May/June 2010, Vol 3, No 4

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ MAY/JUNE 2010

VOLUME 3, NUMBER 3

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

COMMENTARY

No, You Can’t Keep Your Health Plan: Insurers and Doctors Are Already Consolidating Their Business in the Wake of ObamaCare’s Passage Scott Gottlieb, MD

The Health Reform Law: Key Changes to Be Implemented in 2010 Kip Piper, MA, FACHE

Correspondence: Article Supported by a Pharmaceutical Company Raises Concern Kevin Slavik, RPh, MHA ™

CLINICAL

Prevalence of Treated Bipolar Disorders and Associated Comorbidities in Managed Care and Medicaid Populations Jeff J. Guo, PhD; Nick C. Patel, PharmD, PhD; Hong Li, PhD; Paul E. Keck Jr, MD

Stakeholder Perspective by Nirav R. Shah, MD, MPH BUSINESS

Impact of Etanercept Treatment on Absenteeism and Productivity: The Work Loss and Productivity Survey Denise Globe, PhD; Peter Mazonson, MD, MBA; Chris Santas, MBA; Regina Murphy, MBA; Annie Cheng; Xingyue Huang, BPharm, PhD; Arthur Kavanaugh, MD

Stakeholder Perspective by Atheer A. Kaddis, PharmD

Health Benefit Coverage, Reimbursement, and Influences on Traditional Pharmaceutical Channels F. Randy Vogenberg, RPh, PhD

Stakeholder Perspective by Gary M. Owens, MD DEPARTMENTS ◆

Industry Trends

◆

Generic Drug Trends

◆

ASH Highlights

◆

AMCP Highlights

◆

Drug Pipeline

©2010 Engage Healthcare Communications, LLC www.AHDBonline.com

DEXILANT WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

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

DEXILANT 60 mg 200

DEXILANT 30 mg

0 0

6

12

18

24

Time (h)

s DEXILANT 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41 Conclusions of comparative efficacy cannot be drawn from this information.

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

Important Safety Information DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.

Most commonly reported treatment-emergent adverse reactions: diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).

Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations.

Please see adjacent brief summary of prescribing information for DEXILANT.

FORMERLY

KAPIDEX™ (dexlansoprazole)

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE DEXILANT is indicated for: K D85 851<9>7 ?6 1<< 7B145C ?6 5B?C9F5 5C?@8179D9C 6?B E@ D? G55;C K =19>D19>9>7 851<9>7 ?6 6?B E@ D? =?>D8C 1>4 K D85 DB51D=5>D ?6 851BD2EB> 1CC?391D54 G9D8 >?> 5B?C9F5 71CDB?5C?@81751< B56<EH 49C51C5 ( 6?B G55;C CONTRAINDICATIONS - " $* 9C 3?>DB19>4931D54 9> @1D95>DC G9D8 ;>?G> 8I@5BC5>C9D9F9DI D? 1>I 3?=@?>5>D ?6 D85 6?B=E<1D9?> I@5BC5>C9D9F9DI 1>4 1>1@8I<1H9C 81F5 255> B5@?BD54 G9D8 - " $* EC5 [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Gastric Malignancy )I=@D?=1D93 B5C@?>C5 G9D8 - " $* 4?5C >?D @B53<E45 D85 @B5C5>35 ?6 71CDB93 =1<97>1>3I ADVERSE REACTIONS Clinical Trials Experience *85 C165DI ?6 - " $* G1C 5F1<E1D54 9> @1D95>DC 9> 3?>DB?<<54 1>4 E>3?>DB?<<54 3<9>931< CDE495C 9>3<E49>7 @1D95>DC DB51D54 6?B 1D <51CD =?>D8C 1>4

@1D95>DC DB51D54 6?B ?>5 I51B &1D95>DC B1>754 9> 175 6B?= D? I51BC =5491> 175 I51BC G9D8 65=1<5 1E31C91> <13; C91> 1>4 ?D85B B135C )9H B1>4?=9J54 3?>DB?<<54 3<9>931< DB91<C G5B5 3?>4E3D54 6?B D85 DB51D=5>D ?6 =19>D5>1>35 ?6 851<54 1>4 CI=@D?=1D93 ( G8938 9>3<E454 @1D95>DC ?> @<1352? @1D95>DC ?> - " $* =7

@1D95>DC ?> - " $* =7 1>4 @1D95>DC ?> <1>C?@B1J?<5 =7 ?>35 419<I C 3<9>931< DB91<C 1B5 3?>4E3D54 E>45B G945<I F1BI9>7 3?>49D9?>C 14F5BC5 B513D9?> B1D5C ?2C5BF54 9> D85 3<9>931< DB91<C ?6 1 4BE7 31>>?D 25 49B53D<I 3?=@1B54 D? B1D5C 9> D85 3<9>931< DB91<C ?6 1>?D85B 4BE7 1>4 =1I >?D B56<53D D85 B1D5C ?2C5BF54 9> @B13D935 #?CD ?==?><I (5@?BD54 4F5BC5 (513D9?>C *85 =?CD 3?==?> 14F5BC5 B513D9?>C D81D ?33EBB54 1D 1 89785B 9>3945>35 6?B - " $* D81> @<1352? 9> D85 3?>DB?<<54 CDE495C 1B5 @B5C5>D54 9> *12<5

Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies Placebo Adverse Reaction 91BB851 24?=9>1< &19> $1EC51

(N=896) %

DEXILANT 30 mg (N=455) %

DEXILANT 60 mg (N=2218) %

DEXILANT Total (N=2621) %

Lansoprazole 30 mg (N=1363) %

+@@5B (5C@9B1D?BI Tract Infection

,?=9D9>7 <1DE<5>35

4F5BC5 (513D9?>C (5CE<D9>7 9> 9C3?>D9>E1D9?> > 3?>DB?<<54 3<9>931< CDE495C D85 =?CD 3?==?> 14F5BC5 B513D9?> <5149>7 D? 49C3?>D9>E1D9?> 6B?= - " $* D85B1@I G1C 491BB851

%D85B 4F5BC5 (513D9?>C %D85B 14F5BC5 B513D9?>C D81D G5B5 B5@?BD54 9> 3?>DB?<<54 CDE495C 1D 1> 9>3945>35 ?6 <5CC D81> 1B5 <9CD54 25<?G 2I 2?4I CICD5= Blood and Lymphatic System Disorders: 1>5=91 <I=@8145>?@1D8I Cardiac Disorders: 1>79>1 1BB8ID8=91 2B14I31B491 385CD @19> 545=1 =I?31B491< 9>61B3D9?> @1<@9D1D9?> D138I31B491 Ear and Labyrinth Disorders: 51B @19> D9>>9DEC F5BD97? Endocrine Disorders: 7?9D5B Eye Disorders: 5I5 9BB9D1D9?> 5I5 CG5<<9>7 Gastrointestinal Disorders: 124?=9>1< 49C3?=6?BD 124?=9>1< D5>45B>5CC 12>?B=1< 6535C 1>1< 49C3?=6?BD 1BB5DD C 5C?@817EC 25J?1B 2?G5< C?E>4C 12>?B=1< 2B51D8 ?4?B 3?<9D9C =93B?C3?@93 3?<?>93 @?<I@ 3?>CD9@1D9?> 4BI =?ED8 4E?45>9D9C 4IC@5@C91 4IC@81791 5>D5B9D9C 5BE3D1D9?> 5C?@8179D9C 71CDB93 @?<I@ 71CDB9D9C 71CDB?5>D5B9D9C 71CDB?9>D5CD9>1< 49C?B45BC 71CDB?9>D5CD9>1< 8I@5B=?D9<9DI 49C?B45BC ( E<35BC 1>4 @5B6?B1D9?> 85=1D5=5C9C 85=1D?385J91 85=?BB8?94C 9=@19B54 71CDB93 5=@DI9>7 9BB9D12<5 2?G5< CI>4B?=5 =E3EC CD??<C >1EC51 1>4 F?=9D9>7 ?B1< =E3?C1< 2<9CD5B9>7 @19>6E< 456531D9?> @B?3D9D9C @1B5CD85C91 ?B1< B53D1< 85=?BB8175 General Disorders and Administration Site Conditions: 14F5BC5 4BE7 B513D9?> 1CD85>91 385CD @19> 389<<C 655<9>7 12>?B=1< 9>6<1==1D9?> =E3?C1< 9>6<1==1D9?> >?4E<5 @19> @IB5H91 Hepatobiliary Disorders: 29<91BI 3?<93 38?<5<9D891C9C 85@1D?=571<I Immune System Disorders: 8I@5BC5>C9D9F9DI Infections and Infestations: 31>4941 9>653D9?>C 9>6<E5>J1 >1C?@81BI>79D9C ?B1< 85B@5C @81BI>79D9C C9>EC9D9C F9B1< 9>653D9?> FE<F? F179>1< 9>653D9?> Injury, Poisoning and Procedural Complications: 61<<C 6B13DEB5C :?9>D C@B19>C ?F5B4?C5

@B?354EB1< @19> CE>2EB> Laboratory Investigations: "& 9>3B51C54 "* 9>3B51C54 )* 9>3B51C54 29<9BE29> 453B51C54 9>3B51C54 2<??4 3B51D9>9>5 9>3B51C54 2<??4 71CDB9> 9>3B51C54 2<??4 7<E3?C5 9>3B51C54 2<??4 @?D1CC9E= 9>3B51C54 <9F5B 6E>3D9?> D5CD 12>?B=1< @<1D5<5D 3?E>D 453B51C54 D?D1< @B?D59> 9>3B51C54 G5978D 9>3B51C5 Metabolism and Nutrition Disorders: 1@@5D9D5 381>75C 8I@5B31<35=91 8I@?;1<5=91 Musculoskeletal and Connective Tissue Disorders: 1BD8B1<791 1BD8B9D9C =EC3<5 3B1=@C =EC3E<?C;5<5D1< @19> =I1<791 Nervous System Disorders: 1<D5B54 D1CD5 3?>FE<C9?> 49JJ9>5CC 85141385C =97B19>5 =5=?BI 9=@19B=5>D @1B5CD85C91 @CI38?=?D?B 8I@5B13D9F9DI DB5=?B DB975=9>1< >5EB1<791 Psychiatric Disorders: 12>?B=1< 4B51=C 1>H95DI 45@B5CC9?> 9>C?=>91 <9294? 381>75C Renal and Urinary Disorders: 4ICEB91 =93DEB9D9?> EB75>3I Reproductive System and Breast Disorders: 4IC=5>?BB851 4IC@1B5E>91 =5>?BB81791 =5>CDBE1< 49C?B45B; Respiratory, Thoracic and Mediastinal Disorders: 1C@9B1D9?> 1CD8=1 2B?>389D9C 3?E78 4IC@>?51 8933E@C 8I@5BF5>D9<1D9?> B5C@9B1D?BI DB13D 3?>75CD9?> C?B5 D8B?1D Skin and Subcutaneous Tissue Disorders: 13>5 45B=1D9D9C 5BID85=1 @BEB9D9C B1C8 C;9> <5C9?> EBD931B91 Vascular Disorders: 455@ F59> D8B?=2?C9C 8?D 6<EC8 8I@5BD5>C9?> 449D9?>1< 14F5BC5 B513D9?>C D81D G5B5 B5@?BD54 9> 1 <?>7 D5B= E>3?>DB?<<54 CDE4I 1>4 G5B5 3?>C945B54 B5<1D54 D? - " $* 2I D85 DB51D9>7 @8IC9391> 9>3<E454 1>1@8I<1H9C 1E49D?BI 81<<E39>1D9?> 35<< <I=@8?=1 2EBC9D9C 35>DB1< ?25C9DI 38?<53ICD9D9C 13ED5 453B51C54 85=?7<?29> 458I4B1D9?> 49125D5C =5<<9DEC 4IC@8?>91 5@9CD1H9C 6?<<93E<9D9C 71CDB?9>D5CD9>1< @19> 7?ED 85B@5C J?CD5B 8I@5B7<I35=91 8I@5B<9@945=91 8I@?D8IB?949C= 9>3B51C54 >5EDB?@89<C # 453B51C5 >5EDB?@5>91 ?B1< C?6D D9CCE5 49C?B45B @?<I49@C91 @?<IEB91 B53D1< D5>5C=EC B5CD<5CC <57C CI>4B?=5 C?=>?<5>35 D8B?=2?3ID85=91 D?>C9<<9D9C %D85B 14F5BC5 B513D9?>C >?D ?2C5BF54 G9D8 - " $* 2ED ?33EBB9>7 G9D8 D85 B135=1D5 <1>C?@B1J?<5 31> 25 6?E>4 9> D85 <1>C?@B1J?<5 @13;175 9>C5BD , () ( * %$) C53D9?> Postmarketing Experience 4F5BC5 B513D9?>C 81F5 255> 945>D96954 4EB9>7 @?CD 1@@B?F1< ?6 - " $* C D85C5 B513D9?>C 1B5 B5@?BD54 F?<E>D1B9<I 6B?= 1 @?@E<1D9?> ?6 E>35BD19> C9J5 9D 9C >?D 1<G1IC @?CC92<5 D? B5<912<I 5CD9=1D5 D859B 6B5AE5>3I ?B 5CD12<9C8 1 31EC1< B5<1D9?>C89@ D? 4BE7 5H@?CEB5 Eye Disorders: 2<EBB54 F9C9?> Gastrointestinal Disorders: ?B1< 545=1 General Disorders and Administration Site Conditions: 61391< 545=1 Immune System Disorders: 1>1@8I<13D93 C8?3; B5AE9B9>7 5=5B75>3I 9>D5BF5>D9?> )D5F5>C ?8>C?>C CI>4B?=5 D?H93 5@945B=1< >53B?<IC9C C?=5 61D1< Respiratory, Thoracic and Mediastinal Disorders: @81BI>751< 545=1 D8B?1D D978D>5CC Skin and Subcutaneous Tissue Disorders: 75>5B1<9J54 B1C8 <5E3?3ID?3<1CD93 F1C3E<9D9C DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics - " $* 31EC5C 9>8929D9?> ?6 71CDB93 1394 C53B5D9?> - " $* 9C <9;5<I D? CE2CD1>D91<<I 453B51C5 D85 CICD5=93 3?>35>DB1D9?>C ?6 D85 , @B?D51C5 9>8929D?B 1D1J1>1F9B G8938 9C 45@5>45>D E@?> D85 @B5C5>35 ?6 71CDB93 1394 6?B 12C?B@D9?> 1>4 =1I B5CE<D 9> 1 <?CC ?6 D85B1@5ED93 56653D ?6 1D1J1>1F9B 1>4 D85 45F5<?@=5>D ?6 , B5C9CD1>35 *85B56?B5 - " $* C8?E<4 >?D 25 3? 14=9>9CD5B54 G9D8 1D1J1>1F9B D 9C D85?B5D931<<I @?CC92<5 D81D - " $* =1I 9>D5B65B5 G9D8 D85 12C?B@D9?> ?6 ?D85B 4BE7C G85B5 71CDB93 @ 9C 1> 9=@?BD1>D 45D5B=9>1>D ?6 ?B1< 29?1F19<129<9DI 5 7 1=@939<<9> 5CD5BC 497?H9> 9B?> C1<DC ;5D?3?>1J?<5 Warfarin ? 14=9>9CDB1D9?> ?6 - " $* =7 1>4 G1B61B9> =7 494 >?D 16653D D85 @81B=13?;9>5D93C ?6 G1B61B9> ?B $( ?G5F5B D85B5 81F5 255> B5@?BDC ?6 9>3B51C54 $( 1>4 @B?D8B?=29> D9=5 9> @1D95>DC B5359F9>7 && C 1>4 G1B61B9> 3?>3?=9D1>D<I >3B51C5C 9> $( 1>4 @B?D8B?=29> D9=5 =1I <514 D? 12>?B=1< 2<5549>7 1>4 5F5> 451D8 &1D95>DC DB51D54 G9D8 - " $* 1>4 G1B61B9> 3?>3?=9D1>D<I =1I >554 D? 25 =?>9D?B54 6?B 9>3B51C5C 9> $( 1>4 @B?D8B?=29> D9=5 Tacrolimus ?>3?=9D1>D 14=9>9CDB1D9?> ?6 45H<1>C?@B1J?<5 1>4 D13B?<9=EC =1I 9>3B51C5 G8?<5 2<??4 <5F5<C ?6 D13B?<9=EC 5C@5391<<I 9> DB1>C@<1>D @1D95>DC G8? 1B5 9>D5B=5491D5 ?B @??B =5D12?<9J5BC ?6 .&

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects &B57>1>3I 1D57?BI *85B5 1B5 >? 145AE1D5 1>4 G5<< 3?>DB?<<54 CDE495C G9D8 45H<1>C?@B1J?<5 9> @B57>1>D G?=5> *85B5 G5B5 >? 14F5BC5 65D1< 56653DC 9> 1>9=1< B5@B?4E3D9?> CDE495C ?6 45H<1>C?@B1J?<5 9> B1229DC 531EC5 1>9=1< B5@B?4E3D9?> CDE495C 1B5 >?D 1<G1IC @B5493D9F5 ?6 8E=1> B5C@?>C5 - " $* C8?E<4 25 EC54 4EB9>7 @B57>1>3I ?><I 96 3<51B<I >55454

A reproduction study conducted in rabbits at oral dexlansoprazole doses up to 30 mg per kg per day (approximately 9-fold the maximum recommended human dexlansoprazole dose (60 mg) revealed no evidence of harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.

Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Carcinogenesis, Mutagenesis, Impairment of Fertility], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established.

Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole.

Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive.

CLINICAL PHARMACOLOGY Pharmacodynamics Antisecretory Activity The effects of DEXILANT 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for five days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study.

Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.

Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology].

Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day.

Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology].

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended lansoprazole human dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended lansoprazole human dose based on BSA).

The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended lansoprazole human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in the full prescribing information] Information for Patients Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued.

To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following: DEXILANT is available as a delayed release capsule.

DEXILANT may be taken without regard to food.

DEXILANT should be swallowed whole.

K <D5B>1D9F5<I - " $* 31@CE<5C 31> 25 ?@5>54 1>4 14=9>9CD5B54 1C follows: - Open capsule; - Sprinkle intact granules on one tablespoon of applesauce; - Swallow immediately.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 5,045,321; 5,093,132; 5,433,959; 6,462,058; 6,664,276; 6,939,971; and 7,285,668.

DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners. Š2009, 2010 Takeda Pharmaceuticals America, Inc. For more detailed information, see the full prescribing information for DEXILANT or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.

KAP0110 R6-Brf; March 2010 L-LPD-0310-2

Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANTâ&#x201E;˘, KAPIDEXâ&#x201E;˘ (dexlansoprazole), and Dual Delayed Releaseâ&#x201E;˘ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc. Š2010 Takeda Pharmaceuticals North America, Inc. LPD-01139 6/10 Printed in U.S.A.

