, but I do believe that giving people the back door to a low-cost kind of Chevrolet model healthcare system, because it is cheap, gathers enough people into it that they have some bargaining leverage to get better deals. That might be the way we tiptoe toward what might ultimately be somewhat of a single payer system.”

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AMCP HIGHLIGHTS

Technology in Healthcare: The Wave of the Future

By Maude Campbell

Based on a presentation by David Brailer, MD, PhD, at the Academy of Managed Care Pharmacy Annual Meeting, April 18, 2008, in San Francisco, CA.

T

he 3 main areas fueling healthcare reform initiatives are cost, access, and quality; these areas have given resonance to the progress of healthcare information technology (HIT), because cost, access, and quality cannot be fixed without an information infrastructure in place, David Brailer, MD, PhD told the meeting attendees. “It is not so much that HIT infrastructure is so special or magic, it is because all these areas need very specific, clinically valid, timely, patient-specific, actionable information.”

A 2007 poll of Medicare beneficiaries showed that 90% would prefer electronic prescriptions.

Progress has been made since the Bush administration announced in 2004 that HIT would be a major agenda item. Whereas in 2004 only 20% of hospitals had electronic medical records (EMR) and 5% had systems underway, today about 65% of US hospitals either have an EMR system or are putting one in place.

Physicians’ offices have progressed more slowly, with about 20% to 25% having EMR compared with only 10% in 2004. About 10% of physicians now use electronic prescribing. A huge standards initiative is underway to coordinate HIT across the different practices and hospitals to ensure system compatibility, said Dr Brailer, who predicts that in the next presidency, Medicare may make EMR use a condition of participation.

A 2007 poll of Medicare beneficiaries showed that 90% would prefer electronic prescriptions, allowing physicians to check their coverage and review their medical history. “The American public really underDr Brailer is founder and chairman of Health Evolution Partners, a private equity fund focused on transforming the healthcare industry. He served as the National Coordinator for Health Information Technology under the Bush administration.

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stands that it is important that your information follows you,” Dr Brailer observed.

But while the basic building blocks are coming together, enormous challenges remain before an efficient HIT infrastructure is created in which everyone has an EMR that is connected to a central system. The primary issue is who will pay for it. The cost is estimated to be $100 billion over a decade, but this pales when we think of total healthcare expenditures. The problem is that the doctors and hospitals who are paying for it are not the people who benefit from it, because of Medicare’s obsolete reimbursement policies and fee-forservice medicine. “If you use a tool to improve efficiency and quality, your cost of care is lower, because you are seeing patients less frequently, they are being admitted less frequently, they are less likely to need lab tests, and less imaging is being done…. All that [savings] accrues to the payer.” It is clear, Dr Brailer says, that the federal government will not pay for it.

Privacy is another key challenge. Online EMR repositories, such as Google Health and Microsoft Health Vault, are not coverage entities under the Health Insurance Probability and Accountability Act (HIPAA) and, therefore, are not subject to state privacy rules. Such entities could choose to make the information available to a pharmaceutical company directly or sell it for insurance underwriting use.

“Privacy challenges are going to flare up in the next couple of years,” says Dr Brailer. “HIPAA was never designed for a digital era.”

Americans understand that person-based portability of their health records has great benefits, and that every time they enter an emergency room they will not be asked the same questions about what lab tests they have had or what imaging studies they have had done, but 3 aspects of HIPAA make this impossible, he says.

1. Patients cannot require to send their medical information to a third party. Under HIPAA, the information can only be given to the patient. Many doctors or hospitals will not send it on the patient’s behalf, even when the patient asks for it.

2. Providers have 120 days from the time of the patient’s request to send the information, which

AMCP HIGHLIGHTS

makes this useless. “120 minutes is okay maybe, depending on what it is; 120 seconds is perfect.”

3. Information can be sent in whatever format providers deem efficient; they do not have to put it in an electronic format. HIT would become if and when there is an economic and regulatory pathway to portability, but this will require a comprehensive redo of the old HIPAA policies, suggests Dr Brailer.

The HIT Revolution The transition into HIT is not only going to result in people having an electronic record. “This challenge that we have of trying to get the HIT revolution started is going to turn around and become a key disruptor of the brands we trust in healthcare, whether they are pharma, hospital, physician, or payor brands.

It happens in every industry,” Dr Brailer says. “Look at what’s happened with retail. Most of the top level retail brands in American of 15 years ago don’t exist.”

He outlines some of the advantages and consequences of HIT: Remote monitoring. HIT will likely shift primary care to the home. There is clear evidence that remote monitoring systems using an array of very inexpensive, passive sensors can help keep patients out of nursing homes for basic, low-skill care. Such systems monitor whether someone is up and around, and whether they have done certain activities of daily living. These technologies are now available for about $200. “The ability to monitor compliance, utilization, and functional status anywhere we go is one of the key attributes of moving forward,” he says.

Formulaic prescribing. The incorporation of EMR and HIT architecture will create a new class of prescriptions. For example, a patient with a urinary tract infection with an EMR containing lab results, culture results, known medication allergies, and current medications will be able to walk up to a kiosk and walk away with the appropriate treatment. “About 25% of prescriptions are formulaic, they follow an automated thought process that is driven by factual data, where subjective data have some roll but not very much,” Dr Brailer says.

“There may be regulatory barriers and people may be shocked if this happens, but they were shocked when you could walk up to a machine and take $200 out.”

Geographic control. HIT “will disrupt geographic cartels,” Dr Brailer says. “If I could describe healthcare in any way I’d say it is an industry comprised of geographic cartels.” Hospital systems, payors, radiology groups, and other specialty groups try to control their geographic markets. HIT will make it possible, for

example, to send radiology views remotely so that a radiologist in another location can read the results for a more competitive price. “This will start generating a tremendous amount of increased radiology utilization,” he predicts. Dermatology and pathology are other likely areas that will be subject to similar disruption.

Super-consumers. Overall, 5% to 10% of consumers shape the market place. In healthcare, it is estimated that about 2% of Americans are active consumers, really paying attention to their options and treatments or treatment alternatives. Websites for specific chronic illnesses already exist where patients can talk to other similar patients and find out what they are being treated with. The Internet induces a level of highly informed user, but not expert-mediated information. “ Globalization. “I think you will see globalization of medical services,” Dr Brailer says. “I’ve seen evidence of people in other countries beginning to develop tools…to develop and manage the medical operations of a health plan, to be able to handle all the basic primary care discussion with patients and the follow up, to be the people to respond to patient e-mails and help hammer out their problems….Much of it is happening in Asia from one Asian country to another. The United States is not the centerpiece of the global healthcare system.”

“The ability to monitor compliance, utilization, and functional status anywhere we go is one of the key attributes of moving forward.”

Improved care, reduced cost. Dr Brailer believes that these innovations will “flip” healthcare on its head and form new ways “to deliver better care, more patient-focused care, more integrated and cost-effective care.” This will shift the power to patients “in ways we haven’t even begun to imagine,” and generate new types of competition and decision making. One new focus will be toward prevention.

“You will see two kinds of organizations. The ones that stick their heads in the sand and say it is not going to happen, and in my view, get torn asunder by it. And you’re going to see people who get it and are out ahead of it.” Some of the best health systems and physician organizations are already living this revolution in real time and understand that it is not theory, but that it is well underway, he concluded.

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AMCP HIGHLIGHTS

Medication Therapy Management Projectâ&#x20AC;&#x201D;The Latest Information for Managed Care Pharmacy

By Sandy Paton

Based on a presentation by Marissa Schlaifer, RPh; Linda Baggett, RPh, CGP; and Kimberly Vernachio, PharmD, at the Academy of Managed Care Pharmacy Annual Meeting, April 17, 2008, San Francisco, CA.

M

arisa Schlaifer, RPh, Director of Pharmacy Affairs at the Academy of Managed Care Pharmacy (AMCP) described a new medication therapy management (MTM) program that was developed by the AMCP to serve as a guide for MTM programs for those designing and those purchasing an MTM program.

There are differences between MTM programs and MTM services, Dr Schlaifer explains. MTM programs are developed by health plans or other healthcare groups and focus on optimizing therapeutic outcomes, whereas MTM services describe the components of MTM programs delivered by healthcare professionals.

MTM programs that implement effective MTM services enhance patient care and lead to better health, while decreasing healthcare system costs.

Drug therapy management programs are designed to ensure that medications provided to eligible beneficiaries are used appropriately, thus reducing adverse events and optimizing therapeutic outcomes through improved medication use.

Technology played a great role in all aspects of the MTM programs.

The MTM Validation Project This new MTM initiative was intended to guide all purchases of MTM programs, whether they are under Medicare Part D, commercial, or other settings. The National Committee for Quality Assurance (NCQA) was contracted to conduct the validation study. The NCQA surveyed 20 representative Medicare Part D Ms Schlaifer is Director of Pharmacy Affairs at the Academy of Managed Care Pharmacy; Ms Baggett and Dr Vernachio are Medicare Pharmacotherapy Specialists at Aetna, Inc.

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and nonâ&#x20AC;&#x201C;Medicare Part D programs and conducted indepth site visits with 5 of the programs. Phase 1 consisted of telephone surveys with purchasers, pharmacies, physicians, and consumer advocacy organizations and regulators.

The NCQA found great variety among the programs. Technology played a great role in all aspects of the MTM programs. In addition to regular mail and personal communications and interventions, they used fax, the Internet, and e-mail. The features and operational aspects were confirmed as realistic and valuable as a general direction for MTM programs. Among the 20 programs surveyed, pharmacists were identified as the primary deliverers and managers.

All the information gathered was then presented to the AMCP Advisory Panel, which reviewed it and made recommendations on how to modify the original document. The MTM consensus document was pulled together by a broad array of stakeholders, including representatives from the American Association of Retired Persons, AMCP, American Academy of Family Physicians, American Geriatric Society, American Pharmacists Association, Veterans Administration, and National Business Coalition on Health, and representatives from health plans, pharmacy benefit managers, integrated health systems, and stand-alone MTM programs. Many of the details of the program are contained in a January 2008 AMCP supplement.

Features of a Successful MTM Program Linda Baggett, RPh, CGP, and Kimberly Vernachio, PharmD, Pharmacotherapy Specialists at Aetna, described the qualities of a Medicare MTM program at Aetna that can serve as a model for implementing successful MTM programs. They began by noting that a significant proportion of medical errors are related to adverse events, and hospitalizations are significantly attributed to adverse events. The Institute of Medicine reported that as of January 2000, 44,000 to 98,000 deaths occurred annually as a result of medical errors.

Of these, approximately 7000 deaths annually are relat-

AMCP HIGHLIGHTS

ed to adverse drug reactions.1 Statistics point to adverse drug reactions as a serious problem, occurring in 1 of 5 patient injuries or death per year.2 Drug-related issues are responsible for 33% of hospital admissions in older patients, including misuse (eg, nonadherence, wrong indication, and contraindication) and adverse drug reactions (eg, electrolyte imbalances from changes in cardiovascular medications).3 Aetna’s MTM program has been a work in progress since 2006. Aetna has identified the following 7 key features that characterize a successful MTM program.

Such a program should: • Be patient-centered • Use an interdisciplinary approach and be teambased • Have effective communication among team members • Clearly define the perspective on each issue regarding population-based or individual perspective • Be flexible in design • Use an evidence-based medical approach • Promote its services; a good program does no good unless others know about it.

From the start, Aetna assumed that the number of drugs a patient was taking would provide a strategy for intervention. This approach led to the development of a screening algorithm. The number of prescriptions quantitated the number of drug-related opportunities for intervention. Members taking 14 or more drugs were considered the most complex members; however, polypharmacy turned out not to be the first issue requiring attention. The number of drugs was not necessarily supportive of meaningful opportunities for intervention.

Identifying Risk Groups Program coordinators eventually differentiated clinical risk groups based on medication (eg, anticoagulant use, diabetes mellitus, congestive heart failure, dementia, asthma and chronic obstructive pulmonary disease, end-stage renal disease, and rheumatoid arthritis).

The highest risk group was patients older than age 80, the frail elderly. These patients were at highest risk and received direct care from pharmacists. The vast majority of their members were between ages 71 and 80 years. Aetna expected to find most of their drug-related issues in this group. They also expected that the frail elderly would have more medical issues, which did not turn out to be the case. Instead they found that drug-related issues in patients younger

than age 60 years were just as great as those in patients older than age 80. The proportions were identical across the ages.

Another finding was that most of their patients had 3 physicians. They then reached out to all these physicians, who needed to be a part of their effort in coordinating care.

Postintervention follow-up by letters to patients (low touch) and letters plus critical calls (high touch) served to reduce events and, therefore, costs. Cost avoidance occurred whether the intervention was low touch ($476 per member annually) or high touch ($2506 per member annually). Getting to the most optimal outcome in a cost-effective manner was the next problem to solve. It was once again brought home that any intervention would reduce events and thus costs.

Drug-related issues are responsible for 33% of hospital admissions in older patients, including misuse and adverse drug reactions.

Focus for the Future?

A pharmacy-based intervention program is critical to the success of future program expansions. The focus should remain on opportunities to expand clinical and safety issues in medication therapy, as well as meeting the educational needs of physicians about drug-related issues and coordinating this information with members.

The focus should be on pill burden (ie, the number of medications a patient takes each day). Therapy must be streamlined to facilitate successful patient implementation. Aetna is currently looking at alternative strategies for compliance and persistence. The data are beginning to suggest that there is a finite longevity to any intervention, which may very well vary by the type of intervention.

References 1. Committee on Quality of Health Care in America: Institute of Medicine. To Err is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000.

2. Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991;324:377-384.

3. Cooper JW Jr, Burfield AH. Medication therapy management strategies for geriatric patient interventions: Medicare Part D implementation. Ann Long Term Care. 2007;15:33-38.

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Responding to FDA Alerts: How to Reduce Risks and Liability

By Sandy Paton

Based on a presentation by Kathleen Orrico, PharmD, at the Academy of Managed Care Pharmacy Annual Meeting, April 17, 2008, San Francisco, CA.

S

nafu, a common term used to describe a situation marked by error or confusion, has been adopted by the Palo Alto Medical Foundation as the title of a committee dedicated to reducing risks and liability by providing prompt response to US Food and Drug Administration (FDA) drug safety warnings, medical product recalls, and other drug and device safety issues.

Through their Safety, Notification, and Follow-up (SNAFU) Committee, the Palo Alto Medical Foundation serves as a conduit for these FDA alerts to pharmacists, physicians, and patients.

Information imparted to providers must be concise, offer important facts, and suggest a course of action and support tools.

The SNAFU Committee is made up of pharmacists, physicians, directors of materials management and clinical services, nursing and patient safety officers, and public relations department to address toxicity issues (both possible and probable) and device warnings. The selection of committee members was based on constructing a global view of safety activities.

The process begins by reviewing the FDA MedWatch alerts to determine how and where to disseminate information that will contribute to patient safety. Only alerts worthy of notice are sent to avoid unnecessary noise. Email conversations are initiated as soon as an alert is identified. A plan can then be quickly developed and an action voted on. For example, when the MedWatch Public Health Advisory posted a problem concerning liver toxicity associated with telithromycin (Paxil) in 2006, the SNAFU Committee had first to determine the Kathleen Orrico, PharmD, is Health Sciences Assistant Clinical Professor, University of California at San Francisco.

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extent of risk to the patient population, which prescribers and patients to notify, whether specialists should be involved, and what materials should be developed.

The time to implement these tasks was an important part of the picture, including whether preventive action should be taken. The chosen plan of action included an e-mail alert to member physicians, who could then decide the next course of action based on their patient base. In matters of pressing issues, phone call follow-ups are also conducted, alerting physicians to check their websites and Outlook postings. In this case, a follow-up e-mail further recommended avoiding use of the drug.

After the 2 warnings, alerts were issued. Only 4 patients met Palo Alto’s internal guidelines for antibiotic failure and multi-drug resistance. Of 21 patients who received telithromycin, 13 had received it as a sample.

This finding prompted further scrutiny into why a broad-spectrum antibiotic was being sampled in the first place. The SNAFU Committee recommended that such samples be disallowed and requested that the Pharmacy & Therapeutics (P&T) Committee add this prohibition to the sample policy.