EDITORIAL BOARD

CLINICAL EDITOR

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

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

GOVERNMENT EDITOR

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

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA

ACTUARY

HEALTH OUTCOMES RESEARCH

David Williams Milliman Health Consultant Windsor, CT CANCER RESEARCH

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

HEALTH INFORMATION TECHNOLOGY

Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL MANAGED CARE & GOVERNMENT AFFAIRS

Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL MANAGED MARKETS

CARDIOLOGY RESEARCH

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

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ

Jeffrey A. Bourret, MS, RPh, FASHP Senior Director, Customer Marketing & Innovation, US Specialty Customers Pfizer Specialty Business Unit Collegeville, PA Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim Ridgefield, CT PATIENT ADVOCACY

EMPLOYERS

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA Senior Fellow, Jefferson School of Population Health Joshua N. Liberman, PhD Vice President, Strategic Research CVS Caremark, Hunt Valley, MD

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Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta Paul Anthony Polansky, BSPharm, MBA Former Executive VP and Chief Pharmacy Officer, Sanovia Corp., Philadelphia, PA Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality and biomedical research consultancy J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago REIMBURSEMENT POLICY

Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account Amgen, Thousand Oaks, CA

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

Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Co., Philadelphia, PA

PERSONALIZED MEDICINE

RESEARCH & DEVELOPMENT

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

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

PHARMACOECONOMICS

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

EPIDEMIOLOGY RESEARCH

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

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

SPECIALTY PHARMACY

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

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FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS COMMENTARY

167 No, You Can’t Keep Your Health Plan: Insurers and Doctors Are Already Consolidating Their Business in the Wake of ObamaCare’s Passage Scott Gottlieb, MD

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

168 Correspondence: Article Supported by a Pharmaceutical Company Raises Concern Kevin Slavik, RPh, MHA

Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889

180 The Health Reform Law: Key Changes to Be Implemented in 2010 Kip Piper, MA, FACHE

Associate Editor Lara J. Reiman lara@engagehc.com 732-992-1892 Editorial Assistant Jessica A. Smith

CLINICAL

171 Prevalence of Treated Bipolar Disorders and Associated Comorbidities in Managed Care and Medicaid Populations Jeff J. Guo, PhD; Nick C. Patel, PharmD, PhD; Hong Li, PhD; Paul E. Keck Jr, MD 178 Stakeholder Perspective by Nirav R. Shah, MD, MPH

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

BUSINESS

191 Impact of Etanercept Treatment on Absenteeism and Productivity: The Work Loss and Productivity Survey Denise Globe, PhD; Peter Mazonson, MD, MBA; Chris Santas, MBA; Regina Murphy, MBA; Annie Cheng; Xingyue Huang, BPharm, PhD; Arthur Kavanaugh, MD 199 Stakeholder Perspective by Atheer A. Kaddis, PharmD 225 Health Benefit Coverage, Reimbursement, and Influences on Traditional Pharmaceutical Channels F. Randy Vogenberg, RPh, PhD 229 Stakeholder Perspective by Gary M. Owens, MD Continued on page 164 American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory

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

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

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

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TABLE OF CONTENTS

(Continued)

DEPARTMENTS

189 INDUSTRY TRENDS Bundled Payment: A Promising Initiative of Payment Reform Jim Evans 201 GENERIC DRUG TRENDS Impact of 2 Copay Waivers in a Generic Incentive Program Anthony F. Liu, MSCS; Tom Jecklin; Geoffrey Lee; James Hogan 206 DDW HIGHlIGHTS New Approaches to Treating HCV Infection 210 AmERICAN SoCIETY of HYPERTENSIoN HIGHlIGHTS long-Term VA Study Raises the Bar for BP Control New ARB outperforms older Agents Phase 4 Study Targets Hispanics with Hypertension 213 AMCP HIGHLIGHTS medication Adherence: Effectiveness of Physician Alerts to Resolve Potential Gaps in Pharmacotherapy Joshua N. Liberman, PhD; Janice Moore, MPH; Asif Ally, RPh, MBA; Troyen A. Brennan, JD, MD 217 Patient out-of-Pocket Cost Affects Adherence to oral oncology medications Cost-Effectiveness Trends for 20 Top-Selling Drugs Effect of Diabetes medication Adherence on Costs and outcomes Applying Pharmacogenomics in oncology Care 220 DRUG PIPELINE Promising New Approaches to multiple Sclerosis medications: AAN 2010

By Alice Goodman CAPTION CONTEST

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The dose of BYSTOLIC may need to be reduced.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Body as a Whole: asthenia.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

For the treatment of hypertension

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

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

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

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

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

BYSTOLIC should not be combined with other beta blockers.

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

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

44-1014950

01/09

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

COMMENTARY

No, You Can’t Keep Your Health Plan: Insurers and Doctors Are Already Consolidating Their Businesses in the Wake of ObamaCare’s Passage Scott Gottlieb, MD

P

resident Obama guaranteed Americans that after health reform became law they could keep their insurance plans and their doctors. It is clear that this promise cannot be kept. Insurers and physicians are already reshaping their businesses as a result of Mr Obama’s plan.

The healthcare reform law caps how much insurers can spend on expenses and take for profits. Starting next year, health plans will have a regulated “floor” on their medical-loss ratios, which is the amount of revenue they spend on medical claims. Insurers can only spend 20% of their premiums on running their plans if they offer policies directly to consumers or to small employers. The spending cap is 15% for policies sold to large employers.

This regulation is going to have its biggest impact on insurance sold directly to consumers—what is referred to as the “individual market.” These policies cost more to market. They also have higher medical costs, owing partly to selection by less healthy consumers.

Finally, individual policies have high start-up costs. If insurers cannot spend more of their revenue getting plans on track, fewer new policies will be offered.

This will hit Wellpoint, one of the biggest players in the individual market, particularly hard. The insurance company already has a strained relationship with the White House: Earlier this month Mr Obama accused Wellpoint of systemically denying coverage to breast cancer patients, although the facts do not bear that out.

Restrictions on how insurers can spend money are compounded by simultaneous constraints on how they can manage their costs. Beginning in 2014, a new federal agency will standardize insurance benefits, placing minimum actuarial values on medical policies. There are also mandates forcing insurers to cover a lot of expensive primary care services in full. At the same time, insurers are being blocked from raising premiums—for now by political jawboning, but the threat of legislative restrictions looms.

One of the few remaining ways to manage expenses is to reduce the actual cost of the products. In healthcare, this means pushing providers to accept lower fees and reduce their use of costly services like radiology or other

Dr Gottlieb, a former official at the Centers for Medicare & Medicaid Services, is a fellow at the American Enterprise Institute and a practicing internist. He is partner to a firm that invests in healthcare companies. Reprinted from the Wall Street Journal. Used with permission.

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diagnostic testing. To implement this strategy, companies need to be able to exert more control over doctors. So insurers are trying to buy up medical clinics and doctor practices. Where they cannot own providers outright, they will maintain smaller “networks” of physicians that they will contract with so they can manage doctors more closely. That means even fewer choices for beneficiaries.

Insurers hope that owning providers will enable health policies to offset the cost of the new regulations.

Doctors, meanwhile, are selling their practices to local hospitals. In 2005, doctors owned more than two thirds of all medical practices. By next year, more than 60% of physicians will be salaried employees. About a third of those will be working for hospitals, according to the American Medical Association. A review of the open job searches held by one of the country’s largest physician-recruiting firms shows that nearly 50% are for jobs in hospitals, up from about 25% five years ago.

Last month, a hospital I am affiliated with outside of Manhattan sent a note to its physicians announcing a new subsidiary it is forming to buy up local medical practices. Nearby physicians are lining up to sell—and not just primary care doctors, but highly paid specialists like orthopedic surgeons and neurologists. Similar developments are unfolding nationwide.

Consolidated practices and salaried doctors will leave fewer options for patients and longer waiting times for routine appointments. Like the insurers, physicians are responding to the economic burdens of the president’s plan in one of the few ways they’re permitted to.

For physicians, the strains include higher operating costs. The Obama health plan puts expensive new mandates on doctors, such as a requirement to purchase IT systems and keep more records. Overhead costs already consume more than 60% of the revenue generated by an average medical practice, according to a 2007 survey by the Medical Group Management Association. At the same time, reimbursement under Medicare is falling.

Some specialists, such as radiologists and cardiologists, will see their Medicare payments fall by more than 10% next year. Then there is the fact that medical malpractice premiums have risen by 10% to 20% annually for specialists such as surgeons, particularly in states that have not passed liability reform.

The bottom line—defensive business arrangements designed to blunt ObamaCare’s economic impacts will mean less patient choice. ■

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Article Supported by a Pharmaceutical Company Raises Concern TO THE EDITOR: In reading your March/April 2010 issue, I could not help noticing that the study “Healthcare Costs Associated with Switching from Brand to Generic Levothyroxine”1 was funded by Abbott Laboratories, and 3 of the authors are paid consultants for Abbott.1 It amazes me that your publication would not recognize that these relationships pose a serious conflict of interest and not reject the publication of such a study, because of these inherent potential biases.

1. Katz M, Scherger J, Conard S, et al. Healthcare costs associated with switching from brand to generic levothyroxine. Am Health Drug Benefits. 2010;2:127-134.

Kevin Slavik, RPh, MHA Sr Director of Pharmacy Health Care Service Corporation BlueCross BlueShield of Chicago, IL, Texas, New Mexico, and Oklahoma

EDITOR’S RESPONSE: Thank you for your thoughtful comment and for the opportunity to address this important issue in American Health & Drug Benefits. The question of a potential bias of any article published in the journal is indeed a major concern for us, as it is for many healthcare publications.

Unlike many publications in the industry, however, it is the mission of this journal to encourage submission of articles from all those who have a stake in healthcare—including payers, employers, insurers, providers, government agencies, patient advocacy groups, and yes, pharmaceutical companies—in support of our fundamental goal of stakeholder integration for the improvement of healthcare. It is the stated objective of this journal to promote an open dialogue among all those participating in healthcare toward the promotion of health and wellness in the United States.

To ensure that articles published in this journal are free of bias and therefore have the potential to benefit various stakeholders, we conduct a very strict, carefully managed, and often prolonged peer-review process.

This process at times appears to be detrimental to the idea of expediting the publication of an article and potentially even alienating some authors, but we make no exceptions to this thorough process that was established with the launch of this journal. Each article is reviewed by 2 or 3 (and at times 4 or 5) reviewers, most of whom are either readers of this journal or members of the editorial board, all with specific healthcare expertise.

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Although the peer review is conducted in a blinded fashion, according to which authors’ names and affiliations are withheld from the reviewers, any study support from a commercial or a public body is fully disclosed to the reviewers and subsequently to the readers, as was the case with this particular article. Reviewers are asked specifically to assess the potential bias of each article, and any suggestion of bias in the content of the article is a reason for immediate rejection of that article.

In addition, according to our author disclosure policy, all authors must sign a disclosure form for each article, listing all their potential conflicts of interest, and any such information is subsequently listed with the published article, as was the case with this article.

Finally, although Abbott paid for the study itself, it did not provide any support for the publication of the article, nor did it have any influence on the publication or the editing of the article; the latter entails careful fact-checking of all factual statements and references.

Indeed, none of the articles published in this journal (to differentiate from journal supplements) is supported by any outside funding. ■

Letters to the Editor American Health & Drug Benefits welcomes Letters to the Editor from readers. Letters can be in reference to an article that was published in the journal or can discuss a subject relevant to the focus of the journal and is not in reference to a specific article published in the journal.

Letters are considered for publication provided they are original and do not include materials that have been published or submitted for publication elsewhere (including online publications).

Letters in reference to a journal article must be submitted within 6 months of the publication date of the article.

Letters should not exceed 350 words and up to 4 references, and must be signed by the author(s).

Professional affiliation and full contact information should be provided with the letter.

How to submit a Letter to the Editor: Send letters via e-mail to editorial@AHDBonline.com, or via our website at www.AHDBonline.com. You will receive an e-mail acknowledging the receipt of your letter. Anonymous letters cannot be considered for publication and will not be acknowledged.

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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

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REFERENCES Cite references consecutively in the text (as superscript numbers), then place each complete reference at the end of the article under heading “References.” Use proper citation format according to the AMA Manual of Style. See examples below. Use the most up-to-date, post-1990 references, citing primary sources only. Try to limit the number of references to about 30. Do not use automatic numbering or footnote/ endnote features.

PERMISSIONS Authors must secure a written permission to reuse or adapt any table or figure from a previously published (online or in print) article or from any source. Provide the letter of permission when submitting the manuscript, or indicate that permission will be provided, and cite the original source with the graphic element in the manuscript.

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Length: 2500-3000 words, plus tables and figures.

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

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

Schizophrenia. Oxford, England: Blackwell Press; 2003.

3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. www.bloomberg.com/apps/news?pid=newsarchive&sid=aLfUw 7_sYMRY. Accessed March 13, 2008.

HOW TO SUBMIT MANUSCRIPTS Save the entire manuscript as a Word file and attach individual files for each image. Save images individually as an image file (jpg). Digital graphics must be saved at a high resolution of at least 300 dpi. Submit the manuscript to editorial@ ahdbonline.com. For assistance with the submission, call 732-992-1892.

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

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Prevalence of Treated Bipolar Disorders and Associated Comorbidities in Managed Care and Medicaid Populations Jeff J. Guo, PhD; Nick C. Patel, PharmD, PhD; Hong Li, PhD; Paul E. Keck Jr, MD Objective: To examine the prevalence trends of patients in Medicaid and managed care organization populations treated for a bipolar disorder, and to measure treated key psychiatric and medical comorbidities associated with bipolar disorder.

Method: A longitudinal, retrospective cohort design was conducted using a populationbased multistate medical claims database. From January 1998 to December 2002, a total of 136,763 patients (13,471 in Medicaid and 123,292 in managed care organizations) with a bipolar disorder were identified. Using monthly population-based enrollee denominators, the cumulative monthly prevalence rate of bipolar disorders was calculated for both populations, and was stratified by sex and age-groups (age 0-64 years for Medicaid patients and age 0-99 years for managed care organization patients). Frequencies of key psychiatric and clinical comorbidities were compared between the 2 populations.

Results: Bipolar disorder prevalence rates increased with age, peaking (0.7% for managed care, 2.1% for Medicaid) between the ages of 35 and 49 years. Bipolar disorders were more prevalent in females than in males throughout the study period. The most frequent comorbidities included anxiety disorder (37% in managed care organization vs 36% in Medicaid), hypertension (18% vs 13%, respectively), diabetes mellitus (7.4% vs 7.2%, respectively), obesity (6.1% vs 7.9%, respectively), alcohol use disorder (6.5% vs 8.2%, respectively), and substance use disorder (5.6% vs 9.6%, respectively).

Conclusion: Prevalence rates of bipolar disorders were higher in patients in Medicaid compared with the managed care population. The prevalence of patients treated for a bipolar disorder has been increasing in both populations. Clinicians should consider managing key medical comorbidities when treating symptoms of bipolar disorder. [AHDB. 2010;3(3):171-178.]

B

ipolar disorder (BPD) is characterized by cyclic mood swings of manic, hypomanic, and depressive episodes. BPD often begins in adolescence or early adulthood and continues throughout life, with recurring mood episodes. Estimated relapse rates during the first year after illness onset range between 37% and

Dr Guo is Associate Professor of Pharmacoeconomics and Pharmacoepidemiology, James J. Winkle College of Pharmacy, University of Cincinnati Medical Center, OH; Dr Patel is a Clinical Pharmacist, LifeSynch, Las Colina, TX; Dr Li is Group Director, Asia Pacific, Global Health Economics and Outcomes Research, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT; Dr Keck is President and CEO, Lindner Health Center of HOPE, Mason, OH, and the Craig and Frances Lindner Professor of Psychiatry and Neuroscience and Executive Vice Chairman of the Department of Psychiatry, University of Cincinnati College of Medicine, OH.

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44%.1,2 Globally, BPD is a major cause of disability, suicide, and death.3 BPD affects more than 2.3 million adult Americans, or 1% of the population, by conservative estimates.4,5 A number of epidemiologic studies have reported prevalence rates of BPD. Variability in reported prevalence rates may be attributed to differences in sampling between studies, as well as ascertainment. For example, the lifetime prevalence rate for BPD in the United States was 0.8% in the Epidemiological Catchment Area (ECA) study and 1.6% in the National Comorbidity Study (NCS).6,7 The NCS surveyed only noninstitutionalized individuals aged 15 to 54 years who met the Diagnostic and Statistical Manual of Mental Disorders-Third Edition-Revised (DSM-III-R) criteria for BPD, whereas the ECA included persons aged 18 to 64 years with the full spectrum of DSM-III-R BPD.6,7 Using

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KEY POINTS u

u

u

u

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Bipolar disorder affects more than 2.3 million adult Americans, or 1% of the population, by conservative estimates.

Higher prevalence rates have been reported when ascertainment includes the full spectrum of bipolar disorders.

Psychiatric and medical comorbidities in patients with bipolar disorder have been suggested to have an impact on the treatment of this illness.

Although managed care databases provide data from medical records and claims about patient diagnoses and treatments, population-based clinical studies examining the prevalence of this disorder and related comorbidities are scarce.

This longitudinal, retrospective cohort design study examined the prevalence trends of this disorder using a population-based multistate medical claims database totaling 136,763 patients, 13,471 in Medicaid and 123,292 in managed care organizations.

In this study, the prevalence rates increased with age, peaking between ages 35 and 49 years. The prevalence was greater in females than in males throughout the study period.

The most frequent comorbidities included anxiety disorder, hypertension, type 2 diabetes, alcohol use disorder, and substance use disorder.

Clinicians should consider managing key medical comorbidities when treating the symptoms of bipolar disorder.

medical claims data, the treated prevalence rate of BPD has been estimated at between 0.2% and 0.5%.8-10 Higher prevalence rates have been reported when ascertainment includes the full spectrum of BPDs. (Ascertainment was used because of multiple subtypes of BPD that were not assessed consistently in published studies.) Studies based on survey questionnaires have reported a wide spectrum of prevalence rates of BPDs ranging from 3.0% to 6.5% in adult populations.11-14 Using the Mood Disorder Questionnaire screening instrument, Hirschfeld and colleagues and Das and colleagues found that from 3.7% to 9.8% of American adults may suffer from a BPD,14,15 with higher rates occurring in low-income populations.15 Psychiatric and medical comorbidities in patients with BPD have received increasing attention in recent years,16-21 because of the possibility that specific bipolar comorbidity associations may have an impact on the treatment of BPDs.7,17,22,23 High prevalence rates of certain

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psychiatric comorbidities among patients with BPD have been reported, including personality disorders (9%89%),21,24,25 alcohol and substance abuse (17%60.7%),14,26-29 and anxiety disorders (25.2%-30.6%).15,19,29 These findings, however, were based on self-reported survey or interview data that might have been subject to limitations of incomplete recall or information bias.30,31 Numerous health insurance plans in US managed care organizations (MCOs) cover mental health services indicated by multiple research reports.5,16,18,32,33 Although managed care databases provide data from medical records and claims about patient diagnoses and treatments, population-based clinical studies examining the prevalence of BPDs and related comorbidities are scarce.