Provider, Patient Notification Information imparted to providers must be concise, offer important facts, and suggest a course of action and support tools. In addition, it must be determined “who needs to know.” The Committee is rarely hampered by privacy concerns based on Health Insurance Portability and Accountability Act compliance issues. Thus, when patients need to know, patients are notified. At times, however, there are areas of sensitivity. For example, when paroxetine was contraindicated in pregnant women, notification was sent to all women of possible childbearing age (12 to 55 years). They attempted to cast a wide net to patients but a narrow net to providers. Patients were advised to self-monitor for signs and symptoms. Only 1 pregnant woman was taking paroxetine. The overall goal was to reduce the possibility of harm to a patient and lessen the risk of liability to the medical group.

AMCP HIGHLIGHTS

Implementing a SNAFU Assigning committees already in existence (eg, P&T, patient safety, drug information service) to assist in the effort is recommended. Each person would receive and review the MedWatch E-List (Listserv) notifications. They would also subscribe to the automatic message-delivering system sponsored by the National Institutes of Health (http://www.fda.gov/ medwatch.elist.html). Patients can be alerted to the process by website postings, newsletters, letters, emails, or handouts at the point of care.

Dr Orrico urges organizations to map out an internal communication plan to ensure a consistent message to patients and staff, including front-line personnel. Materials should be richly referenced and MedWatch findings should be incorporated into the process. The importance of maintaining current distribution lists should be emphasized. As a plan of action, allowing MedWatch to do the work is suggested; let them sort out the problems, but make noise as you notice possible problems in the workplace such as fatalities, increased hospitalizations, and medically significant events.

Adverse events can also be reported to the Vaccine Adverse Event Reporting System (www.vaers.hhs.gov), the United States Pharmacopeia and Institute for Safe Medication Practices (www.ismp.org), the pharmaceutical company itself, and the in-house risk manager.

Important recommendations include signing up for the MedWatch Listserv, booking an appointment to check and read the MedWatch site weekly, knowing the drugs used in your organizations daily practice, and, first and foremost, thinking preventatively (ie, determining which measures might be put in place to reduce risk).

Reporting unsafe practices, citing heparin vials that look identical; scrutinizing off-label usage of drugs; and following evidence-based guidelines (eg, maintaining recommended hemoglobin/hematocrit levels for erythropoietin) are further encouraged.

Identifying patients affected by a drug or a device is

Table 2007 FDA Safety Alerts Product type Drugs and therapeutic biologics Medical devices Nutritional products Vaccines, biologics (VAERS)

N 103 35 18 2

FDA indicates Food and Drug Administration; VAERS, Vaccine Adverse Event Reporting System.

not an easy task, and keeping track of sampling is important. If at all possible, Dr Orrico urges providers to document distribution of samples on electronic health records. Having a log of who has received a sample can save time and energy later. Maintaining effective communication is essential. In 2007 alone, there were more than 150 safety alerts for drugs and biologics, medical devices, and dietary supplements (Table), and the number of MedWatch postings is increasing dramatically every year.

Recommendations Summary It is important not to hurry an investigation or rush needlessly into action. The following actions are recommended: • Overcommunicate to be on the safe side, but be sure the message is well crafted • When necessary, convene your SNAFU Committee quickly either by phone, e-mail, or in person • For large issues, use a tracking form to avoid missing or overlooking loose ends • Create a searchable and accessible electronic health record • Have a wide array of expertise to call on • Always hold a debriefing session with your committee.

Knowing what patients want and what makes sense to them adds to the success of a program.

SUBSCRIBE TO AMERICAN HEALTH & DRUG BENEFITS™ at www.AHDBonline.com Engage Healthcare Communications, LLC • 241 Forsgate Drive, Suite 205A • Jamesburg, New Jersey 08831

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Medicare Coverage for Erythropoiesis-Stimulating Agents: The Perfect Storm Interview (Part 1) with Samuel M. Silver, MD, PhD

Medicare policy changes have an immediate impact on health plans with regard to setting payment policy for providers. So when Medicare tightened payment guidelines for a lucrative class of anemia drugs—erythropoiesis-stimulating agents—an ambitious set of rules was put into effect. Health plans often follow suit in short order, enforcing public guidelines on private payors, even when saving money is not a consideration. However, when Medicare takes an unreasonably hard line, plans tend to focus on members and physicians more fervently, attempting to soften the hard line. In this first part of the interview, Dr Silver examines the coverage decisions set by the Centers for Medicare & Medicaid Services for the use of erythropoiesis-stimulating agents and discusses the issues surrounding their adoption, indications versus off-label use, as well as lingering questions about their role in tumor progression and other risk factors. [AHDB. 2008;1(4):46-50.]

R

obert Henry: Medicare’s recommendations for erythropoiesis-stimulating agents (ESAs) revolves around several key stakeholders with diverse agendas—those of the US Food and Drug Administration (FDA), the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), and pharmaceutical companies. What are the coverage issues for these various stakeholders?

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look like the “bad guys” interested only in profit margins and not in the patient; but this issue is far more complicated than that. Physicians do try to do the best for their patients, and yet financial incentives can be an inappropriate driver.

Henry: Dr Randy Vogenberg will be leading the discussion to explore the issue from the different stakeholders’ perspectives.

Sam Silver: This is a very sensitive issue. Articles published in the New York Times were quite negative with regard to perverse economic incentives for physicians’ prescribing of ESAs. Oncologists are seeking flexibility in determining how to use the ESA medications based on a hemoglobin level cut-off of less than 12 g/dL. Professional medical societies value evidencebased findings. Practicing oncologists can be made to

F. Randy Vogenberg: I am a pharmacist by training, with a PhD in healthcare administration, and I have been involved in employer-related benefit issues. I also work with pharmacy benefit managers, health plans, benefit consultants, and brokers, so I see this issue from a variety of perspectives in terms of the financial and clinical implications in the marketplace.

Dr Silver is Professor of Internal Medicine, Director, Cancer Center Network, Division of Hematology/Oncology, and Director, Medical Management Center, University of Michigan Health Systems, Ann Arbor, MI.

Silver: During my 10 years of being the director of Bone Marrow Transplantation at the University of Michigan, I got interested in reimbursement issues for clinical trials, especially with regard to bone marrow

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REGULATORY

transplantations for breast cancer in the 1990s. I eventually became active at ASH and chaired several committees, including their Reimbursement Subcommittee, and I am finishing my term on their Executive Committee. I was also a member of the Board of the American Society of Blood and Marrow Transplantation and currently serve on several committees of ASCO. In addition, I am still practicing hematology/oncology, while remaining involved in reimbursement.

Hematologists and oncologists have been looking for the Holy Grail—how to avoid transfusions—for quite some time, and thought they had found it in ESAs. We all had concerns about blood products since the arrival of HIV, particularly in the hemophilic population. Red blood cell transfusions are fraught with possible complications, including hepatitis and other side effects, such as transfusion-associated lung injury.

Consequently, we allowed patients to run low hemoglobin counts secondary to their underlying malignancies and chemotherapy, but this negatively affected their quality of life (QOL). Today many of us use transfusions as needed, without a particular target in mind, and we tend to focus on symptomatology rather than on any target hemoglobin level that signals the need for transfusion.

Vogenberg: Could you discuss the evolution of the uses and concerns regarding ESAs? Silver: When ESAs came on the market, they were well embraced. The FDA-labeled indication was to decrease the number of transfusions or avoid them altogether, but in time, studies implied that increasing hemoglobin levels also improved patients’ QOL. The pharmaceutical industry embraced and publicized these studies to physicians and through direct marketing to patients. And so, years after the original FDA indication, these agents became associated with QOL issues.

With all the off-label uses common today, we forgot that these drugs were actually indicated to avoid transfusions, and the focus shifted to QOL. Around 2004, it became apparent that patients with end-stage renal disease (ESRD) and chemotherapyinduced anemia were having thromboembolic events as a result of treatment with ESAs, especially in patients whose hemoglobin levels were driven to more than 12 g/dL. The Oncology Drug Advisory Committee (ODAC) noted that appropriate studies were not being conducted to examine the effects of these drugs on ESRD patients or on tumor progression.1 Rather, existing studies examined transfusion-avoid-

KEY POINTS ESAs are indicated for treating patients as a way to avoid transfusions, but the focus in practice has since shifted to off-label use for quality-of-life concerns.

Safety issues have become a serious concern with ESAs, as findings of early death, tumor progression, and serious cardiovascular events linger.

In 2007, ESAs had the highest drug expenditures in Medicare Part B. In November 2007, the FDA strengthened its “black box” warning for the use of ESAs, because of increased evidence of tumor progression and reduced survival.