Furthermore, little information exists about the characteristics of patients with BPD in the managed care Medicaid population, despite an increasing number of Medicaid enrollees who are also enrolled in MCOs.34 We therefore proposed to examine the monthly prevalence trend of patients treated for a BPD in a large US MCO population and to examine the occurrence of treated psychiatric disorders and medical comorbidities associated with BPDs.

Patients and Method Study Design A longitudinal, retrospective cohort study was conducted. The primary data source was a multistate managed care claims database (PharMetrics) from January 1998 to December 2002 (5 calendar years). This database includes more than 45 million lives enrolled in MCOs with 70 health plans, including managed care Medicaid programs, in 4 US regions: Midwest (34.1%), East (15.6%), South (23.9%), and West (26.4%). Population distributions in the database are similar to the US population distribution by age and sex distributions.35 This geographically diversified claims database provides a large population perspective of health information, and the use of a managed care claims database to conduct epidemiologic studies has been well documented.36-40 Patient names, insurance plan identification numbers, and other patient identifiers were deleted from the claims database to protect patient confidentiality.

Randomized patient numbers and their birth years were used for identification and calculation of age, respectively. The research project was approved by the University of Cincinnati Medical Center Institutional Review Board.

Patient Cohort Selection The PharMetrics managed care claims database included all pharmacy, medical, and institutional claims.

Each medical claim was recorded with accompanying

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diagnostic codes (International Classification of Diseases, Ninth Revision [ICD-9]) that justified the medical service. Between 1998 and 2002, a total of 709,865 patients, including 6.2% Medicaid enrollees, had at least 1 diagnosis of an affective disorder (ICD-9 code 296.xx) or cyclothymia (ICD-9 code 301.13). Of these, 136,763 patients, including 9.8% Medicaid enrollees, had a bipolar diagnosis indicated by one of the following ICD-9 codes—296.0, 296.1, 296.4-296.8, or 301.13. The final group of patients with BPD consisted of 2 separate cohorts—123,292 managed care patients and 13,471 Medicaid patients. Patients with a diagnosis of depression only (ICD-9 codes 296.2x and 296.3x) or schizophrenia (ICD-9 code 295.xx) during the study period were excluded from this cohort. Medicaid recipients aged ≥65 years were excluded from this cohort, because they might also have had Medicare coverage, and therefore, their Medicaid claims might not have reflected a complete medical picture.

After identifying patients with a bipolar diagnosis, we further categorized those patients with possible diagnostic subcategories, including bipolar I disorder, manic or hypomanic (ICD-9 codes 296.0x, 296.1x, 296.4x), bipolar I disorder, mixed mania (ICD-9 code 296.6x), bipolar I disorder, depressed (ICD-9 code 296.5x), and bipolar II disorder (ICD-9 code 296.89). Furthermore, patients were categorized based on the presence of psychotic features, which was indicated by a “4” as the fourth digit of the ICD-9 diagnosis code. Because numbers of patients with only BPD, not otherwise specified, or cyclothymia, were less than 0.1%, patients with these diagnoses were not subcategorized.

Data Analytic Strategy A bipolar diagnosis indicated by defined ICD-9 codes was used to estimate prevalence rates. The numerator included patients with a bipolar diagnosis in medical claims at any time during the study period up to that month. The denominator included all enrolled persons in either the MCO (non-Medicaid) or the Medicaid program for each month during the calendar year. The cumulative prevalence rate of BPD per 100 enrollees was calculated for each calendar month during the study period. Because of the dynamic enrollment and turnover rate in Medicaid and MCOs, we assessed monthly prevalence rates to capture the prevalence pattern and measure the prevalence trend more accurately. Confidence intervals ([CIs], 95%) were constructed to assess the average monthly prevalence of BPD. Graphs of monthly prevalence rates were constructed to depict the circular trend of the bipolar prevalence rate. The prevalence rate at the highest point (ie, plateau point) was identified and considered as the prevalence rate during the study period.

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Prevalence rates of treated BPD in the MCO and Medicaid populations were stratified by sex and age categories. A patient’s age was calculated as the number of years between the birth year and the index date of bipolar diagnosis. The index date of a bipolar diagnosis was the first date of a bipolar diagnosis indicated by defined ICD-9 codes during the study period. Age categories were <12 years, 12 to 17 years, 18 to 34 years, 35 to 49 years, 50 to 64 years, and ≥65 years.

Descriptive methods were used to examine background characteristics of both bipolar cohorts. Demographic characteristics and frequencies of comorbidities were compared between the managed care and Medicaid populations, using chi-square tests for categorical variables and t-tests for continuous variables. In addition, the following major psychiatric and medical comorbidities were evaluated: 1. Major psychiatric disorders: alcohol use disorder (ICD-9 code 303), substance use disorders (ICD-9 code 304), anxiety disorders (ICD-9 code 300), impulse control disorders (ICD-9 code 312), personality disorders (ICD-9 code 301), and eating disorders (ICD-9 code 307.5) 2. Key medical comorbidities: cerebrovascular diseases (ICD-9 codes 433-438), ischemic heart diseases (ICD9 codes 411-414), neoplasm/cancer (ICD-9 codes 140-208, except 173, 211.5, 230, 235, 239.0), arthritis (ICD-9 codes 711-716), obesity (ICD-9 codes 278, 278.0), diabetes mellitus (ICD-9 code 250), hypertension (ICD-9 code 401), and chronic obstructive pulmonary disease (COPD; ICD-9 code 496).

Results Demographic Characteristics The total monthly enrollees in this managed care population increased from 6 million in 1998 to 14 million in 2002. The proportion of Medicaid enrollees in MCOs increased from 3.2% (N = 178,668) in January 1998 to 4.4% (N = 603,937) in January 2000, and to 10.8% (N = 1.35 million) in January 2002.

Compared with the Medicaid cohort (N = 13,471), the managed care cohort (N = 123,292) had significantly longer periods of enrollment (19.4 months vs 27.3 months, respectively; P <.001), fewer female patients (64.2% vs 60.7%, respectively; P <.001), and a higher mean age (29.4 years vs 36.5 years, respectively; P <.001) (Table).

More children and young adult patients (aged 0-34 years) and fewer middle-aged adults (aged 35-64 years) were diagnosed with a BPD in the Medicaid cohort compared with the MCO cohort. There was a slightly higher frequency of psychosis in the MCO cohort than in the Medicaid cohort (8.2% vs 7.5%).

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Table Demographics and Clinical Characteristics of Patients with Bipolar Disorder in Managed Care and Medicaid (N = 136,763)

Variable Mean age, yr (SD)b Female, n (%)b Mean mo enrolled (SD)b Age-groups, yr <12b 12-17b 18-34b 35-49b 50-64b â&#x2030;Ľ65 Psychotic featuresc Manic Mixed Depressed Hypomanic

Managed care cohorta

Medicaid cohort

(N = 123,292)

(N = 13,471)

36.5 (15.2) 74,838 (60.7) 27.3 (15.5) N(%) 3699 (3.0) 12,083 (9.8) 35,878 (29.1) 44,632 (36.2) 24,042 (19.5) 2959 (2.4) 10,110 (8.2) 18,001 (14.6) 52,399 (42.5) 37,727 (30.6) 15,164 (12.3)

29.4 (13.8) 8662 (64.3) 19.4 (13.9) N(%) 1118 (8.3) 2330 (17.3) 4836 (35.9) 4014 (29.8) 1172 (8.7) 0 1010 (7.5) 1697 (12.6) 7571 (56.2) 3287 (24.4) 916 (6.8)

Key psychiatric comorbidities Previous major depressionb Alcohol use disorderb Substance use disorderb Anxiety disorderd Impulse control disorderb Personality disorderb Eating disorderb

55,654 (45.1) 8002 (6.5) 6879 (5.6) 45,951 (37.3) 2663 (2.2) 4697 (3.8) 1467 (1.2)

5625 (41.8) 1110 (8.2) 1293 (9.6) 4878 (36.2) 492 (3.7) 609 (4.5) 101 (0.8)

9173 (7.4) 22,439 (18.2) 7570 (6.1) 2762 (2.2) 1073 (0.9) 4377 (3.6) 3255 (2.6)

963 (7.2) 1753 (13.0) 1068 (7.9) 210 (1.6) 48 (0.4) 296 (2.2) 232 (1.7)

4056 (3.3)

537 (4.0)

Key medical comorbidities Diabetes mellitus Hypertensionb Obesityb Arthritisb Neoplasmb Ischemic heart diseaseb Cerebrovascular diseaseb COPDb a

The managed care cohort was compared with the Medicaid cohort using student t-test for age and months enrolled, and chi-square test for other categorical variables between the 2 groups. b P <.001. cDiagnosis categories were based on the final bipolar-related diagnosis recorded during the study. dP <.05.

COPD indicates chronic obstructive pulmonary disease; SD, standard deviation.

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Treated Prevalence The average monthly prevalence rates of patients treated for BPD were 0.31% (95% CI, 0.29-0.33) for the MCO population, with a plateau point of 0.5%, and 0.47% (95% CI, 0.45-0.49) for the Medicaid population, with a plateau point of 0.6%. Figure 1 and Figure 2 demonstrate the trend of the cumulative monthly prevalence rate, stratified by sex, in both populations.

The prevalence rate of BPD in females was higher than that in males. In the MCO population, the prevalence rate of BPD was 0.37% (95% CI, 0.34%-0.40%) in females, with a plateau point of 0.6%, and 0.24% (95% CI, 0.22%-0.26%) in males, with a plateau point of 0.4%. In the Medicaid population, the prevalence rate was 0.55% (95% CI, 0.53%-0.58%) for females, with a plateau point of 0.7%, and 0.36% (95% CI, 0.34%0.38%) for males, with a plateau point of 0.5%.

Figure 3 and Figure 4 indicate that monthly prevalence rates increased with age, peaking at 35 to 49 years in both populations. The plateau points of monthly prevalence rates during the 5-year period by age categories in the MCO and Medicaid populations, respectively, were <12 years, 0.1% and 0.2%; 12 to 17 years, 0.6% and 0.8%; 18 to 34 years, 0.6% and 1.2%; 35 to 49 years, 0.7% and 2.1%; and, 50 to 64 years, 0.5% and 1.3%.

Current Key Psychiatric Disorders and Medical Comorbidities In the MCO cohort, 44% of patients had at least 1 comorbid psychiatric disorder and 29% had at least 1 comorbid medical condition. In the Medicaid cohort, 46% of patients had at least 1 comorbid psychiatric disorder and 25% had at least 1 comorbid medical condition. The most frequent comorbid psychiatric disorder was an anxiety disorder (36% and 37% in the MCO and Medicaid populations, respectively), followed by an alcohol disorder (6.5% and 8.2%, respectively), a substance disorder (5.6% and 9.6%, respectively), and a personality disorder (3.8% and 4.5%, respectively).

The most frequent medical comorbidity was hypertension (13% and 18%, respectively), followed by diabetes mellitus (7.2% and 7.4%, respectively), obesity (6.1% and 7.9%, respectively), and COPD (3.3% and 4.0%, respectively) (Table).

Discussion This is the first multistate, population-based study based on medical claims data that examines the prevalence of treated BPDs in MCO and Medicaid populations and assesses their related psychiatric and medical comorbidities during a 5-year period. The monthly prevalence of BPDs increased to a peak of 0.7% in the managed care population and 2.1% in the Medicaid

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Figure 1 Monthly Bipolar Prevalence Rate (per 100 Enrollees) in Managed Care Population, by Sex Female Male Overall

Managed Care Population Prevalence per 100 enrollees

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Month (January 1998-December 2002) Arrow indicates plateau point of treated prevalence.

Figure 2 Monthly Bipolar Prevalence Rate (per 100 Enrollees) in Medicaid Population, by Sex Female Male Overall

Medicaid Population 0.7 Prevalence per 100 enrollees

population at ages 35 to 49 years, then declined to 0.5% in the managed care cohort and 1.3% in the Medicaid cohort at ages 50 to 64 years (Figures 3 and 4). This indicates that BPDs are most prevalent among young to middle-aged adults, most likely because individuals in these age-groups have passed through the period of greatest risk for illness onset.6,7,13,41,42 Possible explanations for a lower BPD prevalence rate among persons aged 50 to 64 years may be attributed to deaths in patients with bipolar, changes in healthcare coverage, or a reduction in healthcare service utilization.

The trends seen in the data (Figures 1-4) demonstrate that the monthly prevalence rate of BPDs was cyclical, starting near zero in the first month, then reaching a peak every December. Each January, the trough of the monthly BPD prevalence rate was the result of changing health enrollment in managed care plans for some patients and starting enrollment for many new managed care recipients. The variations in monthly BPD prevalence rates most likely do not reflect an underlying circular annual trend in BPD diagnoses or bipolar episodes.

Cyclic trends are primarily an artifact of the cumulative method used to identify BPDs and changing enrollment on a calendar year cycle.

The prevalence rates of patients treated for a BPD in the Medicaid population were higher than those in the managed care population. The higher BPD prevalence in the Medicaid population may be related to the low socioeconomic status characteristic of Medicaid programs. These findings are consistent with 2 recent surveys, which indicate that the lifetime prevalence of BPD was highest among participants with the lowest annual household income.14,15,43 Other community-based studies have also shown that economically disadvantaged persons have higher rates of mental disorders compared with persons of higher socioeconomic status.44,45 Unlike the managed care population, the monthly BPD prevalence rate in the Medicaid population declined in 2001 and 2002, because of a high attrition rate and a relatively short enrollment period. This decline was most likely a result of the increase in the total number of Medicaid managed care enrollees from 700,000 in July 2001 to 1.4 million in June 2002, as many state Medicaid programs transferred their beneficiaries into MCOs. This dramatic increase in the denominator of the BPD prevalence rate probably contributed to the lower prevalence rate seen during this period. The BPD prevalence rate likely returned to the plateau level when Medicaid enrollment became stable, as indicated in November and December 2002 in Figures 2 and 4.

There is an increasing prevalence of patients treated for BPD in Medicaid and MCO populations. Many pos-

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Month (January 1998-December 2002) Arrows indicate plateau point of treated prevalence.

sible factors contribute to this trend, such as patient education about mental illness, nationwide direct-to-consumer advertisement, and wide-spectrum mental health coverage in Medicaid and MCOs. Because of the nature of managed care enrollment policy, we were unable to observe the true plateau level of BPD prevalence.

Instead, we obtained the plateau points of BPD prevalence rates. In this study, the BPD prevalence rate at plateau points for adults aged 18 to 64 years ranged from 0.6% to 2.1%.

The prevalence of treated BPDs (0.31%-0.47%) fell within the range of published rates, including those from the ECA study and NCS.8-10 However, prevalence rates in age-specific categories reported by Hirschfeld and col-

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Figure 3 Monthly Bipolar Prevalence Rate (per 100 Enrollees) in Managed Care Population, by Age-Group Age, yrs <12 12-17 18-34

35-49 50-64 â&#x2030;Ľ65

Managed Care Population Prevalence per 100 enrollees

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 3 5 7 9 11 1 3 5 7 9 11 1 3 5 7 9 11 1 3 5 7 9 11 1 3 5 7 9 11

Month (January 1998-December 2002) Arrow indicates plateau point of treated prevalence.

NOTE: The average monthly prevalence rates for the spectrum of bipolar disorder per 100 enrollees for the non-Medicaid cohort, by age-group, were: <12 yrs, 0.054 (95% CI, 0.047-0.061); 12-17 yrs, 0.32 (95% CI, 0.28-0.34); 18-34 yrs, 0.33 (95% CI, 0.30-0.36); 35-49 yrs, 0.43 (95% CI, 0.40-0.46); 50-64 yrs, 0.33 (95% CI, 0.31-0.35).

CI indicates confidence interval.

Figure 4 Monthly Bipolar Prevalence Rate (per 100 Enrollees) in Medicaid Population, by Age-Group Age, yrs <12 12-17 18-34

35-49 50-64

Medicaid Population

Prevalence per 100 enrollees

2.5 2 1.5 1 0.5 0 1 3 5 7 9 11 1 3 5 7 9 11 1 3 5 7 9 11 1 3 5 7 9 11 1 3 5 7 9 11

Month (January 1998-December 2002) Arrows indicate plateau point of treated prevalence.

NOTE: The average monthly prevalence rates for the spectrum of bipolar disorder per 100 enrollees in the Medicaid cohort, by age-group, were: <12 yrs, 0.07 (95% CI, 0.066-0.081); 12-17 yrs, 0.53 (95% CI, 0.49-0.57); 18-34 yrs, 0.82 (95% CI, 0.77-0.87); 35-49 yrs, 1.50 (95% CI, 1.39-1.60); 50-65 yrs, 0.89 (95% CI, 0.81-0.98).

CI indicates confidence interval.

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leagues14,43 and Das and colleagues15 are higher than our estimated prevalence rates. These studies screened adults for lifetime BPDs. Our estimation of BPD prevalence was solely based on retrospective medical claims from patients who were diagnosed and treated during a 5-year period. We were unable to capture patients who were diagnosed with a BPD before or after the study period, as well as those patients who remained untreated. The prevalence rate of treated BPDs was higher for females (0.6%-0.7%) than for males (0.4%-0.5%) in both populations. This result is consistent with treated prevalence rates reported by UnĂźtzer and colleagues (females, 0.5%; males, 0.3%) in an MCO.9 Patients diagnosed with BPDs showed high proportions of psychiatric comorbidities, including anxiety disorders, personality disorders, and alcohol and substance abuse. Treated psychiatric comorbidity rates in the present study are at the lower end of published lifetime psychiatric comorbidity rates, based on survey questionnaire and interview data. For example, the occurrence of personality disorders ranged from 9% to 89%,21,24,25 alcohol/substance abuse ranged from 20% to 60%,14,15,26-29 and anxiety disorders ranged from 30% to 93%.7,28 This may be best explained by the underdiagnosis or underrecognition of psychiatric comorbidities in general medicine clinics.

Das and colleagues reported that only 68% of patients with BPD and only 49% of patients with depressive disorders had a documented mental disorder or psychiatric symptom in their medical records.15 Hirschfeld and colleagues reported prevalence rates of 7.3% for diabetes, 15.3% for hypertension, and 2.2% for COPD43; these rates are consistent with our observed rates (diabetes, 7.2%-7.4%; hypertension, 13.0%-18.2%; COPD, 3.3%4.0%). This finding suggests that components of metabolic syndrome are likely to be present in patients with a BPD.38-41 Clinicians should consider managing these general medical conditions at the same time they are treating bipolar symptoms.

In a separate economic study using the same patient population, the bipolar treatment cost was considerable, with an average charge of $22,110 per-patient per-year or an $11,641 reimbursed amount per-patient per-year.39 The total treatment cost was attributed to the cost related to treatment of BPD (30%) and its comorbid conditions (70%). These total treatment costs were significantly associated with key comorbidities, such as drug use disorder, cerebrovascular disease, ischemic heart disease, diabetes mellitus, and hypertension.39 Limited literature is available about the prevalence of treated patients with BPDs and associated comorbidities in managed care populations. Whereas most managed care health plans and state Medicaid programs cover a

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large proportion of US patients with mental illnesses, the findings of this present study provide useful information for health and drug benefit policy, as well as for planning disease management strategies.

Limitations Because the Medicaid population in this study was limited to those enrolled in MCOs, these findings may not be generalizable to the fee-for-service Medicaid population. Because of the limitations of medical claim databases, the diagnostic information extracted may not be always reliable or valid. Undercoding and/or overcoding can occur in diagnosis files. Undercoding can occur, because insurance claim forms limit the number of diagnoses that can be documented, or providers simply do not make the effort to record secondary diagnoses.

Furthermore, because of the retrospective nature of a claims database review, it was not possible to verify the accuracy of the ICD-9 codes that physicians used or to identify possible misclassification of bipolar I and II disorders, because of illness progression. It is possible that this study underestimated prevalence rates because of the following reasons: 1. The limited time window of managed-care enrollment, changes in patient Medicaid eligibility, and mental health services through community clinics not billed to Medicaid 2. The difficulty of recognizing hypomania in some patients13 3. The exclusion of some patients with depression only (ICD-9 codes 296.2 and 296.3), which may cause the present study to underestimate patients with ostensible unipolar depression.46 It is difficult to assess the lifetime prevalence rate of BPDs or the long-term prognosis for patients with a BPD diagnosis using a medical claims database. If a patient with a BPD had no claim for treatment during the study period, that individual would not have been detected as a patient with lifetime BPD. Comorbid conditions were identified by diagnostic codes, without considering the combination of medications for diabetes, obesity, hypertension, and other diseases.

Conclusion Prevalence rates of BPDs were higher in Medicaid compared with the MCO population. The prevalence of patients treated for a BPD is increasing in the US MCO and Medicaid populations. Our study shows that BPD patients have a host of comorbid conditions. Clinicians should consider managing these general medical comorbidities at the same time they are treating symptoms of BPD. It is important to manage these conditions when treating patients with a BPD, because comorbid psychi-

atric and medical conditions are associated with increased morbidity and mortality. ■ Acknowledgments This project was conducted with an educational grant provided by the Bristol-Myers Squibb Pharmaceutical Research Institute. The opinions and conclusions expressed in this manuscript are solely those of the authors. The authors would like to thank Dongming Jiang, PhD, for his programming and statistical data analysis. We also appreciate Raymond Jang, PhD, Patricia K. Corey-Lisle, PhD, and William Carson, MD, for their support and expertise.

This study was presented at the Collegium Internationale Neuro-Psychopharmacologicum Biannual Meeting, Paris, France, June 20-24, 2004, and at the American Psychiatry Association Annual Meeting, Atlanta, GA, May 24-26, 2005.

Disclosure Statement Dr Guo receives research grants from Baxter Healthcare, BristolMyers Squibb, Eli Lilly, Johnson & Johnson, and Novartis; Dr Patel has been a consultant for AstraZeneca, Johnson & Johnson, Merck, and Pfizer; Dr Li is an employee of Bristol-Myers Squibb; and Dr Keck receives research grants from Abbott, AstraZeneca, BristolMyers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Ortho-McNeil, Pfizer, and Shire.

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2. O’Connell RA, Mayo JA, Flatow L, et al. Outcome of bipolar disorder on longterm treatment with lithium. Br J Psychiatry. 1991;159:123-129.

3. National Alliance on Mental Illness (NAMI). Understanding bipolar disorder and recovery: what you need to know about this medical illness. August 2008. www.nami. org/Content/ContentGroups/Helpline1/NAMI_Bipolar_Disorder_Aug08.pdf.

Accessed June 30, 2007.

4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, DSM-IV. Washington, DC: American Psychiatric Association; 1994.

5. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA. 1996;276:293-299.

6. Weissman MM, Bruce ML, Leaf PJ, et al. Affective disorders. In: Robins LN, Regier DA, eds. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York, NY: Free Press; 1990:53-80.

7. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19.

8. Johnson RE, McFarland BH. Treated prevalence rates of severe mental illness among HMO members. Hosp Comm Psychiatry. 1994;45:919-924.

9. Unützer J, Simon G, Pabiniak C, et al. The treated prevalence of bipolar disorder in a large staff-model HMO. Psychiatr Serv. 1998;49:1072-1078.

10. Bebbington P, Ramana R. The epidemiology of bipolar affective disorder. Soc Psychiatry Psychiatr Epidemiol. 1995;30:279-292.

11. Akiskal HS, Bourgeois ML, Angst J, et al. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders.

J Affect Disord. 2000;59(suppl 1):S5-S30.

12. Hirschfeld RM. Bipolar spectrum disorder: improving its recognition and diagnosis. J Clin Psychiatry. 2001;62(suppl 14):5-9.

13. Angst J. The emerging epidemiology of hypomania and bipolar II disorder.

J Affect Disord. 1998;50:143-151.

14. Hirschfeld RM, Calabrese JR, Weissman MM, et al. Screening for bipolar disorder in the community. J Clin Psychiatry. 2003;64:53-59.

15. Das AK, Olfson M, Gameroff MJ, et al. Screening for bipolar disorder in a primary care practice. JAMA. 2005;293:956-963.

16. Keck PE Jr, McElroy SL, Strakowski SM, et al. 12-month outcome of patients with bipolar disorder following hospitalization for a major or mixed episode. Am J Psychiatry. 1998;155:646-652.

17. Keck PE, McElroy SL. Bipolar disorder, obesity, and pharmacotherapy-associated weight gain. J Clin Psychiatry. 2003;64:1426-1435.

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18. Hilty DM, Brady KT, Hales RE. A review of bipolar disorder among adults.

Psychiatr Serv. 1999;50:201-213.

19. Wozniak J, Biederman J, Monuteaux MC, et al. Parsing the comorbidity between bipolar disorder and anxiety disorders: a familial risk analysis. J Child Adolesc Psychopharmacol. 2002;12:101-111.

20. Goodwin RD, Hoven CW. Bipolar-panic comorbidity in the general population: prevalence and associated morbidity. J Affect Disord. 2002;70:27-33.

21. George EL, Miklowitz DJ, Richards JA, et al. The comorbidity of bipolar disorder and axis II personality disorders: prevalence and clinical correlates. Bipolar Disord.

2003;5:115-122.

22. Frank E, Cyranowski JM, Rucci P, et al. Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar I disorder. Arch Gen Psychiatry. 2002;59:905-911.

23. McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry. 2001;158:420-426.

24. Koenigsberg HW, Kaplan RD, Gilmore MM, Cooper AM. The relationship between syndrome and personality disorder in DSM-III: experience with 2,462 patients. Am J Psychiatry. 1985;142:207-212.

25. Turley B, Bates GW, Edwards J, Jackson HJ. MCMI-II personality disorders in recent-onset bipolar disorders. J Clin Psychol. 1992;48:320-329.

26. Escamilla MA, Batki S, Reus VI, et al. Comorbidity of bipolar disorder and substance abuse in Costa Rica: pedigree- and population-based studies. J Affect Disord.

2002;71:71-83.

27. Feinman JA, Dunner DL. The effect of alcoholism and substance abuse on the course of bipolar affective disorder. J Affect Disord. 1996;37:43-49.

28. Winokur G, Coryell W, Akiskal HS, et al. Alcoholism in manic depressive (bipolar) illness: familial illness, course of illness, and the primary-secondary distinction.

Am J Psychiatry. 1995;152:365-372.

29. Brady KT, Lydiard RB. Bipolar affective disorder and substance abuse. J Clin Psychopharmacol. 1992;12(suppl 1):17S-22S. 30. Dunn J, Ferri CP. Epidemiological methods for research with drug misusers: review of methods for studying prevalence and morbidity. Rev Saude Publica. 1999;33: 206-215.

31. Hantouche EG, Akiskal HS, Lancrenon S, et al. Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multisite study (EPIDEP). J Affect Disord. 1998;50:163-173.

32. Li J, McCombs JS, Stimmel GL. Cost of treating bipolar disorder in the California Medicaid (Medi-Cal) program. J Affect Disord. 2002;71:131-139.

33. Stender M, Bryant-Comstock L, Phillips S. Medical resource use among patients treated for bipolar disorder: a retrospective, cross-sectional, descriptive analysis. Clin Ther. 2002;24:1668-1676.

34. Heisler M, DeMonner SM, Billi JE, Hayward RA. Medicaid managed care: are academic medical centers penalized by attracting patients with high-cost conditions?

Am J Manag Care. 2003;9:19-29.

35. PharMetrics. PharMetrics Patient-Centric Database: a large medical claims data source in US. Watertown, MA, 2004. www.pharmetrics.com. Accessed August 1, 2006.

36. Walkup J, Crystal S, Sambamoorthi U. Schizophrenia and major affective disorder among Medicaid recipients with HIV/AIDS in New Jersey. Am J Public Health.

1999;89:1101-1103.

37. Mullins CD, Cooke JL Jr, Wang J, et al. Disparities in prevalence rates for lung, colorectal, breast, and prostate cancers in Medicaid. J Natl Med Assoc. 2004;96:809-816.

38. Guo JJ, Keck PE Jr, Corey-Lisle PK, et al. Diabetes mellitus associated with atypical antipsychotic use among patients with bipolar disorder: a retrospective, population-based, case-control study. J Clin Psychiatry. 2006;67:1055-1061.

39. Guo JJ, Keck PE, Li H, Patel NC. Treatment costs related to bipolar disorder and comorbid conditions among Medicaid patients with bipolar disorder. Psychiatr Serv.

2007;58:1073-1078.

40. Guo JJ, Keck PE, Li H, Corey-Lisle PK, et al. Risk of diabetes mellitus associated with atypical antipsychotic use among Medicaid patients with bipolar disorder: a nested case-control study. Pharmacotherapy. 2007;27:27-35.

41. Loranger AW, Levine PM. Age at onset of bipolar affective illness. Arch Gen Psychiatry. 1978;35:1345-1348.

42. Burke KC, Burke JD Jr, Regier DA, Rae DS. Age at onset of selected mental disorders in five community populations. Arch Gen Psychiatry. 1990;47:511-518.

43. Hirschfeld RM, Holzer C, Calabrese JR, et al. Validity of the mood disorder questionnaire: a general population study. Am J Psychiatry. 2003;160:178-180.

44. Dohrenwend BP, Levav I, Shrout PE, et al. Socioeconomic status and psychiatric disorders: the causation-selection issue. Science. 1992;255:946-952.

45. Regier DA, Farmer ME, Rae DS, et al. One-month prevalence of mental disorders in the United States and sociodemographic characteristics: the Epidemiologic Catchment Area Study. Acta Psychiatr Scand. 1993;88:35-47.

46. Benazzi F. Underdiagnosis of bipolar II disorders in the community. J Clin Psychiatry. 2003;64:1130-1131.

STAKEHOLDER PERSPECTIVE Bipolar Disorder Prevalence Often Underestimated MEDICAL/PHARMACY DIRECTORS: The study by Guo and colleagues represents the first multistate study based on claims data that examines the prevalence trends of bipolar disorder in managed care, which likely underestimate the true rates of the disease; the symptoms of this condition are often not recognized or characterized as bipolar disorder for years.

Despite the less than 1% prevalence of bipolar disorder in the US population, this condition presents a particular challenge to payers, because many patients are misclassified as having a major depressive disorder, and because of the extent of disability it causes during the prime years of employment. In addition, bipolar disorder often presents with other mental illnesses and concomitant substance abuse, which add to the disease burden.

Based on this study, the authors suggest that the prevalence of this condition is increasing in the managed care and Medicaid populations, and patients diag-

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nosed with this disorder have higher psychiatric conditions than is reported in the literature.

PATIENTS: Patients with bipolar disease have crossed a major hurdleâ&#x20AC;&#x201D;they have obtained a diagnosis that will at least give them some hope of appropriate treatment. However, available pharmacologic treatment options, including mood stabilizers, atypical antipsychotics, and antidepressants have varying effectiveness and extensive side-effect profiles, and most patients will end up receiving multiple medications over time with some ancillary treatments (eg, cognitive behavioral therapy or electroconvulsive therapy) as well.

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

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than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs, SSRIs, or Savella. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use]. Discontinuation of Savella should be considered in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding-SSRIs and SNRIs, including Savella, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Savella and NSAIDs, aspirin, or other drugs that affect coagulation. Activation of Mania-No activation of mania or hypomania was reported in the clinical trials evaluating effects of Savella in patients with fibromyalgia. However those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, Savella should be used cautiously in patients with a history of mania. Patients with a History of Dysuria-Because of their noradrenergic effect, SNRIs including Savella, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with Savella (1%) than in placebo-treated patients (0.5%). Caution is advised in use of Savella in patients with a history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention, and may experience testicular pain or ejaculation disorders. Controlled Narrow-Angle Glaucoma-Mydriasis has been reported in association with SNRIs and Savella; therefore, Savella should be used cautiously in patients with controlled narrow-angle glaucoma. Do not use Savella in patients with Uncontrolled Narrow-Angle Glaucoma [see Contraindications]. Concomitant Use with Alcohol-In clinical trials, more patients treated with Savella developed elevated transaminases than did placebo treated patients [see Warnings and Precautions]. Because it is possible that milnacipran may aggravate pre-existing liver disease, Savella should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

ADVERSE REACTIONS: Clinical Trial Data Sources-Savella was evaluated in three double-blind placebocontrolled trials involving 2209 fibromyalgia patients (1557 patients treated with Savella and 652 patients treated with placebo) for a treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Leading to Discontinuation-In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with Savella 100 mg/day, 26% of patients treated with Savella 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in ≥ 1% of patients in the Savella treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with Savella 200 mg/day compared to Savella 100 mg/day. Most Common Adverse Reactions-In the placebo-controlled fibromyalgia patient trials the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence ≥ 5% and twice placebo) in patients treated with Savella were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Table 2 lists all adverse reactions that occurred in at least 2% of patients treated with Savella at either 100 or 200 mg/day and at an incidence greater than that of placebo. Table 2 in the full PI shows the incidence of common adverse reactions that occurred in at least 2% of patients treated with Savella at either 100 or 200 mg/day and at an incidence greater than that of placebo. Cardiac disorders: Palpitations, Tachycardia; Eye Disorders: Vision blurred; Gastrointestinal Disorders: Nausea, Constipation, Vomiting, Dry mouth, Abdominal pain; General Disorders: Chest pain, Chills, Chest discomfort; Infections: Upper respiratory tract infection; Investigations: Heart rate increased, Blood pressure increased; Metabolism and Nutrition Disorders: Decreased appetite; Nervous System Disorders: Headache, Dizziness, Migraine, Paresthesia, Tremor, Hypoesthesia, Tension headache; Psychiatric Disorders: Insomnia, Anxiety; Respiratory Disorders: Dyspnea; Skin Disorders: Hyperhidrosis, Rash, Pruitius; Vascular Disorders: Hot flush, Hypertension, Flushing. Weight Changes-In placebo-controlled fibromyalgia clinical trials, patients treated with Savella for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the Savella 100 mg/day and the Savella 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebotreated patients. Genitourinary Adverse Reactions in Males-In the placebo-controlled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with Savella, and occurred at a rate greater than in placebotreated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased. Other Adverse Reactions Observed During Clinical Trials of Savella in Fibromyalgia-Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with Savella for periods up to 68 weeks. The listing does not include those events already listed in Table 2, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section. Gastrointestinal Disorders – diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension; General Disorders – fatigue, peripheral edema, irritability, pyrexia; Infections – urinary tract infection, cystitis; Injury, Poisoning, and Procedural Complications – contusion, fall; Investigations – weight decreased or increased; Metabolism and Nutrition Disorders – hypercholesterolemia; Nervous System Disorders – somnolence, dysgeusia; Psychiatric Disorders – depression, stress; Skin Disorders – night sweats. Postmarketing Spontaneous Reports-The following additional adverse reactions have been identified from spontaneous reports of Savella received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Savella. However, because these adverse reactions were 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. These events include: Blood and Lymphatic System Disorders – leukopenia, neutropenia, thrombocytopenia; Cardiac Disorders – supraventricular tachycardia; Eye Disorders – accommodation disorder; Endocrine Disorders – hyperprolactinemia; Hepatobiliary Disorders – hepatitis; Metabolism and Nutrition Disorders – anorexia, hyponatremia; Musculoskeletal and Connective Tissue Disorders – rhabdomyolysis; Nervous System Disorders – convulsions (including grand mal), loss of consciousness, Parkinsonism; Psychiatric Disorders – delirium, hallucination; Renal and Urinary Disorders – acute renal failure; Reproductive System and Breast Disorders – galactorrhea; Skin Disorders – erythema multiforme, Stevens Johnson syndrome; Vascular Disorders – hypertensive crisis.

DRUG INTERACTIONS: Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations]. Monoamine Oxidase Inhibitors - [See Contraindications] Serotonergic Drugs - Due to the mechanism of action of SNRIs and SSRIs, including Savella, and the potential for serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)–like reactions, caution is advised when Savella is co-administered with other drugs that may affect the serotonergic neurotransmitter systems. This includes drugs such as triptans, lithium, tryptophan, antipsychotics and dopamine antagonists. Co-administration of Savella with other inhibitors of serotonin re-uptake may result in hypertension and coronary artery vasoconstriction, through additive serotonergic effects. Concomitant use of Savella with other SSRIs, SNRIs, or tryptophan is not recommended [see Warnings and Precautions]. Triptans - There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Savella with a triptan is clinically warranred, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions]. Catecholamines - Savella inhibits the reuptake of norepinephrine. Therefore concomitant use of Savella with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [see Warnings and Precautions – Effects on Blood Pressure and Effects on Heart Rate]. CNS-active drugs - Given the primary CNS effects of Savella, caution should be used when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action. Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to Savella. Clinically Important Interactions with Select Cardiovascular Agents - Digoxin: Use of Savella concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects.

Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Co-administration of Savella and intravenous digoxin should be avoided [see Warnings and Precautions]. Clonidine: Because Savella inhibits norepinephrine reuptake, coadministration with clonidine may inhibit clonidine’s anti-hypertensive effect.