In March 2008, the Oncology Drug Advisory Committee recommended limiting the use of these agents in the cancer setting to circumstances where chemotherapy is not given for curative purposes, and not to exclude their use in patients with head and neck cancer or breast cancer.

ance and QOL issues associated with hemoglobin levels higher than 12 g/dL. ODAC asked Johnson & Johnson and Amgen to undertake appropriate studies on potential risks with these agents. Studies continued to accumulate during 2006 and 2007 from patients with renal insufficiency–associated anemia and from those with chemotherapy-induced anemia, raising concerns about the risks of early death, tumor progression, and serious cardiovascular events.

In 2007, ESAs had the highest drug expenditures in Medicare Part B,2,3 and safety issues became a serious concern. Alarming findings were emerging from several studies.

In a European study, Henke and colleagues used erythropoietin-beta (not available in the United States) for locally advanced head and neck cancer with target hemoglobin levels ranging from 12 g/dL to 13 g/dL.4 The study’s findings showed a significant hazard ratio for localized progression of head and neck cancer. There were concerns regarding the study’s validity, however, because this study did not include a systematic review of tumor progression by use of radiologic data.

Leyland-Jones and colleagues examined the use of ESAs in patients with metastatic breast cancer, showing decreased survival at 12 months.5 Another study by Wright and colleagues on metastatic non–small-cell lung cancer also demonstrated reduced survival with ESAs compared with placebo.6

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Finally, there was an Amgen study conducted in Eastern Europe.7 It was conducted on patients with multiple types of cancer who had not received chemotherapy or radiation. These patients were randomized to receive transfusions alone or ESAs. Survival was shortened in patients who were not receiving chemotherapy. This finding caused particular concern at the FDA, because this use of ESAs was completely off-label: This was not chemotherapy-induced anemia but rather it was the anemia associated with cancer itself. We do not know whether the shorter survival was from the tumor progression or whether it was related to the thromboembolic events, but there certainly appeared to be a shortened survival in the ESA arm of the study.7

This finding caused particular concern at the FDA, because this use of ESAs was completely off-label: This was not chemotherapy-induced anemia but rather it was the anemia associated with cancer itself.

The findings from these studies led to the first black box warning for ESAs, issued by the FDA in March 2007.8 The FDA announced that physicians should only use the lowest dose of an ESA necessary to avoid the need for blood transfusions caused by anemia.

Based on the Henke study,4 the FDA also noted that there was a reduced time to tumor progression in patients with advanced head and neck cancer with the use of these agents. This study, as well as the European study which showed a decreased survival in patients with cancer-related anemia who received ESAs,7 led the FDA to determine that ESAs are not indicated in patients whose hemoglobin levels are more than 12 g/dL or in patients who are not receiving chemotherapy or radiation.

In May 2007, the New York Times published a frontpage story titled, “Doctors Reaping Millions for Use of Anemia Drugs.”9 The article described how 2 of the world’s largest drug companies are paying hundreds of millions of dollars to doctors every year in return for giving their patients “anemia medications” and in doses that regulators now say may be unsafe. It was noted that the doses were legal, but that very few people apart from the doctors were aware of the high doses

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used. Critics, including prominent cancer and renal experts, said that the payments gave physicians an incentive to prescribe the medications at levels that may increase patients’ risks of heart attacks or strokes.

We thus have what I call, “ESAs—the perfect storm.”

The ESAs are supportive-care drugs, but providing them in doses higher than indicated by the FDA appears to result in an increased incidence of thromboembolic events, early death, and possibly tumor progression.

Vogenberg: Was there a marketing issue surrounding all this?

Silver: When ASH/ASCO issued their guidelines in 2003, they reviewed QOL issues in the literature and were not impressed by the evidence. Apparently there was a very high dropout rate of patients in the involved studies. The scales used in the studies did not make clear what a clinically significant benefit meant from a QOL point of view. Perhaps if they had compared differences in QOL in patients with hemoglobin levels of 8 g/dL versus 11 g/dL (instead of higher levels), the QOL issues could have been clearer.

The marketing issue revolved around the QOL issue. If one could show conclusively that QOL increased when hemoglobin levels increased above the indicated level, it would have provided sufficient evidence to raise hemoglobin levels.

Vogenberg: There are many issues surrounding QOL from a payor perspective, including a strong bias against it. I think that might have contributed to this perfect storm situation.

Silver: True. But, as you know, marketing and research go hand in hand. This is nothing new, but it certainly is an issue, especially when dealing with QOL and survival.

The day after the New York Times article appeared, ODAC reviewed the clinical trials data. The companies released a lot of data on QOL, which did not convince ODAC. The companies did agree that there was an increased incidence of thromboembolic events, but they tried to dismiss the issue of tumor progression. I think the issue of tumor progression is something we really do not understand, and it has not been well demonstrated. In December 2007, the National Cancer Institute convened a meeting of investigators who concluded that there were compelling in vitro data to continue investigations on ESAs and tumor progression.

REGULATORY

The ODAC review indicated that the FDA should consider adding to the product labeling further restrictions on the use of ESAs in patients with the types of tumors implicated in available trials, which the FDA did in November 2007.10 Because the issue of tumor progression had not been sorted out, it was suggested that additional trials should be conducted.

Vogenberg: Have there been any data regarding the long-term use of ESAs in patients?

Silver: There is a wealth of data that show that using ESAs in inpatients with low-grade myelodysplastic syndrome (MDS) could lower their transfusion requirements. MDS is a chronic disease, and thus therapy may be required for many years. Using ESAs in cancer chemotherapy is very short-term—6 to 9 months at most. But this discussion is premature, because there is no FDA indication for its use in MDS, and it is unlikely that an indication would be added soon, given the current atmosphere.

The Centers for Medicare & Medicaid Services (CMS) recently issued a National Coverage Determination (NCD) on ESAs for non–renal disease indications. CMS remains mute on the use of ESAs for the treatment of anemia associated with myelodysplasia, since they stated it was a premalignant condition, and the Medicare NCD was for the chemotherapy-induced anemia in cancer patients. This is a major issue for me as a hematologist, because there are good data for the use of ESAs in low-grade MDS. Based on this NCD, Medicare has now placed its coverage of ESAs for MDS at the hands of Part B carrier medical directors and Part A fiscal intermediaries.

But the NCD stated that CMS still did not think that ESAs work for MDS, which could bias local carriers against it. CMS remained silent on differentiating types of tumors, but from the point of view of ASH, one of the things we considered most onerous in the NCD was that the trigger point was defined as a hemoglobin level of 10 g/dL. If a patient’s level was above 10 g/dL, you were to avoid ESA therapy.

So, initiation of therapy was at a hemoglobin level of less than 10 g/dL, and maintenance was also at less than 10 g/dL. This is a serious paradigm shift from how ESAs had been used, and yet there was no evidence to support it. This ruling requires significant and frequent testing of patients to ensure that their hemoglobin levels did not exceed the new 10-g/dL threshold.

Vogenberg: Did anyone challenge CMS on this?

Silver: Several societies challenged this. The FDA said that there were no new data available that would allow them to change their minds. ASH/ASCO then issued guidelines about ESA use in late 2007, saying that starting with hemoglobin levels of less than 10 g/dL was very reasonable, but the maintenance range should be between 10 g/dL and 12 g/dL. The recommendation was also concordant with FDA labeling that if a patient’s hemoglobin rose above 11 g/dL, you should start to cut back on the ESA dose. So essentially, they were looking at the midrange hemoglobin level between 10 g/dL and 12 g/dL.

So, initiation of therapy was at a hemoglobin level of less than 10 g/dL, and maintenance was also at less than 10 g/dL. This is a serious paradigm shift from how ESAs had been used, and yet there was no evidence to support it.

Vogenberg: As a clinician, how do you determine how to proceed, because it may take a couple of days before you see a response?

Silver: That’s very true. It remains to be seen how this will affect transfusions. I have suggested to CMS and to members of Congress that we should use claimbased data to look retrospectively and prospectively at the transfusion requirements of Medicare beneficiaries who are and those who are not receiving ESAs for chemotherapy-induced anemia, to determine transfusion use before and after the new NCD. It may now be more difficult to compare these time periods with claim-based data, because physicians will allow hemoglobin levels to get lower than they have allowed in the past.

Disclosure Statement Dr Silver is a consultant to Bear Stearns, Lehman Brothers, and the Gerson Lehrman Group, and receives grant/research support from Blue Cross Blue Shield of New Jersey.

References 1. The Oncology Drug Advisory Committee. Safety concerns associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, LP, for the treatment of anemia associated with cancer chemotherapy. May 4, 2004. http://www.fda.gov/ohrms/dockets/ac/04/ briefing/4037B2_04_FDA-Aranesp-Procrit.htm#_ednref45. Accessed April 29, 2008.

www.AHDBonline.com

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REGULATORY

2. Steinbrook R. Erythropoietin, the FDA, and oncology. N Engl J Med. 2007;356:2448-2451.

3. Duh MD, Weiner JR, White LA, et al. Management of anaemia: a critical and systematic review of the cost effectiveness of erythropoiesisstimulating agents. Pharmacoeconomics. 2008;26:99-120.

4. Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255-1260.

5. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol. 2005;23:5960-5972.

6. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non–small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007;25:1027-1032.

7. Glaspy J, Smith R, Aapro M, et al. Results from a phase 3, randomized,

AHDB Stakeholder Perspective UnitedHealthcare’s Response to the ESA Debate PAYORS: It is important to remember why UnitedHealthcare became interested in the issue of the erythropoiesis-stimulating agents (ESAs).

Following the US Food and Drug Administration (FDA) warning about potential problems with ESAs, UnitedHealthcare launched a pilot study in New York, New Jersey, and Connecticut, requiring precertification for any ESA injection. We used the guidelines issued by professional cancer societies to set our maximum hemoglobin coverage limit at 12 g/dL. Higher hemoglobin levels were not covered. This 6-month pilot study revealed a 35% reduction in the use of ESAs, indicating that 1 of 3 doses that were being administered could have potentially harmed the patient.

Physicians and patients have become confused about the purpose of these medications. As Dr Silver states in his article, ESAs were originally created to avoid transfusions—a dangerous procedure even with current sophisticated screening. The quality-of-life (QOL) marketing, misaligned economic incentives, and the erroneously perceived safety profile made it

double-blind, placebo-controlled study of darbepoetin alfa for the treatment of anemia in patients not receiving chemotherapy or radiotherapy.

Paper presented at the American Association for Cancer Research Annual Meeting Proceedings; April 14-18, 2007; Los Angeles, CA. 8. FDA Alert. Information for healthcare professionals: erythropoiesisstimulating agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)]. Rockville, MD: US Food and Drug Administration; March 9, 2007. http://www.fda.gov/cder/drug/InfoSheets/ HCP/RHE2007HCP.htm. Accessed April 6, 2008.

9. Berenson A, Pollack A. Doctors reaping millions for use of anemia drugs. New York Times. May 9, 2007:A1.

10. New FDA warnings: communication about an ongoing safety review.

Erythropoiesis-stimulating agents (ESAs) epoetin alfa (marketed as Procrit, Epogen) darbepoetin alfa (marketed as Aranesp). November 8, 2007. http://www.fda.gov/cder/drug/early_comm/ESA.htm. Accessed April 6, 2008.

easy to become lax about the actual FDA indications for this therapy. Even now, the ESA problem is still not resolved.

Every therapy has a potential for toxicity.

Transfusion medicine has improved substantially since the emergence of the HIV epidemic in the 1970s, but Dr Silver aptly summarizes the significant risks that still exist. If oncologists use transfusion for QOL reasons rather than for physiologic problems, such as angina, orthostatic hypotension, or resting dyspnea, we will simply be trading one set of problems for another.

RESEARCH: We can expect a rush of studies that will examine rates of transfusions before and as a result of the recent coverage changes for ESAs, but if these studies do not examine the hemoglobin levels and the medical indications for those transfusions, these studies will be worthless. The unanswered question that needs to be examined is: Is it worth any toxicity at all to treat patients with a hemoglobin level above 10 g/dL? HEALTH PLANS: So while that debate goes on, UnitedHealthcare will continue its present policy of simply asking professionals to adhere to their own guidelines.

Lee Newcomer, MD UnitedHealthcare, Minneapolis, MN

Correction In Table 2 in the article “Not waiting for Godot: the evolution of health promotion at PPG industries” (April 2008, page 31), STD indicates short-term disability, not sexually transmitted disease, as is incorrectly noted there.

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AMERICAN HEALTH & DRUG BENEFITS

May 2008

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AACR MEETING HIGHLIGHTS

Anticancer Drug Development Trends: Translational Medicine

By Caroline Helwick

M

ore than 17,000 of the world’s best cancer scientists convened in April in San Diego for the annual meeting of the American Association for Cancer Research (AACR). Breakthroughs in molecular targeting of the seemingly limitless tumor-cell–signaling pathways were highlighted in many of the 6000 abstracts presented.

Eileen P. White, PhD, Chair of the AACR 2008 program committee, noted, “This meeting is a showcase for the best science that is happening everywhere: the best molecular biology, cell biology, drug development.”

The common goal of these research efforts is to bring drugs to the pharmacy sooner, to save lives, the “bench to bedside” approach. “We now know that cancer is not just one disease but hundreds of different diseases. The challenge is to identify the characteristics of a patient’s particular tumor and tailor treatment to those characteristics. Personalized medicine is critical to this process and is the aim of the future,” Dr White said.

Laboratory research is moving rapidly into the clinical setting, she noted. “Basic and clinical sciences are merging, and this interface is what we call translational medicine.”

New Pathways and Therapies A remarkable increase is evident in our understanding of the genomic drivers of malignancy and the cellular pathways that are highjacked to support oncogenesis. Inhibitors of the epidermal growth factor receptor and vascular endothelial growth factor sound mundane now that the molecular lexicon contains so many new members. Researchers are rapidly expanding the range of tumor targets that are “druggable” by small-molecule and antibody-based technologies.

Control of translation—namely, genetic factors—is also important in the regulation of cell growth and proliferation. A number of translation initiation factors are overexpressed or deregulated in tumors or cause malignant transformation. Genes and gene complexes believed to be important in tumor formation have been recently targeted for cancer therapy.

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You will be hearing more about these: • The protein p53 is a transcription factor activated by many stresses that impinge upon cells as they progress from normalcy to malignancy. Activation is good, but p53 is mutated in 50% of cancers (to facilitate growth) and inactivated in the other 50%. Regulation of p53 offers immense therapeutic opportunities.

• Mutations in the phosphoinositide-3 kinase (PI3K) pathway occur in many solid tumors, and most cancers have elevated PI3K signaling. PI3K, therefore, has become a promising therapeutic target.

• The mammalian target of rapamycin (mTOR) signaling pathway is a conserved serine/threonine kinase that helps integrate growth factor and environmental signals (hypoxia, nutrients) and regulate the cell cycle, hence mTOR inhibitor has become a focus of drug development.

• The serine/threonine kinase Akt serves as a convergence point for many molecular alterations in cancer and controls cellular processes that contribute to cancer development. Akt activation confers resistance to many cancer therapies and is a poor prognostic factor.

• The insulinlike growth factor (IGF) system is a linked network of growth factors, binding proteins, and receptors that are involved in normal growth and metabolism.

• Inhibitors of c-MET and its ligand, hepatocyte growth factor/scatter factor (HGF/SF), have been leading therapeutic targets. Inappropriate c-MET signaling occurs in virtually all types of solid tumors and can participate in all stages of cancer development. Biologics and small-molecule inhibitors directed against this pair are promising therapeutics.

• Blockade of transforming growth factor- (TGF- ) is expected to impede growth, progression, and metastatic potential of malignant disease. Increased expression and production of TGF- occurs in many neoplasms and is associated with reduced survival.

• Ras proteins play a key role in mediating signaling events involved in many cellular responses; therefore, critical elements of the Ras pathways are potential targets for therapeutic intervention.

• Histone deacetylase (HDAC) is a family of 11 enzymes that help regulate cancer through their role in the control of gene expression. HDAC inhibitors selectively switch on tumor suppressor genes.

• Heat shock protein 90 (HSP90) is a cellular chaperone protein required for the activation of several protein kinases. HSP90 inhibitors have been shown to have antiproliferative and antitumor activities.

AACR MEETING HIGHLIGHTS

• The pathways of cell death and cell survival provide many opportunities for therapeutic targeting in cancer, such as with drugs targeting the B-cell leukemia/lymphoma 2 (Bcl-2) family and the tissue disturbance of the death ligand (TRAIL) receptors.