USE IN SPECIFIC POPULATIONS: Pregnancy-Pregnancy Category C. Milnacipran increased the incidence of dead fetuses in utero in rats at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m2 basis). Administration of milnacipran to mice and rabbits during the period of organogenesis did not result in embryotoxicity or teratogenicity at doses up to 125 mg/kg/day in mice (3 times the maximum recommended human dose [MRHD] of 200 mg/day on a mg/m2 basis) and up to 60 mg/kg/day in rabbits (6 times the MRHD of 200 mg/day on a mg/m2 basis). In rabbits, the incidence of the skeletal variation, extra single rib, was increased following administration of milnacipran at 15 mg/kg/day during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women. Savella should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects; Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective serotonin reuptake inhibitors late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. In rats, a decrease in pup body weight and viability on postpartum day 4 were observed when milnacipran, at a dose of 5 mg/kg/day (approximately 0.2 times the MRHD on a mg/m2 basis), was administered orally to rats during late gestation. The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m2 basis). Labor and Delivery-The effect of milnacipran on labor and delivery is unknown. The use of Savella during labor and delivery is not recommended. Nursing Mothers-There are no adequate and well-controlled studies in nursing mothers.

It is not known if milnacipran is excreted in human milk. Studies in animals have shown that milnacipran or its metabolites are excreted in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from milnacipran, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. Because the safety of Savella in infants is not known, nursing while on Savella is not recommended. Pediatric Use-Safety and effectiveness of Savella in a fibromyalgia pediatric population below the age of 17 have not been established [see Box Warning and Warnings and Precautions]. The use of Savella is not recommended in pediatric patients. Geriatric Use-In controlled clinical studies of Savella, 402 patients were 60 years or older, and no overall differences in safety and efficacy were observed between these patients and younger patients. In view of the predominant excretion of unchanged milnacipran via kidneys and the expected decrease in renal function with age renal function should be considered prior to use of Savella in the elderly [see Dosage and Administration]. SNRIs, SSRIs, and Savella, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions].

DRUG ABUSE AND DEPENDENCE: Controlled Substance-Milnacipran is not a controlled substance.

Abuse-Milnacipran did not produce behavioral signs indicative of abuse potential in animal or human studies. Dependence-Milnacipran produces physical dependence, as evidenced by the emergence of withdrawal symptoms following drug discontinuation, similar to other SNRIs and SSRIs. These withdrawal symptoms can be severe. Thus, Savella should be tapered and not abruptly discontinued after extended use [see Discontinuation of Treatment with Savella].

OVERDOSAGE: There is limited clinical experience with Savella overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg, alone or in combination with other drugs, were reported with none being fatal. In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with Savella only. The most common signs and symptoms included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes.

Management of Overdose-There is no specific antidote to Savella, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Because there is no specific antidote for Savella, symptomatic care and treatment with gastric lavage and activated charcoal should be considered as soon as possible for patients who experience a Savella overdose. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered.

The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

Manufactured for: Forest Pharmaceuticals, Inc.

Manufactured by: Forest Laboratories, Inc.

Licensed from Pierre Fabre Medicament and Cypress Bioscience, Inc. ©2009 Forest Laboratories, Inc. Revised: December 2009

9:46 AM

HEALTHCARE REFORM

The Health Reform Law: Key Changes to Be Implemented in 2010 Kip Piper, MA, FACHE

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t is impossible to overstate the extraordinary range and complexity of the newly enacted health reform law. Taken together, the Patient Protection and Affordable Care Act (PPACA) and the Health Care and Education Reconciliation Act (HCERA) will, for better or for worse, result in thousands of changes to the coverage, financing, regulation, payment, and delivery of healthcare services in the United States. The practical demands of implementation, as well as the mass of rulemaking and other policymaking yet to be, will create an astonishing array of challenges and opportunities for virtually every stakeholder in American healthcare.

Although many of the provisions of the health reform will go into effect in future years—particularly 2014— some key changes are effective on various dates in 2010.

The following is a brief rundown of some of the more notable changes for 2010.

Temporary Initiatives to Improve Health Coverage PPACA provides for several initiatives to help the uninsured and underinsured between now and 2014, when federal subsidies, Medicaid expansion, and staterun health insurance exchanges begin. These are: • Temporary national high-risk pool to provide healthcare coverage to individuals with preexisting conditions who are unable to buy coverage; this includes $5 billion in federal funding to help subsidize coverage • Temporary reinsurance program for employers that provide coverage to retirees older than age 55 years who are not eligible for Medicare.

Consumer Protections In the form of mandates on individual and small group health plans, several consumer protections take effect during 2010: • Insurers must provide dependent coverage for adult children up to age 26 years • Insurers may not impose preexisting condition exclusions for children • Individual and group health plans are prohibited from placing lifetime limits on the dollar value of coverage Mr Piper is a Senior Consultant to TogoRun, Sellers Dorsey, and Fleishman-Hillard. He blogs at piperreport.com.

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• Before 2014, health plans may only impose annual limits on coverage, based on rules to be set by the Secretary of the Department of Health and Human Services (HHS) • Insurers are prohibited from rescinding coverage, except in cases of fraud.

Tax Credits for Small Employers Small employers are eligible for a new federal tax credit if they have 25 or fewer employees, have average annual wages of <$50,000, and purchase health insurance for employees.

Health Insurance Rate Regulation PPACA dramatically changes the landscape for health insurance rate setting. Key provisions include: • Medical loss ratio (MLR) reporting: health insurers must report the proportion of premium dollars spent on clinical services (provider claims), quality, and other costs (eg, administration, marketing) • Rebates if MLR exceeds federal minimums: the amount of premium revenues spent on clinical services and quality must be at least 85% for large group plans and 80% for plans in the individual and small group markets; starting from benefit year 2011, if a plan’s MLR falls below the required level, the insurer must rebate the difference to consumers • New federal-state process for reviewing health plan premium increases: requirement for health plans to justify their premium increases; if a state determines that a plan’s premium increases are unjustified, the state may recommend that the plan be excluded from the exchange market.

Medicare Changes to Medicare Part D drug benefit: • Medicare beneficiaries who reach the Part D coverage gap (the so-called doughnut hole) in 2010 will receive a $250 rebate • Medicare will begin the process of requiring drug manufacturers to provide 50% discounts for drug utilization in the Part D coverage gap; this is part of the new policy to phase out the Medicare Part D doughnut hole by 2020.

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In addition, the annual Medicare market basket updates for inpatient hospital, skilled nursing facility, home health, and hospice providers will be reduced.

Congress also banned new physician-owned hospitals in Medicare and limited the future growth of certain existing physician-owned hospitals.

Medicaid Drug Benefit In the Medicaid prescription drug rebate program, PPACA has made the following major changes: • For most brand-name drugs, minimum rebate increases by 8%, from 15.1% to 23.1% of the average manufacturer price (AMP) • For clotting factors and brand drugs approved exclusively for pediatric use, minimum rebate increases to 17.1% of the AMP • Medicaid rebate for generic (noninnovator, multisource) drugs increases from 11% to 13% of the AMP • Imposed federal take-back of all rebates applicable to the increased percentages, even if the state was already receiving supplemental rebates; this has the effect of cutting federal Medicaid funding to states • Extended federal Medicaid rebate to drug utilization in Medicaid health plans; previously, the federally mandated rebates only applied to fee-for-service Medicaid drug utilization.

Medicaid Coverage Expansion Options Although the major nationwide expansion of Medicaid eligibility will take effect in 2014, PPACA provides states with new options to expand Medicaid eligibility through the Medicaid State Plan, without waivers: • Extend Medicaid coverage to low-income, childless adults • Through Medicaid’s sister program, the Children’s Health Insurance Program (CHIP), cover children of state employees if certain conditions are met • Extend Medicaid family planning services coverage to certain low-income individuals.

PPACA also expanded the role of the Medicaid and CHIP Payment and Access Commission to advise Congress on issues affecting adults in Medicaid, including dual-eligibles.

The HHS Secretary is required to create a public comment process for section 1115 Medicare research and demonstration waivers.

Innovation and Coordination: Medicare and Medicaid The health reform law creates a new Center for Medicare & Medicaid Innovation (CMI) in the

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Centers for Medicare & Medicaid Services (CMS).

CMI, which must be established in 2010, is charged with the development and implementation of pilots and demonstrations to improve quality and cost-effectiveness in Medicare and Medicaid. The projects will likely focus on delivery system reforms and payment reforms in Medicare and Medicaid, including joint Medicare-Medicaid initiatives. CMI was given $10 billion to operate the demonstrations, and another $500 million for evaluations and administration.

Congress also created the Federal Coordinated Health Care Office within CMS, with the mission of improving federal and state coordination on issues affecting access, quality, and cost of caring for the 8 million dual-eligible beneficiaries enrolled in Medicare and Medicaid.

Regulatory Pathway for Biosimilars The law authorizes a new regulatory pathway for the US Food and Drug Administration to use in approving biosimilars (or follow-on biologics). The law grants biologics innovators 12 years of exclusive use before a biosimilar version may be developed.

Comparative Effectiveness Research PPACA creates a new nonprofit Patient-Centered Outcomes Research Institute to oversee federal comparative effectiveness research (CER). With a governing board appointed by the US Comptroller General, the institute will set research priorities and contract with federal agencies and research institutions to conduct, assess, translate, and disseminate research on the effectiveness and comparative effectiveness of therapies and technologies.

The institute’s funding will be coming from a mix of Medicare Trust Fund dollars, an assessment on health plans (risk and self-insured plans), and annual congressional appropriations. Once the Medicare and health plan portions of the funding begin in 2013, the institute is expected to have a roughly $500-million annual budget for CER. These changes are a mere sampling of the many initiatives and activities required under PPACA and HCERA. In addition, HHS, other federal agencies, and states—not to mention employers, healthcare providers, health plans, and other stakeholders—will be extremely busy readying the rules, policies, procedures, staffing, contracting, and infrastructure needed to carry out the far more numerous and complex changes required for 2011 and beyond.

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Federal Drug Price Controls in Medicaid: Expansion of Mandated Rebates under Health Reform Law

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ederally mandated rebates for prescription drugs in Medicaid were expanded significantly under the new health reform law, with extraordinary financial, administrative, and compliance implications for pharmaceutical manufacturers, state Medicaid programs, and Medicaid health plans.

Most notably, the Patient Protection and Affordable Care Act (PPACA), as amended by the Health Care and Education Reconciliation Act (HCERA), requires1-3: • Higher minimum rebates from drug manufacturers for both brand and generic outpatient drugs dispensed to Medicaid beneficiaries • Extension of minimum rebates to drug utilization in Medicaid managed care organizations • Diversion of all savings from the higher minimum rebates to federal government, resulting in a significant cut to states.

The new requirements are expected to generate $38 billion in federal savings over the next 10 years, according to a letter dated March 20, 2010, from Douglas W. Elmendorf, Director of the Congressional Budget Office (CBO), to House Speaker, Nancy Pelosi.4 This article provides a primer on the Medicaid prescription drug rebate program and the major changes effective for 2010.

Basics of Medicaid Drug Rebate Two terms are key to understanding the workings of the Medicaid drug rebate program–average manufacturer price (AMP) and best price.

Average manufacturer price. The concept of AMP is a creature of federal law, created in 1991 for calculation and administration of mandated rebates on outpatient drugs. AMP is the average price wholesalers pay manufacturers for drugs that are sold to retail pharmacies.

To arrive at the actual price paid by wholesalers, AMP is the calculated net of cash discounts, volume discounts, rebates, and other price concessions. Therefore, every drug by every manufacturer has a unique AMP, and AMP figures fluctuate throughout the year. On a monthly or quarterly basis, drug makers must report AMP figures to the Centers for Medicare & Medicaid Services (CMS). PPACA requires CMS to begin to disclose online the weighted average of the most recently reported monthly AMP for multiple-source drugs.

Best price. Best price is the lowest manufacturer price paid for a prescription drug by a purchaser or payer,

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including any retailer, wholesaler, or commercial health plan. Best price, however, excludes prices charged to Medicare Part D drug plans, certain federal agencies, 340B discount program participants, and state pharmaceutical assistance programs.

As with AMP, the intent is for a drug’s best price to be determined net of financial concessions by drug makers, including discounts and rebates. The best price for each drug is reported to CMS and shared with states, but is otherwise confidential.

Federal Rebate Agreements with Drug Manufacturers To ensure Medicaid coverage of their outpatient prescription drug products, pharmaceutical manufacturers must sign a rebate agreement with CMS. If a manufacturer has a rebate agreement, its drugs are covered nationwide in Medicaid, with a few exceptions. If a drug maker declines to sign a federal rebate agreement, a state Medicaid program may exclude coverage of the nonrebated products.

Rebate agreements apply to brand and generic drugs, orals and biologics, whether dispensed by pharmacies or administered by physicians in any outpatient setting.

About 550 pharmaceutical companies have federal rebate agreements. For single-source and multisource innovator (brand-name) drugs dispensed or administered on an outpatient basis, the federal minimum rebate for the drug is the greater of: 1. AMP minus percentage set in statute.

2. Difference between AMP and best price (AMP minus best price).

If a brand drug’s AMP increases faster than inflation, the minimum rebate is increased based on change in AMP compared with Consumer Price Index (CPI).5 For noninnovator multisource drugs (generics), the minimum federal rebate is AMP minus percentage set in statute.

Supplemental Rebates and Preferred Drug Lists In addition to the federal minimum rebates, state Medicaid agencies may negotiate supplemental rebate agreements with drug manufacturers. For bargaining power, states may leverage preferred drug lists (PDLs).

Most states use PDLs for some therapeutic classes.

Increasingly, states also join in multistate drug purchasing arrangements.6-8 Under these rebate agreements, the drug maker agrees

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to pay the state Medicaid program a rebate higher than the minimum required under the federal rebate agreement. Drug makers unwilling to offer supplemental rebates may see their drug placed on a nonpreferred list.

Nonpreferred drugs require some prior authorization and, in narrow circumstances, may include a higher beneficiary copayment. Therefore, nonpreferred drugs can expect substantially lower utilization.

Drug Price and Utilization Reporting Drug manufacturers report their best price and AMP figures to CMS, typically on a monthly basis. Using these manufacturer and drug-specific data, CMS calculates and provides states the minimum federal rebate percentage for that quarter for each covered drug. Before PPACA, rebate amounts were increasingly based on the difference between AMP and best price, instead of the “AMP minus X%” minimum. Federal and state officials are concerned about the accuracy and timeliness of manufacturers’ best price and AMP figures. Pricing data are subject to federal and state audits and are often the subject of litigation.

States determine Medicaid drug utilization for the quarter and report the data to drug manufacturers and CMS. States must report utilization data to manufacturers within 60 days after each quarter.9 State Medicaid utilization data are based on National Drug Codes (NDCs) for all outpatient drugs, including physicianadministered drugs. Drug makers may dispute state utilization data.10 Changes to Medicaid Drug Rebate New minimum rebates in 2010. Effective retroactively to January 1, 2010, the health reform law significantly increased minimum rebates on Medicaid drugs: • Most brand drugs: Minimum federal rebate for most single and multisource innovator drugs was increased by 8%, from 15.1% to 23.1% of AMP • Generic drugs: Minimum federal rebate for noninnovator multisource drugs was increased by 2%, from 11% to 13% of AMP • Clotting factors and pediatric indication drugs: Minimum federal rebate for these innovator drugs increased from 15.1% to 17.1% of AMP. For new line extensions (eg, time-release formulations) of brand oral drugs, the law sets a new method of determining rebate. In addition, Congress capped drug rebates to no more than 100% of AMP, regardless of best price and inflation.

Extension of rebates to Medicaid health plan utilization. Since its inception in 1991, the Medicaid drug rebate program applied only to Medicaid fee-for-service (FFS) drug utilization. Therefore, states were unable to

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collect the federally mandated rebates on drugs dispensed to Medicaid beneficiaries enrolled in Medicaid plans. Although Medicaid plans were able to negotiate rebates similar to commercial plans and pharmacy benefit managers, the rebates were far from those mandated for Medicaid FFS. PPACA extended Medicaid drug rebate to Medicaid health plan drug utilization starting March 23, 2010.

State Medicaid programs will receive federal minimum rebates on all Medicaid-covered outpatient drugs dispensed or administered to Medicaid beneficiaries, excluding drugs already discounted under the federal 340B program.

States will include Medicaid health plan drug utilization in their quarterly reports to drug manufacturers and CMS. To support Medicaid-wide (FFS and managed care) drug utilization by states, Medicaid health plans must report covered drug utilization by Medicaid beneficiaries using full 11-digit NDCs to identify utilization by manufacturer, dosage form, strength, and package size.

Since Medicaid rebates also apply to drugs and biologics administered by physicians in physician offices, clinics, and outpatient hospitals, Medicaid health plans must also report utilization of physician-administered drugs.

Federal law requires that state capitation rates for Medicaid health plans are actuarially sound, with the drug portion of rates based on actual cost related to rebates.

Federal retention of savings from increased rebates.

Much to the frustration of state leaders, PPACA includes a controversial provision for the federal government to retain all the savings associated with the new, higher minimum rebate percentages. Therefore, CMS is taking the entire rebate amount between 15.1% and 23.1%—for both FFS and MCOs. CMS is taking the difference between 11% and 13% on generics. This represents a multibillion-dollar budget hit to states, as well as an added administrative complication.

The following allocation of rebate savings start in 2010: • Brand drugs in Medicaid FFS: states will lose the state share of savings of all existing supplemental rebates between 15.1% and 23.1%. That is, states will lose their share of 8% in brand drug price concessions previously received via best price, state-negotiated supplemental rebates, or multistate group purchasing • Generic drugs in Medicaid FFS: states lose 2% (ie, the difference between the old 11% and new 13% minimum federal rebate) on generics • Brand drugs dispensed in Medicaid managed care: states and CMS will share rebate savings between 0% and 15.1%, CMS gets everything from 15.1% to 23.1%, then states and the federal government share any supplemental rebate above 23.1% Continued www.AHDBonline.com

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• Generic drugs through Medicaid managed care: states and CMS will share between 0% and 11%, then CMS gets everything from 11% to 13%, then states and the federal government share anything above 13%.

Where states and CMS still share minimum and supplemental rebate receipts, the split is based on the state’s federal Medicaid matching rate (federal medical assistance percentage) applicable to the fiscal year when the rebate payment is received.

Conclusions The Medicaid drug rebate program has generated substantial federal and state budget savings. The newly expanded rebates will generate an estimated $38 billion to help finance the federal health insurance reform. The extension of federal minimum rebates to Medicaid managed care utilization will generate federal and state savings and remove the incentive for states to carve out pharmacy benefits and disrupt care management for managed care enrollees. States will be able to leverage managed care utilization to negotiate higher supplemental rebates, particularly for therapy classes used more by the younger populations who are more likely enrolled in Medicaid health plans.

However, the PPACA changes create an array of fiscal and administrative challenges. State Medicaid directors have raised a number of questions for CMS.11 States will lose a large portion of savings from supplemental rebates.