• Proteins with specific functions in mitosis are the target of novel agents known as mitotic kinase and kinesin inhibitors, such as the epothilone class of agents (eg, ixabepilone).

• Proteosomes have enzymatic activity and regulatory functions with respect to cellular protein turnover.

Second-generation proteosome inhibitors are now in clinical development, following the success with bortezomib.

• A host of pro- and antiangiogenic factors regulate an “angiogenic switch” that, when turned on, allows for blood vessel growth and tumor aggressiveness.

Angiogenesis inhibitors targeting this switch are in clinical trials.

A Scientist Perspective “Probably the most interesting pathway is the signaling cascade involving PI3K, Akt, and mTOR, with IGF at the receptor level. A number of compounds have been developed to block each of these components,” said Alex A. Adjei, MD, PhD, senior vice president of clinical research and the Katherine Anne Gioia Chair in Cancer Medicine at Roswell Park Cancer Institute, Rochester, NY. In addition, cancer processes, such as the trafficking of proteins or regulation of gene expression, are also important. Many inhibitors of these processes are in development, such as HSP90 and HDAC inhibitors.

“The number of compounds directed at any one target or process reflects the fact that science has become egalitarian,” he observed. “Gone are the days when we found one drug hitting a target and that one drug got to market 5 years later. Now, when the target is identified, you see 5 to 6 compounds come out of the gate at the same time. We are now in the position of having a lot more drugs than targets.”

“As we understand the different molecular aberrations in cancer, the defects in different kinds of cells, we will be able to give different drugs to different patients. We will be thinking about these numerous molecular targeted agents the way we think about antibiotics today: some work for one infection and not the other.”

LETTERS

Letter to the Editor Continue to Focus on Broader Issues, Not Just on Drug Benefits To the Editor: I wanted to let you know how much I enjoyed reading the inaugural (February) issue of American Health & Drug Benefits. All the articles are on target as far as addressing important issues, and the range of different perspectives is impressive.

I must admit that I am a little confused about whether the primary focus is going to be on drug therapy as opposed to a broader range of subjects. From your mission statement it appears that the focus is clearly on pharmacotherapy and drug benefits, but the articles, especially the one by Gingrich and Desmond, address the much broader issue of healthcare reform. As a physician and a medical director whose focus—while including pharmacotherapy—is on the broader issues of care, I certainly hope that you will continue to highlight issues other than just drug benefits and pharmacotherapy.

This is a “different” type of journal, which is not easy to accomplish in a crowded field of competitors. My congratulations to you, and I will look forward to future issues, which I hope will be made available.

Stephen Gorshow, MD, FACP Vice President and Senior Medical Director Emerging Technology and Clinical Policy Greenwood Village, CO

Letters We welcome your letters and comments about articles published in American Health & Drug Benefits. Please limit your responses to about 400 words. If using references, please provide complete information. All letters are minimally edited for clarity and style, and if published, will appear in the print and the online versions of the journal. Please provide your name, any degree, and affiliation.

Submit letters to editorial@AHDBonline.com.

www.AHDBonline.com

53

FDA WATCH

What Is Happening to the Pipeline?

Mark Senak, JD

I

n January 2008, the independent research firm Sagient released data that evidenced a “significant decline” in new drug approvals by the US Food and Drug Administration (FDA).1 The data showed that in 2007 there was a 13% drop in approvals and a 40% increase in approvable letters.2 The approval by the FDA of biopharmaceutical products is included in this decline. According to a recent article by Ronald A. Rader, president of the Biotechnology Information Institute, looking at a 10-year span from 1996 to 2005 reveals an average of 16.6 drug approvals by the FDA during each of those 10 years,3 compared with only 12 and 11 approvals in 2006 and 2007, respectively, according to the Sagient report.2 The decline from 2006 to 2007 is shown in the Table.

Table Change in FDA Drug Approvals Decision Approval Approval letter

2007 (%)

2006 (%)

Change (%)

64 28

73 20

-13 40

Source: Sagient BioMed Tracker. http://www.biomedtracker.com/ Login.cfm?ReportID=231&CFID=2017815&CFTOKEN=55147424.

Approvable letters, or “complete response letters,” indicate a willingness of the FDA to approve an investigational compound, once certain prerequisites are provided or fulfilled by the drug manufacturer. These additional conditions for approval can vary greatly; they may be as simple as changing a label, or as complex, costly, and time-consuming as conducting new clinical trials to better ensure safety or efficacy of the product.

The slowdown in new products in the United States has a broad ripple effect that negatively affects nearly all stakeholders. First and foremost among them are the very bloodline for new products—investors.

According to the Sagient research, the average stock price change that was the result of an approvable letter dropped from 21.42% in 2006 to 12.89% in 2007,2 meaning that approvable letters are having less of an impact than before and that perhaps investors are adjusting to this new drug approval paradigm.

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Second, US patients and the marketplace at large are affected. In March 2008, an article published in the Wall Street Journal titled “Overseas Drugs Hit U.S. Regulatory Snags”4 cited several large companies that have had drugs approved outside the United States but have hit regulatory blockades inside the United States—these include GlaxoSmithKline, Novartis, and sanofi-aventis, the manufacturers of Cervarix, Galvus (vildagliptin), and rimonabant (also known as Acomplia), respectively, which are still not approved in this country. This means that a growing number of products are available for patients in Europe and in other countries but are not available for US patients.

Third, the slowdown is not good for the FDA itself, at a time when its image has become so battered.

Although the current environment is one that begs a conservative take on risk, many of the approvable letters have not been based on safety issues, hence the slowdown in approvals is occurring for reasons largely unrelated to safety concerns. But the FDA is supposed to be committed to bringing new drugs to the market through a number of its own initiatives, such as the “critical path initiative.”

The outlook for the future does not promise improvement. The FDA recently announced that the agency may intentionally miss action dates, by which time a decision on approval is due, namely, the Prescription Drug User Fee Act (PDUFA) date. In fact, according to a recent article published online in the RPM Report, the FDA has signaled that because of work burden, the agency will be allowing PDUFA dates to be missed.5 The RPM Report quotes Dr Jenkins, head of the FDA’s Office of New Drugs, as follows: “We are faced with the increased workload related to the implementation of FDAAA and FDA’s Safety First/Safe Use initiative. In addition to the resource increases under PDUFA IV, FDA also saw increased appropriations for FY2008 to help meet the growing workload. The new resources will have a significant impact on our workload/staffing balance in the long term, however, in the short term CDER is approximately 550 FTEs below its ceiling for FY08….To that end, I have granted permission to OND division and office directors to make decisions to bring their unit’s workload into better balance with their existing resources. These decisions will be made on a case-by-case basis since the balance is not the same in all divisions or even the same over time in any given division….In the short term our ability to meet PDUFA goals is expected to decrease. In some

FDA WATCH

cases we may have to cut back on work by declining requests from sponsors for guidance (e.g., meetings, multiple cycle SPA reviews) and in other cases we may decide to go past the PDUFA goal date for review of an application. In cases where we decide to go past the PDUFA goal date the sponsor will be notified by the division management of that plan.”5 It is difficult to discern from the “increased workload” when the rate of fees that come to the FDA as user fees under PDUFA has increased substantially. In other words, the pharmaceutical industry is being charged more money for fewer outcomes.

Finally, the delay in product approvals resulting from approvable letters or from deadlines missed by the FDA means that once approved, a product has less time on the market to recover research costs and to supply a profit for the investors. The logical consequence is that prices of the product, once approved, will have to be higher over a shorter period of time.

The United States is by far the largest market for pharmaceutical products, and the current situation is not likely to change that. But, according to the European Federation of Pharmaceutical Industries and Associations, the United States represents nearly twice the sales of pharmaceutical products compared with Europe. In addition, between 1990 and 2006, invest-

ment in new research in the United States grew 5 times compared with only 2.9 times in Europe. That means that for all the potential market and all the investment there are fewer products. The slowdown in drug approvals by the FDA may address the current environment, but in the long-run it has a negative impact on nearly everyone.

References 1. Sagient BioMed Tracker. http://www.biomedtracker.com/Login.cfm?

ReportID=231&CFID=2017815&CFTOKEN=55147424. Accessed April 15, 2008.

2. Reuters. Sagient research reports significant decline in FDA drug approval rate. http://www.reuters.com/article/pressRelease/idUS130687 +09-Jan-2008+PNW20080109. Accessed April 15, 2008.

3. Rader RA. Paucity of biopharma approvals raises alarm: lower numbers, novelty, and economic impact indicate problems. Genet Eng Biotechnol News. 2008;28(6):10. http://www.biopharma.com/approvals_ GEN.html. Accessed April 15, 2008.

4. Whalen J. Overseas drugs hit U.S. regulatory snags. WSJ. March 26, 2008; page B4. http://online.wsj.com/article/SB120648160360663519. html?mod=googlenews_wsj. Accessed April 15, 2008.

5. The RPM Report. FDA’s outlook on the drug approval drought.

February 1, 2008. http://therpmreport.com. Accessed April 15, 2008 [article fee].

Mr Senak is Senior Vice President at Fleishman-Hillard in Washington, DC, and author of Eye on FDA blog, www.eyeonfda.com.

Call for Papers The editors of American Health & Drug Benefits (AHDB) are pleased to invite readers to submit articles for publication on topics examining advances in clinical, business, and regulatory developments relevant to attaining value—a balance of cost, quality, and access—in formulary and benefit design strategies. AHDB offers an open forum for all healthcare stakeholders to present their needs, initiatives, and data, with the goal of achieving patient-centered health and drug benefits that meet the needs of all stakeholders—patients, providers, payors, purchasers, distributors, regulatory, manufacturers, evaluators, and researchers.

Articles should discuss key issues that can improve the quality and efficiency of our healthcare delivery system in general and of formulary and drug benefit strategies in particular. Types of articles and topics sought include: • • • • • • • •

Original research Review articles Expert opinions Diagnosis/treatment guidelines Drug updates Government reports Foundation reports Off-label use/misuse

• Clinical topics: Alzheimer’s/dementia Asthma/allergies Cholesterol management Diabetes Depression

Hypertension Infectious diseases Pain management Schizophrenia Cancer therapy

All papers will undergo a peer-review process. Please submit your manuscript electronically to editorial@AHDBonline.com, or mail to AHDB, 241 Forsgate Drive, Suite 205A, Jamesburg, NJ 08831.

www.AHDBonline.com

55

INDUSTRY TRENDS

INDUSTRY TRENDS—CLINICAL Gordon M. Cummins, MS

Since 2000, there have been approximately 822 compounds for the treatment of depression that are currently in various stages of development (Table 1).

Table 1 Depression Compounds in Development Phase Preclinical Phase 1 Phase 1/2 Phase 2 Phase 2/3 Phase 3 Phase 4 Unknown Total

Compounds, N 2 36 28 114 20 174 168 280 822

Total, % 0.2 4.4 3.4 13.9 2.4 21.2 20.4 34.1 100.00

Source: http://www.clinicaltrials.gov/ct2/results?cond=depression &cntry1=NA%3AUS&rcv_s=01%2F01%2F2000&rcv_e=03%2F 17%2F2008&show_down=Y#down. Accessed March 21, 2008

More than 70% of all of the depression compounds currently in clinical development are sponsored by a select number of organizations. The top organizations sponsoring such trials are listed in Table 2. Of these, approximately 28% of the compounds are sponsored by the National Institute of Mental Health in collaboration with other organizations.

Table 2 Organizations Sponsoring Depression Compounds in Clinical Development Sponsor N National Institute of Mental Health Department of Veterans Affairs Eli Lilly Massachusetts General Hospital National Center for Complementary and Alternative Medicine Stanford University GlaxoSmithKline New York State Psychiatric Institute AstraZeneca National Institute on Drug Abuse Sanofi-aventis University of Pittsburgh Duke University Emory University Yale University Wyeth Merck University of Texas Southwestern Medical Center Indiana University School of Medicine McLean Hospital Weill Medical College of Cornell University Medical University of South Carolina National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Alcohol Abuse and Alcoholism Pfizer

Total %

231 42 22 20

28.1 5.1 2.7 2.4

19 19 18 16 14 14 13 13 12 12 11 10 9

2.3 2.3 2.2 1.9 1.7 1.7 1.6 1.6 1.5 1.5 1.3 1.2 1.1

9 8 8

1.1 1.0 1.0

8 7

1.0 0.9

7

0.9

7 7

0.9 0.9

Source: http://www.clinicaltrials.gov/ct2/results?cond=depression &cntry1=NA%3AUS&rcv_s=01%2F01%2F2000&rcv_e=03%2F 17%2F2008&show_down=Y#down. Accessed March 21, 2008.

INDUSTRY TRENDS—BUSINESS Depression frequently presents in association with a chronic illness in the general population. The presence of comorbid depression has been shown to be predictive of worse outcomes of the medical illness and of increased mortality.1 Major depressive disorder affects approximately 14.8 million (6.7%) of the adult US population (18 or older) in any given year.2

Depression has been associated with the following medical conditions: • 85% of patients with depression experience significant symptoms of anxiety3 • About 75% of patients with obsessive-compulsive disorder report that they have suffered from symptoms of depression4 • Chronic major depression increases the risk of cancer by 88% over 3.8 years of follow-up5 Continued on page 58

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May 2008

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INDUSTRY TRENDS

Continued from page 56 • Patients with cancer have a high rate of psychiatric comorbidity; approximately 50% of those with cancer have emotional difficulties6 • Nearly 50% of women diagnosed with early breast cancer had depression, anxiety, or both in the year after diagnosis7 • About 33% of patients with acute post–myocardial infarction are depressed; depression is a strong independent predictor of negative outcomes in patients with coronary artery disease8 • The prevalence for major depression among patients with HIV or AIDS has been estimated to be between 15% and 40%, far exceeding that seen in the general population9 • 40% of patients with Parkinson’s disease have comorbid depression.10 Not surprisingly, depression plays a major role in overall costs of healthcare services: • Annual economic consequences of depression have been estimated at 11.5 billion euros in the United Kingdom and $83 billion in the United States • The economic burden is staggering, with estimates running as much as $51.5 billion a year in lost productivity.11 An additional $26.1 billion is spent for medical treatment11 • More than 70% of people diagnosed with depression are employed, and depression results in 400 million lost work days annually, according to Keith Dixon, PhD, president of Cigna Behavioral Health. In the private sector, Dr Dixon notes, depressed employees use, on average, more than $4000/year in medical services compared with less than $1000/year used by employees without depression, making depression a significant component of healthcare costs12 • Employers pay almost 75% of the $80-billion price tag for treatment of depressive disorders each year.13

women with early breast cancer: five year observational cohort study.

BMJ. 2005;330(7493):702.

8. Vaccarino V, Karl SV, Abramson J, Krumholz HM. Depressive symptoms and risk of functional decline and death in patients with heart failure. J Am Coll Cardiol. 2001;38(1):199-205.

9. Angelino AF, Treisman GJ. Management of psychiatric disorders in patients infected with human immunodeficiency virus. Clin Infect Dis. 2001;33(6):847-856.

10. McDonald WM, Richard IH, DeLong MR. Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry. 2003; 54(3):363-375.

11. Lerner D, Adler DA, Chang H, et al. Unemployment, job retention, and productivity loss among employees with depression. Psychiatr Serv.

2004;55(12):1371-1378.

12. Dixon K. Direct costs of depression in the workplace are tip of the iceberg; employers have huge stake in promoting depression treatment.

PRNewswire. October 13, 2005. http://www.prnewswire.com/cgibin/ stories.pl?acct=104&story=/www/story/10-13-2005/0004167764&e date. Accessed February 20, 2006.

13. Durso KA. Depression in the workplace: prevalence, cost and productivity impact. Employee Benefit News. December 2004. http:// www.benefitnews.com/detail.cfm?id=6776&terms=%7Cpresenteeism% 7C. Accessed February 20, 2006.

Unmanaged Moment

References 1. Goodnick PJ, Hernandez M. Treatment of depression in comorbid medical illness. Expert Opin Pharmacother. 2000;1(17):1367-1384.

2. Kessler RC, Chiu WT, Demier O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627.

3. Gorman JM. Comorbid depression and anxiety disorders. Depress Anxiety. 1996-1997;4:160-168.

4. The University of Florida Obsessive-Compulsive Disorder Program. http://www.ufocd.org/OtherConditions.htm. Accessed February 20, 2006.

5. Penninx BW, Guralnik JM, Pahor M, et al. Chronically depressed mood and cancer risk in older persons. J Natl Cancer Inst. 1998; 90(24):1888-1893.