Drug makers will see lower margins and higher compliance risks. States and Medicaid health plans will need to navigate and adapt to changes likely to dramatically change rebate negotiations and utilization management practices. Changes to utilization reporting necessary to capture health plan–associated rebates will present technical and compliance challenges for both plans and states.

Long-term, the future expansion of federal price controls under the health reform law raises serious concerns.

Policymakers, eager to finance the costs of coverage expansion and ongoing Medicaid costs, are legislating short-term cuts in unit prices at the long-term expense of value-based benefit designs, medication therapy management, innovation, and patient access.

3. US Department of Health & Human Services. Centers for Medicare & Medicaid Services. Letter to State Medicaid Directors (SMDL#10-006). April 22, 2010. www.cms.gov/smdl/downloads/SMD10006.pdf. Accessed June 4, 2010.

4. Elmendorf DW. Letter, March 20, 2010. www.cbo.gov/ftpdocs/113xx/doc11379/ AmendReconProp.pdf. Accessed June 4, 2010.

5. US Department Of Labor, Bureau of Labor Statistics. Consumer Price Index, All Urban Consumers. May 19, 2010. ftp://146.142.4.23/pub/special.requests/cpi/cpiai.txt.

Accessed June 4, 2010.

6. National Association of State Medicaid Directors. 2007 State Perspectives Medicaid Pharmacy Policies and Practices. November 2007. http://ccf.georgetown. edu/index/cms-filesystem-action?file=issue+areas%2Fpharmacyrpt1107.pdf.

Accessed June 4, 2010.

7. National Conference of State Legislatures. Recent Medicaid Prescription Drug Laws and Strategies, 2001-2009. December 1, 2009. www.ncsl.org/default.aspx?tabid =14456. Accessed June 4, 2010.

8. Kaiser Family Foundation. Summary of New Health Reform Law. April 21, 2010. www.kff.org/healthreform/upload/8061.pdf. Accessed June 4, 2010.

9. US Department of Health & Human Services. Centers for Medicare & Medicaid Services. State Drug Utilization Data Specifications. www.cms.gov/Medicaid DrugRebateProgram/16_StDrugUtilData.asp. Accessed June 4, 2010.

10. US Department of Health & Human Services. Centers for Medicare & Medicaid Services. Background and history of the dispute resolution program. www.cms.gov/ MedicaidDrugRebateDispR/downloads/drpbkgrnd.pdf. Accessed June 4, 2010.

11. Kohler AC. Letter, May 18, 2010. www.nasmd.org/home/doc/lettertoCMS Rebates.pdf. Accessed June 4, 2010.

CAPTION CONTEST Submit your caption at www.AHDBonline.com Winners receive $50 Winners’ names will be posted online

Disclosure Statement Mr Piper is a Consultant to Fleishman-Hillard, GlaxoSmithKline, Philips Healthcare, and TogoRun.

References 1. Patient Protection and Affordable Care Act, HR 3590, 111th Cong, 2nd Sess, Sect 2501-2503 (2010). http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname =111_cong_bills&docid=f:h3590enr.txt.pdf. Accessed June 4, 2010.

2. Health Care and Education Reconciliation Act, HR 4872, 111th Cong, 2nd Sess, Sect 1206 (2010). http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_ cong_bills&docid=f:h4872enr.txt.pdf. Accessed June 4, 2010.

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For your members with moderate to severe plaque psoriasis

Now Available in Prefilled Syringes

Indication STELARA™ is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Dosing STELARA™ is administered by subcutaneous injection.

• For patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks • For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks In patients weighing >100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these patients.

The safety and efficacy of STELARA™ have not been evaluated beyond two years.

Dosage forms and strengths STELARA™ contains 90 mg of ustekinumab per mL. • 45 mg/0.5 mL in a single-use, prefilled syringe, with an NDC number of 57894-060-03 • 90 mg/1 mL in a single-use, prefilled syringe, with an NDC number of 57894-061-03

Please see Important Safety Information and Brief Summary of Prescribing Information for STELARA™ on the following pages. www.STELARAinfo.com

IMPORTANT SAFETY INFORMATION Infections STELARA™ may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were reported. Infections requiring hospitalization included cellulitis, diverticulitis, osteomyelitis, gastroenteritis, pneumonia, and urinary tract infections. STELARA™ should not be given to patients with a clinically important active infection and should not be administered until the infection resolves or is adequately treated.

Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering use of STELARA™ in patients with a chronic infection or a history of recurrent infection.

Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacterium, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA™ will be susceptible to these types of infections. Consider appropriate diagnostic testing as dictated by clinical circumstances.

Pre-Treatment Evaluation of Tuberculosis (TB) Evaluate patients for TB prior to initiating treatment with STELARA™. STELARA™ should not be given to patients with active TB. Initiate treatment of latent TB before administering STELARA™. Patients should be monitored closely for signs and symptoms of active TB during and after treatment with STELARA™.

Malignancies STELARA™ is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA™ in clinical studies. The safety of STELARA™ has not been evaluated in patients who have a history of malignancy or who have a known malignancy.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) One case of RPLS has been reported in a STELARA™-treated patient. If RPLS is suspected, discontinue STELARA™ and administer appropriate treatment.

RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes.

Immunizations Prior to initiating therapy with STELARA™, patients should receive all immunizations recommended by current guidelines. Patients being treated with STELARA™ should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA™. Exercise caution when administering live vaccines to household contacts of STELARA™ patients, as shedding and subsequent transmission to STELARA™ patients may occur. Non-live vaccinations received during a course of STELARA™ may not elicit an immune response sufficient to prevent disease.

Concomitant Therapies The safety of STELARA™ in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone. The relevance of these findings in mouse models for malignancy risk in humans is unknown.

Please see Brief Summary of Prescribing Information for STELARA™ on the following page.

Reference: STELARA™ Prescribing Information 12/2009. Horsham, PA: Centocor Ortho Biotech Inc.

representing the products of www.STELARAinfo.com

©2010 Centocor Ortho Biotech Services, LLC

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25US10030

Most Common Adverse Reactions The most common adverse reactions (≥3% and higher than that with placebo) in clinical trials for STELARA™ 45 mg, STELARA™ 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively.

Brief Summary of Prescribing Information for STELARA™ (ustekinumab) STELARA™ Injection, for subcutaneous use See package insert for Full Prescribing Information INDICATIONS AND USAGE: STELARA™ is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Infections STELARA™ may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA™ (see Adverse Reactions). STELARA™ should not be given to patients with any clinically important active infection. STELARA™ should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering the use of STELARA™ in patients with a chronic infection or a history of recurrent infection. Serious infections requiring hospitalization occurred in the psoriasis development program. These serious infections included cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, and urinary tract infections. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA™ will be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances.

Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA™. Do not administer STELARA™ to patients with active tuberculosis. Initiate treatment of latent tuberculosis prior to administering STELARA™. Consider anti-tuberculosis therapy prior to initiation of STELARA™ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving STELARA™ should be monitored closely for signs and symptoms of active tuberculosis during and after treatment. Malignancies STELARA™ is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA™ in clinical studies (see Adverse Reactions). In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy (see Nonclinical Toxicology). The safety of STELARA™ has not been evaluated in patients who have a history of malignancy or who have a known malignancy. Reversible Posterior Leukoencephalopathy Syndrome One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed during the clinical development program which included 3523 STELARA™-treated subjects. The subject, who had received 12 doses of STELARA™ over approximately two years, presented with headache, seizures and confusion. No additional STELARA™ injections were administered and the subject fully recovered with appropriate treatment. RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy.

Fatal outcomes have been reported. If RPLS is suspected, STELARA™ should be discontinued and appropriate treatment administered. Immunizations Prior to initiating therapy with STELARA™, patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients being treated with STELARA™ should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA™ or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA™ because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of STELARA™ may not elicit an immune response sufficient to prevent disease. Concomitant Therapies The safety of STELARA™ in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone (see Nonclinical Toxicology). ADVERSE REACTIONS: The following serious adverse reactions are discussed elsewhere in the label: Infections (see Warnings and Precautions); Malignancies (see Warnings and Precautions); and RPLS (see Warnings and Precautions). Clinical Studies Experience The safety data reflect exposure to STELARA™ in 2266 psoriasis subjects, including 1970 exposed for at least 6 months, 1285 exposed for at least one year, and 373 exposed for at least 18 months. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions listed below are those that occurred at a rate of at least 1% and at a higher rate in the STELARA™ groups than the placebo group during the placebo-controlled period of STUDY 1 and STUDY 2. The numbers (percentages) of adverse reactions reported for placebo-treated patients (n=665), patients treated with 45 mg STELARA™ (n=664), and patients treated with 90 mg STELARA™ (n=666), respectively, were: Nasopharyngitis: 51 (8%), 56 (8%), 49 (7%); Upper respiratory tract infection: 30 (5%), 36 (5%), 28 (4%); Headache: 23 (3%), 33 (5%), 32 (5%); Fatigue: 14 (2%), 18 (3%), 17 (3%); Diarrhea: 12 (2%), 13 (2%), 13 (2%); Back pain: 8 (1%), 9 (1%), 14 (2%); Dizziness: 8 (1%), 8 (1%), 14 (2%); Pharyngolaryngeal pain: 7 (1%), 9 (1%), 12 (2%); Pruritus: 9 (1%), 10 (2%), 9 (1%); Injection site erythema: 3 (<1%), 6 (1%), 13 (2%); Myalgia: 4 (1%), 7 (1%), 8 (1%); Depression: 3 (<1%), 8 (1%), 4 (1%). Adverse drug reactions that occurred at rates less than 1% included: cellulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of RPLS occurred during clinical trials (see Warnings and Precautions).

Infections In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA™-treated subjects), 27% of STELARA™-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up).

Serious infections occurred in 0.3% of STELARA™-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) (see Warnings and Precautions). In the controlled and non-controlled portions of psoriasis clinical trials, 61% of STELARA™-treated subjects reported infections (1.24 per subject-year of follow-up).

Serious infections were reported in 0.9% of subjects (0.01 per subject-year of follow-up).

Malignancies In the controlled and non-controlled portions of psoriasis clinical trials, 0.4% of STELARA™-treated subjects reported malignancies excluding non-melanoma skin cancers (0.36 per 100 subject-years of follow-up). Non-melanoma skin cancer was reported in 0.8% of STELARA™-treated subjects (0.80 per 100 subject-years of follow-up) (see Warnings and Precautions). Serious malignancies included breast, colon, head and neck, kidney, prostate, and thyroid cancers. Immunogenicity The presence of ustekinumab in the serum can interfere with the detection of anti-ustekinumab antibodies resulting in inconclusive results due to assay interference. In STUDIES 1 and 2, antibody testing was done at time points when ustekinumab may have been present in the serum. In STUDY 1 the last ustekinumab injection was between Weeks 28 and 48 and the last test for anti-ustekinumab antibodies was at Week 52. In STUDY 2 the last ustekinumab injection was at Week 16 and the last test for anti-ustekinumab antibodies was at Week 24. In STUDY 1 (N=743), antibody results were found to be positive, negative, and inconclusive in 38 (5%), 351 (47%), and 354 (48%) patients, respectively. In STUDY 2 (N=1198), antibody results were found to be positive, negative, and inconclusive in 33 (3%), 90 (8%), and 1075 (90%) patients, respectively. The data reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab in a bridging immunoassay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: Drug interaction studies have not been conducted with STELARA™. Live Vaccines Live vaccines should not be given concurrently with STELARA™ (see Warnings and Precautions). Concomitant Therapies The safety of STELARA™ in combination with immunosuppressive agents or phototherapy has not been evaluated (see Warnings and Precautions). CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF , IFN) during chronic inflammation. Thus, ustekinumab could normalize the formation of CYP450 enzymes. A role for IL-12 or IL-23 in the regulation of CYP450 enzymes has not been reported.

However, upon initiation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed (see Clinical Pharmacology). USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B There are no studies of STELARA™ in pregnant women. STELARA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects were observed in the developmental and reproductive toxicology studies performed in cynomolgus monkeys at doses up to 45 mg/kg ustekinumab, which is 45 times (based on mg/kg) the highest intended clinical dose in psoriasis patients (approximately 1 mg/kg based on administration of a 90 mg dose to a 90 kg psoriasis patient). Ustekinumab was tested in two embryo-fetal development toxicity studies. Pregnant cynomolgus monkeys were administered ustekinumab at doses up to 45 mg/kg during the period of organogenesis either twice weekly via subcutaneous injections or weekly by intravenous injections. No significant adverse developmental effects were noted in either study. In an embryo-fetal development and pre- and post-natal development toxicity study, three groups of 20 pregnant cynomolgus monkeys were administered subcutaneous doses of 0, 22.5, or 45 mg/kg ustekinumab twice weekly from the beginning of organogenesis in cynomolgus monkeys to Day 33 after delivery. There were no treatment-related effects on mortality, clinical signs, body weight, food consumption, hematology, or serum biochemistry in dams. Fetal losses occurred in six control monkeys, six 22.5 mg/kg-treated monkeys, and five 45 mg/kg-treated monkeys.

Neonatal deaths occurred in one 22.5 mg/kg-treated monkey and in one 45 mg/kg-treated monkey. No ustekinumab-related abnormalities were observed in the neonates from birth through six months of age in clinical signs, body weight, hematology, or serum biochemistry. There were no treatment-related effects on functional development until weaning, functional development after weaning, morphological development, immunological development, and gross and histopathological examinations of offsprings by the age of 6 months. Nursing Mothers Caution should be exercised when STELARA™ is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding. Ustekinumab is excreted in the milk of lactating monkeys administered ustekinumab. IgG is excreted in human milk, so it is expected that STELARA™ will be present in human milk. It is not known if ustekinumab is absorbed systemically after ingestion; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts. Pediatric Use Safety and effectiveness of STELARA™ in pediatric patients have not been evaluated. Geriatric Use Of the 2266 psoriasis subjects exposed to STELARA™, a total of 131 were 65 years or older, and 14 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects. OVERDOSAGE: Single doses up to 4.5 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately. PATIENT COUNSELING INFORMATION: Instruct patients to read the Medication Guide before starting STELARA™ therapy and to reread the Medication Guide each time the prescription is renewed.

Infections Inform patients that STELARA™ may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the doctor, and contacting their doctor if they develop any symptoms of infection. Malignancies Patients should be counseled about the risk of malignancies while receiving STELARA™.

Prefilled Syringe Manufactured by: Vial Manufactured by: Centocor Ortho Biotech Inc., Centocor Ortho Biotech Inc., Horsham, PA 19044, Horsham, PA 19044, License No. 1821 at License No. 1821 at Baxter Pharmaceutical Solutions, Cilag AG, Bloomington, IN 47403 Schaffhausen, Switzerland 1-800-457-6399 25US10041 © Centocor Ortho Biotech Inc. 2009 December 2009

INDUSTRY TRENDS

Bundled Payment: A Promising Initiative of Payment Reform Jim Evans

A

s the healthcare industry seeks to reduce the cost and improve the quality of care delivery, payment reform has moved to the forefront of the conversation. Among the many factors that are driving this focus on payment reform, 3 trends stand out.

First, the industry is moving away from rewarding activity and toward paying for outcomes, supporting advocates who express the notion that rewarding results is paramount. This is part of a larger shift in healthcare from providing “sick care” to promoting health and wellness.

Second is the realization that for any healthcare reform to succeed, it must bring about greater alignment between payers, providers, employers, and patients— with appropriate incentives to improve quality, efficiency, and outcomes.

And third is the understanding that reducing the enormous variability in care—not just reducing cost— must be inherent to any initiative.

To date, 2 main payment approaches have been deployed in the industry. The fee-for-service model, in which the payer has the full insurance risk, has resulted in poor coordination of care and overutilization, because coordination is generally not reimbursed in fee-for-service models. On the other end of the spectrum, capitation transfers the insurance risk to the provider, by providing a lump sum for the care of each individual, leading to underutilization to the detriment of quality care.

In between these 2 approaches is a system known as “bundled payment” or “global payment”—an emerging approach that is getting significant “buzz” in the industry, and is considered by health economists and other health experts to be one of the most promising initiatives for addressing meaningful payment reform.1

The Benefits of the Bundled Payment Model “Bundled payment” refers to a single payment for all care related to a treatment or condition—a payment that is then divided up among multiple providers across many settings. Also called “episode-based payment” or Mr Evans is Vice President, Claims Performance, McKesson Health Solutions.

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“case rate payment,” bundled payment is seen as an approach that aligns provider and payer incentives to improve both cost and quality. An episode can take many forms—a single rate for all services relating to a particular procedure, combining hospital care and postacute care, or all treatment of a chronic condition for a defined period of time.

In a bundled payment system, providers take on more financial responsibility for outcomes than in a fee-forservice model. As a result, they have an incentive to use resources wisely. This mechanism is designed to address overutilization, by discouraging duplication of services that provide little or no benefit. When multiple providers in various settings are held accountable for the total cost of care, through shared payment, they have an incentive to coordinate care.

Because providers would not receive additional payment for extra treatment resulting from an unintended consequence of care, such as a hospital-acquired infection and readmission, providers have an incentive to improve the quality of care as a way to prevent costly complications.

Cutting Costs with Bundled Payment The Congressional Budget Office has projected that bundling hospital and postacute care for Medicare patients would save $18.6 billion (0.05%) by 2019.2 A recent RAND report concluded that bundled payment was the most promising approach for controlling US healthcare spending.3 Applying the bundled payment model to the care of all patients with 1 of the 6 chronic diseases and 4 acute conditions that require hospitalizations would lead to a spending reduction of 5.4% across 10 years, mostly by reducing avoidable complications.3 For any payment reform model to gain acceptance, it also needs to be aligned with government initiatives. In its goals for value-based purchasing, the Centers for Medicare & Medicaid Services (CMS) has described the possibility of developing “units of payment that go beyond the current approach of paying physicians and hospitals for their individual treatments and instead develop payments for broader bundles of services which

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eventually could even include entire episodes of care for all providers. Physicians and hospitals could then decide how best to provide these services in a more efficient manner on a patient-by-patient basis, and could allocate the payment among themselves in a way that allowed each to share in the savings.”4 This model is already being tested in the current CMS Acute Care Episode Demonstration.

Bundled payment meets many of the government’s goals for value-based purchasing, including payment incentives that are linked to quality and efficiency, joint accountability (clinical and financial) between clinicians and providers, and payment systems that support smooth transitions across providers and settings.

If incentives are truly aligned, and processes are wellintegrated, bundled payment may present a win-win for health systems. Organizations that are prepared to work collaboratively will not only be payment reform leaders but will be among the first to reap the benefits of such a system.

Bundled payment meets many of the government’s goals for value-based purchasing, including payment incentives that are linked to quality and efficiency.

Obstacles to Implementation Although a solid case can be made for bundled payment conceptually, executing this idea presents real challenges, including: • Defining the “episode of care” that is appropriate for a bundled payment, and creating case definitions that are consistent enough to be applied across varying payment arrangements. The American Medical Association has expressed concern that the science of developing reliable episode groupers is in very early stages, and that very little data are available to identify services where consistency of care across patients would lend itself to this approach5 • Persuading physicians and other providers to adopt changes and modify behavior. The necessary collaboration may occur more readily in integrated systems, where bundled payment is likely to first gain ground. However, as accountable care organizations mature, and alignment between facilities and physicians improves, a broad range of successful models may emerge • Shortage of primary care physicians. Providers may be concerned about investing time in a new, unproved primary care model, even if it focuses on better care coordination

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• Current organizational models of disparate stakeholders will pose challenges for bundled payment, especially in community-based care. Physicians may be wary of a hospital in charge of administering their payments • Reconciling bundled payment with regulations against self-referral • Accounting for patients changing insurance or geographic location during the defined treatment episode.

The largest issue we are now facing is how to build the contracting and payment infrastructure to handle a new payment model. For example, contracting systems will need to specify episodes, and payment systems will need to recognize and correctly handle submissions for episode services versus services that are outside of episodes and should be paid separately.

Delivering on the Promise of Bundled Payment Bundled payment is a fast emerging component of payment reform, and perhaps the most promising new initiative for reducing the cost and improving the quality of care delivery. Despite the many challenges in executing bundled payments, there is a strong interest in this option from all stakeholders—providers, payers, and the government.

The early experiments in bundled payment— including the Geisinger system and the Prometheus Payment model—have provided valuable insights and have been used in many savings projections for bundled payment that demonstrate clear advantages over fee-for-service models.

Next-generation payment systems are now available that provide, for the first time, the flexibility to look at claims across multiple providers, multiple facilities, and across time. Industry adoption of this new breed of payment system is critical to ensuring bundled payment moves from the experimental stage to broad market acceptance.

In a follow-up article, we will delve into the current state of bundled payment, including a look at pilot projects, key learnings, and what tools and processes are needed to realize the full potential of bundled payments. ■ References 1. Burns LR. Bending the curve, changing provider organization: implications for wellness-based healthcare. Am Health Drug Benefits. 2010;3(2 suppl 6):S93-S97.

2. Congressional Budget Office. Budget Options Volume 1: Health Care. December 2008. Pub No 3185. www.cbo.gov/ftpdocs/99xx/doc9925/1218HealthOptions.pdf.

Accessed May 18, 2010.

3. Hussey PS, Eibner C, Ridgely MS, McGlynn EA. Controlling US health care spending—separating promising from unpromising approaches. N Engl J Med. 2009;36:2109-2111.

4. Centers for Medicare & Medicaid Services. www.cms.gov/QualityInitiatives GenInfo/downloads/VBPRoadmap_OEA_1-16_508.pdf. Accessed May 18, 2010.

5. American Medical Association. Health System Reform, Get the Facts and Get Involved. October 7, 2009. www.ama-assn.org/ama1/pub/upload/mm/399/resourceuse-outliers.pdf. Accessed May 18, 2010.

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Impact of Etanercept Treatment on Absenteeism and Productivity: The Work Loss and Productivity Survey Denise Globe, PhD; Peter Mazonson, MD, MBA; Chris Santas, MBA; Regina Murphy, MBA; Annie Cheng; Xingyue Huang, BPharm, PhD; Arthur Kavanaugh, MD Objective: To assess the impact of etanercept therapy on work loss and productivity among employed patients with moderate-to-severe rheumatoid arthritis, and to quantify the economic value of changes in work loss and productivity to employers.

Method: This study is based on the Work Loss and Productivity survey that was conducted between December 2006 and January 2007 via telephone interview with all consenting patients with rheumatoid arthritis aged â&#x2030;Ľ18 years who had been receiving etanercept for 5 to 28 months at 13 US rheumatology practices. Of the 101 eligible patients, 86 patients (85.1%) participated in the study. Eligible patients were employed full-time or part-time at the time of the interview. The survey consisted of 13 questions pertaining to employment, absenteeism, and productivity at work, before and after starting etanercept; survey responses pre- and posttreatment were compared. Data on absenteeism and productivity were converted into cost values, using standard wage rates by job category.

Results: Since starting etanercept monthly therapy, missed work days decreased from 1.8 to 0.1 days (P <.001), number of days rheumatoid arthritis limited work monthly decreased from 6.5 to 0.2 (P <.001), and the effect of this disease on productivity improved 3.7 points on a scale of 1 to 10 (P <.001). Using standard wage rate conversions, after starting etanercept therapy, the average annual savings to self-insured employers per employed patient with rheumatoid arthritis was $3889 as a result of decreased absenteeism, and the savings from improved productivity ranged from $9533 to $19,065. Assuming annual per-patient etanercept drug costs of $16,389 (average 2008 selling price), net annual economic impact for self-insured employers per treated patient with rheumatoid arthritis ranged from a cost of $2967 to a savings of $6566, depending on different work output assumptions.

Conclusion: Patients with rheumatoid arthritis treated with etanercept had significant reductions in work-related absenteeism and improvements in productivity. The value of these changes to employers may partially or completely offset the cost of treatment. [AHDB. 2010;3(3):191-200.]

R

heumatoid arthritis (RA) is a chronic, disabling autoimmune disorder that affects approximately 1% of American adults.1 There has been substan-

Dr Globe is Executive Director, Global Health Economics, and Dr Huang is Senior Manager, Global Health Economics, Amgen, Inc., Thousand Oaks, CA; Dr Mazonson is Vice President, Reimbursement Strategy and Health Economics, Mr Santas is Vice President, Reimbursement Strategy and Health Economics, Ms Murphy is Director, Customer Strategy and Product Development, and Ms Cheng is Research Manager, Reimbursement Strategy and Health Economics, McKesson Corporation, San Francisco, CA; Dr Kavanaugh is Professor of Medicine, Division of Rheumatology, Allergy and Immunology, and Director, Center for Innovative Therapy, University of California San Diego, La Jolla, CA.

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tial progress in our understanding of RA disease progression and in the development of therapies for its treatment in recent years. Recommendations by the American College of Rheumatology and other organizations support early aggressive treatment with diseasemodifying antirheumatic drugs (DMARDs), including biologic therapies.2 Current guidelines recommend beginning DMARD therapy with nonbiologic agents, especially methotrexate, alone or in combination with other nonbiologic agents. Addition of a biologic DMARD may be indicated in patients whose disease does not respond to maximally tolerated doses of methotrexate or other nonbiologic DMARD therapy.2 RA is a costly disease, with the fourth highest direct medical expenditures per employee among 11 chronic

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KEY POINTS u u

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Rheumatoid arthritis affects approximately 1% of American adults.

Arthritis is a costly disease, with the fourth highest direct medical expenditures per employee among 11 chronic conditions.

The current study assessed the economic value of changes in work loss and productivity to employers with the use of etanercept therapy among patients with moderate-to-severe arthritis.

Average hours worked weekly increased by 1.8 hours after starting etanercept therapy, and average days missed monthly decreased by 1.7 days.

Using standard wage rates to estimate the economic value resulting from reductions in absenteeism after starting etanercept therapy, the average annual economic impact on employers was $3889 per employed patient with rheumatoid arthritis, and the savings from improved productivity ranged from $9533 to $19,065.

The results of this study suggest that treating a chronic disease such as rheumatoid arthritis can significantly reduce absenteeism and improve productivity, which can potentially offset part or all of the cost of treating the disease.

conditions.3 In addition to its clinical burden and direct cost impact, RA has a significant adverse effect on the patient’s ability to work, absenteeism, and productivity, because of the debilitating nature of the disease, and because most patients develop the disease between age 35 and 50 years, when most employed people are in their prime work years.4 Burden of illness studies have shown that overall, indirect costs may be greater than direct costs for RA.5 Factors associated with being unable to work among patients with RA include pain, impaired physical function, difficulty commuting, and failure to achieve significant improvement with antirheumatic drug therapy.6 Employment status is not simply a function of whether the patient is working but also of the patient’s productivity while at work.

Biologic medications such as tumor necrosis factor (TNF)-alpha antagonists are frequently prescribed for treatment of moderate-to-severe RA.7 TNF-alpha antagonists inhibit the activity of the inflammatory mediator TNF-alpha. Etanercept (Enbrel) is a selfinjected TNF-alpha inhibitor approved for the treatment of moderate-to-severe RA. It has been shown to significantly improve clinical outcomes and functional status in patients with RA when added to multidrug

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nonbiologic DMARD regimens that have not succeeded in fully controlling the disease.8,9 From an economic perspective, the use of TNF-alpha inhibitors continues to increase.10 In 2008, etanercept was ranked the seventh top-selling pharmaceutical drug in dollar volume in the United States.11 The purpose of the Work Loss and Productivity (WLP) survey was to quantify the impact of etanercept therapy among employees with RA on both work loss and lost productivity while at work. Knowing this may enable employers to better understand the direct and indirect economic impact of TNF-alpha inhibitors such as etanercept in employees with moderate-to-severe RA.

Materials and Methods Participants in the WLP survey were recruited from the participant pool of a previously conducted study— Rheumatoid Arthritis Payment (RAP)—that assessed willingness and ability to pay for etanercept among patients with moderate-to-severe RA at various income levels. The RAP study was conducted from April through November 2006 and included 217 patients aged ≥18 years with moderate-to-severe RA from 15 community-based rheumatology practices across the United States who had been taking etanercept for 3 to 24 months. Participants who were employed at the time of the RAP interviews (n = 118; 93 full-time, 25 part-time) were asked to participate in the WLP survey.

The WLP survey was conducted from December 2006 to January 2007; participants received $25 for participating in the study. This study was a retrospective analysis of the impact of etanercept treatment on work loss and productivity among employed patients with RA. Eligibility criteria for study participation included age ≥18 years, having a diagnosis of moderateto-severe RA, and being employed part-time (<40 weekly hours) or full-time (≥40 weekly hours) before and since starting etanercept therapy. Because the WLP study took place shortly after the RAP study, all WLP participants had been taking etanercept for at least 5 months, but not more than 28 months.

We limited the analyses to patients who were working before and after taking etanercept to be able to compare, during a telephone survey, each patient’s work loss and productivity during that period. Of the 118 patients recruited for the study, 17 (14.4%) did not meet the eligibility criteria. These patients either stopped taking etanercept since the RAP study (n = 9), were not working before starting etanercept (n = 7), or were no longer working since starting etanercept (n = 1). Of the remaining 101 eligible patients, 3 were unwilling to participate, 3 did not return phone calls, and 9 were treated at sites that chose not to participate in the WLP study

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The Work Loss and Productivity Survey

(total, n = 15; 14.9%); 86 eligible patients (85.1%) participated in the WLP study.

The WLP study protocol was approved by a centralized institutional review board, and all patients provided informed consent to participate in the study.

Survey Questionnaire and Administration A standardized, telephone-administered survey was developed for this study to collect participant information. Patients were asked to rate their typical work loss and productivity experience before initiation of treatment with etanercept and at the time of the interview.

The final questionnaire consisted of 13 items (see Appendix at www.AHDBonline.com).

Self-reported productivity was measured on a 1-to-10 scale, in which lower numbers represented less impact and higher numbers represented more impact of RA on productivity. This scale was used to estimate the impact of productivity changes for full-time and part-time employees utilizing several different assumptions.

Statistical Analysis Univariate analysis was used to describe the characteristics of the study cohort, including age, sex, education, duration of RA, length of time taking etanercept, and type of employment. One-sample, paired t-tests were used to examine patient changes for all measures before and since taking etanercept, including weekly work hours, missed work days in a month, number of times patients missed ≥5 consecutive work days because of RA, number of days per month RA limited work, and the effect of RA on productivity. McNemar’s tests were used to investigate the relationship between the percentage of patients who reported positive responses before and since taking etanercept for any days missed from work, ≥5 missed days from work, RA limiting the kind of work they could perform, or RA limiting the type of work for more than one half of the work days in a month.

To assess the validity of our findings, we compared results for the subset of 19 patients most recently switched to etanercept (5-10 months before the survey)—because these patients would be least prone to recall bias—with the results for the rest of the cohort.

We selected the timeframe of 5 to 10 months to ensure a large enough sample size for statistical inference, while keeping the timeframe short enough to minimize potential recall bias. In addition, response to etanercept treatment can take 12 to 24 weeks, so the lower criterion was also based on providing sufficient time for the impact of treatment to be recognized by the patient.

We performed one-sample, paired t-tests and McNemar’s tests on these subsets of patients. We also

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compared the results for patients with different employment status (full-time vs part-time), and for patients who worked in 2 different broad job categories (sedentary vs requiring manual labor or mobility).12 A P value of <.05 was considered significant. All analyses were conducted with SPSS software, 14.0 for Windows (SPSS Inc; Chicago, IL).

Calculation of Economic Impact To derive the economic impact of etanercept treatment, we estimated the financial value of changes in employee absenteeism and productivity. For absenteeism, changes in work hours were multiplied by average salary wage estimates, based on patient-reported job categories, to determine the dollar value of the changes in hours worked. For productivity, several assumptions were used to estimate the economic impact of patient-reported productivity changes for full-time and part-time employees.

First, we assumed a 1:1 linear relationship between self-reported productivity and output, such that every 1point reduction in productivity on the 1-to-10 scale was assumed to be equivalent to an 11.1% reduction in output. Under these assumptions, working 40 hours in a week at a productivity level of 2 (or a 1-point reduction in productivity) was equivalent to working 35.6 hours at full productivity.

To take a more conservative approach, we then assumed a 2:1 ratio between self-reported productivity and output. In this scenario, each 1-point reduction in productivity was the equivalent of a 5.5% reduction in output. Based on this 2:1 relationship, working 40 hours weekly at a self-reported productivity level of 2 was equivalent to working 37.8 hours at full productivity.

These same percentage changes were used to estimate productivity changes for part-time employees. We used an annual cost of $16,389 for etanercept therapy based on the drug’s 2008 average selling price (assuming a dose of 25 mg twice weekly).13 Results The majority of the study participants were female (69.8%), with a mean age of 50 years (Table 1). Mean disease duration was 7.9 years, and mean time taking etanercept was 16.5 months. Participants perceived themselves as generally healthy, with 75.6% rating their overall health status as good, very good, or excellent.

Almost all (ie, 97.7%) of the patients reported some level of RA improvement since starting etanercept therapy. All had medical insurance, including some drug coverage, and were employed across a spectrum of job categories, characterized by the 2000 population survey of the Bureau of Labor Statistics (Table 2).12

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Table 1 Main Characteristics of Employed Patients with RA

Characteristic Age, yrs <40 40-59 ≥60

Female

Education Did not graduate high school Graduated high school Some college Graduated college Postgraduate degree Medical information RA duration, yrs <5 5-9 10-14 15-19 20-24 ≥25

All study participants (n = 86) N (%)

Nonparticipants (n = 15) N (%)

14 (16.3) 60 (69.8) 12 (14.0) 60 (69.8)

3 (20.0) 6 (40.0) 6 (40.0) 12 (80.0)

2 (2.3) 28 (32.6) 20 (23.3) 23 (26.7) 13 (15.1)

0 (0) 2 (13.3) 5 (33.3) 5 (33.3) 3 (20.0)

35 (40.7) 29 (33.7) 7 (8.1) 5 (5.8) 7 (8.1) 3 (3.5)

8 (53.3) 3 (20.0) 2 (13.3) 0 (0) 1 (6.7) 1 (6.7)

10 (11.6) 25 (29.1) 25 (29.1) 23 (26.7) 3 (3.5)

— — — — —

Time on etanercept, mo 3-8 9-14 15-20 21-26 ≥27

Self-rated health status 21 (24.4) Fair or poor 30 (34.9) Good 35 (40.7) Very good/excellent Self-rated improvement in RA with etanercept 0 (0) Very much/much worse 1 (1.2) Minimally worse 1 (1.2) No change 6 (7.0) Minimally improved Much/very much improved 78 (90.7)

3 (20.0) 4 (26.7) 8 (53.3) 0 (0) 0 (0) 0 (0) 1 (6.7) 14 (93.3)

Socioeconomic status Annual household income <$40K $40K–<$80K ≥$80K

Employment status Full-time Part-time

13 (15.1) 36 (41.9) 37 (43.0)

4 (26.7) 7 (46.7) 4 (26.7)

70 (81.4) 16 (18.6)

12 (80.0) 3 (20.0)

NOTE: No between-group differences reached statistical significance based on a chi-squared test.

RA indicates rheumatoid arthritis.

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Comparison Before and Since Using Etanercept Patients experienced significant improvement (P <.05, one-sample, paired t-test) on all work loss and productivity measures after starting, compared with before starting, etanercept therapy, with the exception of weekly work hours (P = .059). This included missed days in a month declining from 1.8 to 0.1 days, days RA limited work in a month declining from 6.5 to 0.2 days, and the effect of RA on productivity improving 3.7 points on a 1-to-10 scale (P <.001 for all measures; Table 3). In addition, after starting etanercept, a significant reduction was seen in the percentage of patients who reported any days missed from work (from 58.1% to 11.6%, P <.001; McNemar’s test), ≥5 days missed from work (from 19.8% to 2.3%, P ≤.01), RA limiting the kind of work patients could perform (from 62.8% to 8.1%, P <.001), or RA limiting the type of work patients could perform for more than half the work days per month (from 31.4% to 0%, P <.001).

A subset analysis of patients (n = 19) who most recently started taking etanercept (5-10 months before the survey) showed significant decreases in missed work days monthly from 0.9 to 0.2 days (P = .003) and in number of days RA limited work monthly from 3.5 to 0.3 days (P = .022; Table 4). The effect of RA on productivity improved from a score of 4.2 to 2.1 days (P = .001). There was also a significant reduction in the percentage of patients who reported days missed from work (from 57.9% to 15.8%, P = .008) and RA limiting their work (from 47.4% to 10.5%, P = .016).

Other measures trended toward improvement but none of the results was significant. We performed the same analysis on the remainder of the 67 patients (ie, those who had been receiving etanercept for ≥11 months before the survey); significant improvement was seen on all work loss and productivity measures after starting etanercept compared with before starting etanercept therapy (Table 4).

We performed 2 additional subset analyses. The first looked at patients with different employment status (full-time vs part-time), and the second looked at patients in 2 different broad job categories (ie, sedentary vs requiring manual labor or mobility groups). In the first analysis, for the 70 patients who were employed fulltime, there were significant improvements in all work loss and productivity measures. For the 16 patients who were employed part-time, there was a significant improvement in some measures and a trend toward improvement in the others (Table 5).