6. Derogatis LR, Morrow GR, Fetting J, et al. The prevalence of psychiatric disorders among cancer patients. JAMA. 1983;249(6):751-757.

7. Burgess C, Corneliu V, Love S, et al. Depression and anxiety in

58

AMERICAN HEALTH & DRUG BENEFITS

May 2008

“From January to May I work for the government to pay for my income tax, and from May to October to pay for my malpractice insurance.”

Executive Summaries The Unbearable Lightness of Mental Health

physical wellness from an economic point of view, as well as from the vantage point of employees’ overall health and well-being and finally from the perspective of the US healthcare system in general.

By Alberto Colombi, MD, MPH

In his guest editorial, Dr Alberto Colombi, Medical Director at PPG Industries, Pittsburgh, PA, points a gentle finger at different stakeholders—employers, health insurance plans, benefit design managers, as well as the American public— charging all of us to consider mental “wellness” as important a concept as physical well-being. Making the case that mental health translates into wealth for employers, for health plans, and for society at large, he urges decision makers in healthcare and all of those involved in the delivery of patient care to place screening, diagnosis, intervention, and referral of mental issues on the same footing as the cardinal physical conditions—diabetes, heart disease, and the metabolic syndrome. Using self-reported data from his company’s employees, Dr Colombi makes the business case that mental wellness deserves as much attention as

Schizophrenia: Current Concepts and Approaches to Patient Care

By Peter F. Buckley, MD, and Adriana Foster, MD

Schizophrenia, the most serious mental illness, is still poorly understood by scientists, and the lay public remains largely confused about this condition and continues to harbor notions that it is a “split personality” or a “Jekyll and Hyde” phenomenon. Dr Peter F. Buckley, a world expert on schizophrenia and the author of many books and articles on the subject, is Professor and Chair, Department of Psychiatry and Health Behavior, Medical College of Georgia, Atlanta. He and Dr Foster outline what is known

today about this serious condition and why correct treatment is so important. Stigma, which is fueled by a lack of knowledge, is a major obstacle in the management of schizophrenia, Dr Buckley points out. Antipsychotic medications, both the older, so-called typical agents, and the second-generation, atypical medications, form the bedrock for treatment. These drugs are effective, but patients vary in their response to each drug and their side-effect profile. Individual differences among the available medications suggest that trials with a different medication may be appropriate when one agent fails or is not appropriate for the specific patient.

Therefore, allowing physicians to prescribe the drug that is best suited for the individual patient, regardless of cost, is crucial. Just as important is monitoring for side effects, to ensure efficacy and compliance.

Patients often stop taking their medications for a variety of reasons, which invariably will lead most patients to a relapse of illness. Dr Buckley emphasizes the need for appropriate and individualized management of each patient with the best available treatments.

Continued on page 60

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EXECUTIVE SUMMARIES

Trends in Pharmaceutical Expenditures: The Impact on Drug Benefit Design

Medicare Coverage for ErythropoiesisStimulating Agents: The Perfect Storm

By Joanne LaFleur, PharmD, MSPH; Leslie Fish, PharmD; and Diana I. Brixner, RPh, PhD

Part 1 of an interview with Samuel M. Silver, MD, PhD

In the 1990s, national spending on pharmaceuticals increased at a rapid pace, outpacing increases on hospital and physician services, which had dominated the industry in the years before. However, this trend has shifted in the past few years, as is evident from current national data. Dr Joanne LaFleur, Research Assistant Professor, University of Utah Pharmacotherapy Outcomes Research Center, Salt Lake City, and colleagues describe the new declining spending trends and offer the reasons for these trends. Among the forces pushing traditional pharmaceuticals down are the increasing use of generics and the growing role of biologic agents. Dr LaFleur and colleagues propose that this new drug trend presents an opportunity for health plans to evaluate the value of current and new drug benefit strategies and implement value-based benefit designs in accordance with the shifting focus in healthcare toward personalized patient care. They further suggest that value-based drug benefit design should lead to overall cost-efficiencies by designing access according to patient populations rather than by cost.

In 2007, Medicare changed their policy regarding payment for erythropoiesis-stimulating agents (ESAs), a lucrative class of anemia drugs, thus exerting an almost immediate influence on carriers and limiting the use of these agents. Although some states have mandates that prevent health plans from taking the action prescribed by Medicare, the agency

still wields a great influence. Dr Samuel Silver, Director of the Cancer Center Network, Division of Hematology/Oncology, University of Michigan Health Systems, Ann Arbor, is finishing his term on the American Society of Hematology Executive Committee and also serves on several committees at the American Society of Clinical Oncology. Dr Silver describes the evolution of the clinical use of ESAs from a way to avoid transfusion to a quality-of-life issue and the implications of this shift in practice. He also elaborates on the effect of Medicare’s reimbursement policies on health plans and clinicians and has suggested to members of Congress and to the Centers for Medicare & Medicaid Services to review the current database prospectively to assess the use of transfusion in cancer patients in relation to the recent policy changes.

Unmanaged Moment

“There’s a placebo among us!”

60

AMERICAN HEALTH & DRUG BENEFITS

May 2008

Brief Summary of Prescribing Information USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDISÂŽ tablets should be discontinued as soon as possible.

See WARNINGS: Fetal/Neonatal Morbidity and Mortality INDICATIONS MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS MICARDIS (telmisartan) is contraindicated in patients who are hypersensitive to any component of this product.

WARNINGS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, MICARDIS (telmisartan) tablets should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, MICARDIS tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. There is no clinical experience with the use of MICARDIS tablets in pregnant women. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day). Hypotension in Volume-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with MICARDISÂŽ tablets. This condition should be corrected prior to administration of MICARDIS tablets, or treatment should start under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

PRECAUTIONS General. Impaired Hepatic Function: As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. MICARDIS (telmisartan) tablets should be used with caution in these patients. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensinconverting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with MICARDIS tablets. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of MICARDIS tablets in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated. Information for Patients. Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. Drug Interactions.

Digoxin: When telmisartan was coadministered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible overor under-digitalization. Warfarin: Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio (INR).

Other Drugs: Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day). Genotoxicity assays did not reveal any telmisartanrelated effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test. No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and Mortality. Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, 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 Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients receiving MICARDIS in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS MICARDIS (telmisartan) has been evaluated for safety in more than 3700 patients, including 1900 treated for

over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160mg) monotherapy for up to 12 weeks, an overall incidence of adverse events similar to that of placebo was observed. Adverse events occurring at an incidence of 1% or more in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented as follows: The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of e1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). In addition to the adverse events, the following events occurred at a rate of 1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea and peripheral edema. Discontinuation of therapy due to adverse events was required in 2.8% of 1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in six placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated with telmisartan). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets.

Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of MICARDIS tablets. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS tablets. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS. OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS (telmisartan) tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

DOSAGE AND ADMINISTRATION Dosage must be individualized.The usual starting dose of MICARDIS (telmisartan) tablets is 40 mg once a day. Blood pressure response is dose related over the range of 20-80 mg. Special Populations: Patients with depletion of intravascular volume should have the condition corrected or MICARDIS tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume-Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS, General, Impaired Hepatic Function, and Impaired Renal Function). Most of the antihypertensive effect is apparent within two weeks and maximal reduction is generally attained after four weeks. When additional blood pressure reduction beyond that achieved with 80 mg MICARDIS is required, a diuretic may be added. No initial dosing adjustment is necessary for elderly patients or patients with mild-to-moderate renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored. MICARDIS tablets may be administered with other antihypertensive agents. MICARDIS tablets may be administered with or without food.

Rx only MC-BS (03/07)

Copyright Š 2007, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

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1

fi

More than in the early morning2

USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS Tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

MICARDIS is contraindicated in patients who are hypersensitive to any component of this product. The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of e1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%).

Please see Brief Summary of Product Information on adjacent page.

References: 1. Weber MA,White WB,Giles TD,et al.An effectiveness study comparing algorithm-based antihypertensive therapy with previous treatments using conventional and ambulatory blood pressure measurements. J Clin Hypertens.

2006;8:241-250. 2. White WB,Giles T,Bakris GL,et al.Measuring the efficacy of antihypertensive therapy by ambulatory blood pressure monitoring in the primary care setting. Am Heart J. 2006;151:176-184.

Please visit www.micardis.com for more information, including Prescribing Information.

Copyright Š 2007, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

(10/07)

MC48828