For the subset analysis comparing patients in sedentary jobs with those in jobs involving manual labor or mobility, the magnitude of the difference between before and after starting etanercept was similar, except for

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missed days in a month and missing ≥5 days because of RA (both greater improvement in the manual labor group) and RA limiting the kind of work (greater improvement in the sedentary group) (Table 6).

Average Annual Economic Impact Using standard wage rates to estimate the economic value resulting from reductions in absenteeism, after starting etanercept therapy, the average annual economic impact on employers was $3889 per employed patient with RA. Stratifying patients by income levels, average annual economic impacts resulting from decreased absenteeism alone were $2493, $4351, and $4850 per employed patient with RA with annual household income levels of <$40,000; $40,000 to <$80,000; and ≥$80,000, respectively.

Using standard wage rate conversions and different productivity-to-output assumptions, after starting etanercept therapy, the average annual economic impacts on employers per employed patient with RA as a result of improved productivity were $19,065 and $9533 for productivity-to-output ratios of 1:1 and 2:1, respectively. At a 1:1 productivity-to-output ratio, the average annual economic impacts as a result of improved productivity were $10,092, $27,292, and $33,442 per employed patient with RA with annual household income levels of <$40,000; $40,000 to <$80,000; and ≥$80,000, respectively. At a 2:1 productivity-to-output ratio, the average annual economic impacts resulting from improved productivity for these income groups were $5046; $13,646; and $16,721, respectively.

Taking into account decreased absenteeism and improved productivity as increased value or “savings” to the employer, and using a per-patient etanercept cost of $16,389, net annual savings to the employer for each employed patient with RA after starting etanercept was $6566 at a 1:1 productivity-to-output ratio. Net annual cost to the employer was $2967 at a 2:1 productivity-to-output ratio. Stratifying patients by income levels, assuming a 1:1 productivity-to-output ratio and combining the impact of drug costs with absenteeism and productivity, resulted in a net annual cost of $3803 for each patient with an annual household income level of <$40,000, but net annual savings of $15,254 and $21,904 for patients with annual household income levels of $40,000 to <$80,000 and ≥$80,000, respectively (Table 7).

Discussion The WLP study documents significant improvements in self-reported absenteeism and productivity among employed patients with RA who were taking etanercept and continued using it for 5 to 28 months. Among

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Table 2 Job Categories of Study Participants

Job category a Managerial or professional specialty Technical, sales, and administrative support Precision production, craft, repair Operators, fabricators, laborers Service Total

N (%)

Estimated average annual income, $b

31 (36.0)

73,697

29 (33.7)

40,197

4 (4.7)

37,697

13 (15.1)

27,814

9 (10.5)

25,490

86 (100.0)

44,283

a

Bureau of the Census for the Bureau of Labor Statistics. Current population survey, March 2000. www.census.gov/apsd/techdoc/cps/cpsmar00.pdf. bUS Department of Labor. Bureau of Labor Statistics. 2005 National compensation survey: occupational wages. www.bls.gov/ncs/ocs/sp/ncbl0831.pdf.

Table 3 Comparison of Work Loss and Productivity Before and since Using Etanercept, for All Patients Productivity measure Work hours/wk Missed days/mo

Mean Before Since Mean of etanercept, N etanercept, N difference 37.6

39.3

1.8

1.8

0.1

–1.7a

Number of times missed ≥5 consecutive work days because of RA

0.6

0

–0.5b

Days RA limited work/mo Effect of RA on productivity c

6.5

0.2

–6.3a

5.8

2.1

–3.7a

Proportion of patients Before Since etanercept, % etanercept, % Missed any days because of RA Number of times missed ≥5 consecutive work days because of RA

58.1

11.6a

19.8

2.3b

RA limited the kind of work RA limited the kind of work ≥50% of work days/mo

62.8

8.1a

31.4

0a

a P b P c

<.001. <.01.

Productivity is based on a scale of 1-10; a low number means RA affected productivity a little, a high number means RA affected productivity a lot.

RA indicates rheumatoid arthritis.

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Table 4 Work Loss and Productivity, by Duration of Etanercept Treatment Treatment 5-10 mo before survey Mean of difference, N

Treatment ≥11 mo before survey Mean of difference, N

1.6

2.0a

–0.7b

–1.8c

Number of times missed ≥5 consecutive work days because of RA

–0.2

–0.6a

Days RA limited work/mo

–3.2a

–8.0c

Effect of RA on productivity d

–2.1c

–4.4c

Productivity measure Work hours/wk Missed days/mo

Before etanercept, %

Since etanercept, %

Before etanercept, %

Since etanercept, %

57.9

15.8b

58.2

9.0c

Missed ≥5 consecutive work days because of RA

5.3

0

20.9

3.0b

RA limited the kind of work

47.4

10.5a

73.1

11.9c

RA limited the kind of work ≥50% of work days/mo

10.5

0

40.3

0c

Missed any days because of RA

a P b P c

<.05. <.01.

P <.001. d Productivity is based on a scale of 1-10; a low number means RA affected productivity a little, a high number means RA affected productivity a lot.

RA indicates rheumatoid arthritis.

Table 5 Work Loss and Productivity: Full-Time versus Part-Time Employed Patients

Productivity measure Work hours/wk Missed days/mo

Employed full-time (n = 70) Mean of difference, N

Employed part-time (n = 16) Mean of difference, N

2.3a

–0.7

b

–1.8

c

–1.7

Number of times missed ≥5 consecutive work days because of RA

–0.6

–0.1

Days RA limited work/mo

–6.8b

–3.9a

Effect of RA on productivity d

–3.8b

–3.4b

Before etanercept, %

Since etanercept, %

Before etanercept, %

Since etanercept, %

Missed any days because of RA

61.4

11.4b

43.8

12.5

Missed ≥5 consecutive work days because of RA

21.4

1.4b

12.5

6.3

RA limited the kind of work

65.7

8.6b

50.0

6.3a

RA limited the kind of work ≥50% of work days/mo

32.9

0b

25.0

0

a P b P c

<.05. <.001.

P <.01. d Productivity is based on a scale of 1-10; a low number means RA affected productivity a little, a high number means RA affected productivity a lot.

RA indicates rheumatoid arthritis.

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Table 6 Work Loss and Productivity: Patients in 2 Different Job Categories

Productivity measure Work hours/wk Missed days/mo

Managerial and technical/sales/administrative support jobs (n = 60) Mean of difference, N

Service and manual jobs (n = 26) Mean of difference, N

1.8

–1.6 a

–1.5

–2.2b

Number of times missed ≥5 consecutive work days because of RA

–0.6c

–0.5

Days RA limited work/mo

–6.1a

–6.7a

Effect of RA on productivity d

–3.7a

–3.9a

Before etanercept, %

Since etanercept, %

Before etanercept, %

Since etanercept, %

Missed any days because of RA

56.7

10.0a

61.5

15.4a

Missed ≥5 consecutive work days because of RA

23.3

3.3b

11.5

0

RA limited the kind of work

60.0

8.3a

69.2

7.7a

RA limited the kind of work ≥50% of work days/mo

31.7

0a

30.8

0b

a P b P c

<.001. <.01.

P <.05. d Productivity is based on a scale of 1-10; a low number means RA affected productivity a little, a high number means RA affected productivity a lot.

RA indicates rheumatoid arthritis.

patients in our study, average hours worked weekly increased by 1.8 hours after starting etanercept therapy and average days missed monthly decreased by 1.7 days (13.4 hours) or 3.35 hours weekly, for an overall increase in hours worked weekly of 5.15 hours.

In a methodologically similar study regarding absenteeism among employed patients with RA receiving etanercept in which patients reported their work status via telephone interviews, Yelin and colleagues found unadjusted and adjusted values of 5.4 and 7.4 more hours worked per week, respectively, among patients with RA receiving etanercept versus matched patients who were not using etanercept.14 The lower numbers in our study may relate to the fact that Yelin and colleagues included patients with RA who were formerly not working but returned to the workforce after starting etanercept, whereas our study looked only at patients who remained employed before and after starting etanercept.

A study by Kavanaugh and colleagues showed an average increase of 3.54 hours worked weekly among patients with RA treated with methotrexate and either infliximab or placebo who had a clinically meaningful improvement in their Health Assessment Questionnaire (HAQ) score of ≥0.25.15 In terms of work loss among employed patients with RA before starting etanercept,

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the mean value in our study was 21.6 days per year as compared with a median estimate of mean values from a systematic review of work loss among patients with RA of 39 days per year, with a range of 7 to 84 days.4 The increased number of days of work lost in this systematic review versus our study may reflect the fact that this review included studies from the United States and Europe, as well as studies that were published as early as 1987.4 In addition to improvements in absenteeism and work loss after starting etanercept, our study showed significant improvements in productivity while at work.

After monetizing the value of the improvements seen in our study, results suggest that the costs of etanercept may be partially or completely offset by increased time at work and improved productivity. These findings are supportive of the national Healthy People 2010 arthritis objective to reduce unemployment among adults with physician-diagnosed RA and to decrease the proportion who are limited in their ability to work for pay.16

Limitations Several limitations must be kept in mind when interpreting the results of this study. First, we could not find a suitable, validated questionnaire for this type of retro-

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Table 7 Average Annual Net Savings (Losses) for Patients with RA after Starting Etanercept Income level <$40K $40K-<$80K

≥$80K

All levels, $

Etanercept drug cost Absenteeism savings Productivity savings (1:1a) Productivity savings (2:1b) Total annual per-patient savings (1:1)

16,389

16,389

16,389

16,389

2493

4351

4850

3889

10,092

27,292

33,442

19,065

5046

13,646

16,721

9533

–3803

15,254

21,904

6566

Total annual per-patient savings (2:1)

–8850

1608

5183

–2967

NOTE: Savings is based on drug costs, decreased absenteeism, and improved productivity at work by patient income levels at different productivity-to-output ratio assumptions. a 1:1 relationship between self-reported productivity and output. b 2:1 relationship between self-reported productivity and output.

RA indicates rheumatoid arthritis.

spective study, so we created a questionnaire closely modeled after the validated Work Productivity and Activity Impairment Questionnaire, but modified it to include patients’ pre- and post-etanercept experiences.17 Second, information about days lost from work and productivity at work were based on patients’ self-reporting and may have been subject to recall bias, particularly for the time period before they started treatment.

To address this issue, we performed a subset analysis of patients most recently started on etanercept (5-10 months before the survey)—because these patients would likely be least prone to recall bias—and still found statistically significant improvement in missed work days in a month, number of days RA limited work in a month, and the effect of RA on productivity. The absolute magnitude of these changes was lower than for the rest of the group, suggesting either some degree of recall bias or that patients receiving etanercept for a longer period of time had greater improvements in their RA. Rather than asking each patient about his or her productivity and absenteeism before and after starting etanercept, an alternative would have been to compare patients who started treatment with untreated patients, as was done in a recent nonrandomized study by Wolfe and colleagues.18 Although when the 2 groups were compared at baseline, they differed in many key attributes

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that were known to contribute to the risk of disability (and, by extension, productivity and absenteeism), such as corticosteroid use; analgesic use; HAQ, pain, and severity index scores; joint scores; use of DMARDs in the past; and joint replacement.18 The authors of the study attempted to control for all of these effects,18 but as the authors of an accompanying editorial to the study stated, “These effects and differences cannot simply be disentangled by statistical techniques.”19 Third, we collected data only on patients who were continuously employed before and since starting etanercept, rather than including those who were unemployed or on temporary disability leave before starting etanercept and may have returned to work because of clinical improvement after starting etanercept, or those who may have stopped work because of clinical deterioration after starting etanercept.

We do not know of any published data on the impact of etanercept on unemployed patients with RA who desire employment. We do know that 7 patients in our study returned to work but only 1 patient stopped working after starting etanercept, although we do not know the reasons for these changes. The overall impact of excluding these cohorts depends on the relative numbers of patients in these 2 groups.

Fourth, by restricting the study to patients who had been receiving etanercept for at least 5 months, we were essentially looking only at responders, because nonresponders were unlikely to have remained on treatment long enough to have been part of the study. Nonresponders would likely have been limited to no productivity improvements, but this study did not capture information on these patients. Nonresponders would still incur some drug costs until etanercept was discontinued, although these costs were not captured in this study. However, the majority of the costs of drugs such as etanercept are likely incurred by patients who have an adequate clinical response, and thus take the medications long-term.

Fifth, we examined only the cost impact to employers of providing etanercept to their employees; employers offering dependent care coverage would incur additional costs without the corresponding work gain and productivity benefits.

Finally, because this study focused on the impact of only 1 TNF-alpha inhibitor, etanercept, it is not possible to know how these results would compare with findings for the other available TNF-alpha inhibitors.

Conclusion This study documents significant improvements in absenteeism and work productivity among employed patients with RA who started taking etanercept.

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Although the annual direct costs of biologic DMARDs such as etanercept are higher than the costs of regimens used in patients with less-severe disease, a broader view of the economic impact of these treatments for employed individuals with RA and for their employers should also incorporate the impact of these therapies on indirect costs, including work loss and productivity.

Studies such as this, that estimate the total economic impact of treatment from an employer’s perspective, can be used to develop rational benefit plan designs that incorporate the full economic impact of novel biologic therapies for chronic diseases, including RA. ■ Disclosure Statement This study was funded by a grant from Amgen, Inc., Thousand Oaks, CA. Dr Globe and Dr Huang are employees of Amgen; Dr Mazonson, Mr Santas, Ms Murphy, and Ms Cheng are consultants to McKesson Corporation and have received honoraria or consultancy fees from Amgen; Dr Kavanaugh has nothing to disclose.

References 1. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update.

Arthritis Rheum. 2002;46:328-346.

2. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-784.

3. Ozminkowski RJ, Burton WN, Goetzel RZ, et al. The impact of rheumatoid arthritis on medical expenditures, absenteeism, and short-term disability benefits. J Occup Environ Med. 2006;48:135-148.

4. Burton W, Morrison A, Maclean R, Ruderman E. Systematic review of studies of productivity loss due to rheumatoid arthritis. Occup Med (Lond). 2006;56:18-27.

5. Pugner KM, Scott DI, Holmes JW, Hieke K. The costs of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum. 2000;29:305-320.

6. Lacaille D, Sheps S, Spinelli JJ, et al. Identification of modifiable work-related factors that influence the risk of work disability in rheumatoid arthritis. Arthritis Rheum.

2004;51:843-852.

7. Furst DE, Keystone EC, Fleischmann R, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2009. Ann Rheum Dis. 2010;69(suppl 1):i2-i29.

8. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes.

Arthritis Rheum. 2002;46:1443-1450.

9. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340:253-259.

10. Goldman DP, Joyce GF, Lawless G, et al. Benefit design and specialty drug use.

Health Aff (Millwood). 2006;25:1319-1331.

11. IMS Health. Top 15 US pharmaceutical products by sales. www.imshealth.com/ deployedfiles/imshealth/Global/Content/StaticFile/Top_Line_Data/2008_Top_15_ Products_by_U.S._Sales.pdf. Accessed April 14, 2010.

12. Bureau of the Census for the Bureau of Labor Statistics. Current population survey, March 2000. www.census.gov/apsd/techdoc/cps/cpsmar00.pdf. Accessed April 12, 2010.

13. Centers for Medicare & Medicaid Services. Payment allowance limits for Medicare Part B drugs, effective April 1, 2008 through June 30, 2008. www.cms. gov/apps/ama/license.asp?file=/McrPartBDrugAvgSalesPrice/downloads/April08 ASPbyHCPCS.zip. Accessed April 14, 2010.

14. Yelin E, Trupin L, Katz P, et al. Association between etanercept use and employment outcomes among patients with rheumatoid arthritis. Arthritis Rheum. 2003;48: 3046-3054.

15. Kavanaugh A, Han C, Bala M. Functional status and radiographic joint damage are associated with health economic outcomes in patients with rheumatoid arthritis.

J Rheumatol. 2004;3:849-855.

16. Yelin E, Murphy L, Cisternas MG, et al. Medical care expenditures and earnings losses among persons with arthritis and other rheumatic conditions in 2003, and comparisons with 1997. Arthritis Rheum. 2007;56:1397-1407.

17. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. 1993;4:353-365.

18. Wolfe F, Allaire S, Michaud K. The prevalence and incidence or work disability in rheumatoid arthritis, and the effect of anti-tumor necrosis factor on work disability. J Rheumatol. 2007;34:2211-2217.

19. Verstappen SM, Jacobs JW, Hyrich KL. Effect of anti-tumor necrosis factor on work disability. J Rheumatol. 2007;34:2126-2128.

STAKEHOLDER PERSPECTIVE What Is the Value of Specialty Pharmaceuticals?

PAYERS/PHARMACY DIRECTORS: Readers of American Health and Drug Benefits already know that specialty pharmaceuticals have experienced doubledigit growth in annual cost trends over the past 3 years.

The 2009 cost trend reported for specialty pharmaceuticals by Medco was 14.7%,1 and that reported by Express Scripts for 2009 was 19.5%.2 It is expected that this annual cost trend growth will continue into the future as more specialty pharmaceuticals are marketed in the United States, currently marketed products receive expanded indications, and the number of insured patients continues to grow.

Payers are increasingly concerned about these cost trends, leading most of them to implement strategies to keep these increases under control. Focus on utiliza-

tion management, formulary management, benefit design, channel management, drug therapy management, and vendor strategies are now commonplace in the industry.

What has been more difficult to address is the ability to answer the following fundamental question— What is the value of specialty pharmaceuticals, namely, what am I getting in return for the double-digit cost trend that I am experiencing annually?

The article by Globe and colleagues is a step in the right direction in helping to answer this fundamental question. Is it the answer? No. Does it assist us in assessing the value of specialty pharmaceuticals in treating chronic diseases? Yes. Globe and colleagues evaluated the impact of the use of etanercept—the Continued

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STAKEHOLDER PERSPECTIVE (Continued) highest utilized specialty pharmaceutical—for a debilitating chronic disease, rheumatoid arthritis. The goal of the evaluation was to determine if etanercept could reduce work-related absenteeism and improve work productivity. The Work Loss and Productivity survey was used as the basis for the questions posed during telephone interviews with 86 patients who were receiving etanercept for at least 5 months.

The researchers identified that etanercept therapy resulted in significant reductions in missed work days, number of days that rheumatoid arthritis limited their work monthly, and improved work productivity. Using standard wage rate conversions, net annual economic impact per treated patient ranged from a cost of $2967 to a savings of $6566. This is a significant reduction compared with the annual per-patient etanercept drug cost of $16,389.

Although the researchers provided a thorough description of the limitations of this evaluation, payers and specialty pharmacies should take note that our understanding of the value of specialty pharmaceuticals should include analyses that go above and beyond

utilization data, cost trends, discounts, and rebates.

Regular health assessment evaluations, work productivity tracking, and quality-of-life questionnaires, among other tools, must be included in reporting on specialty pharmaceuticals.

We have many validated assessment tools and screening tools that can and should be used to demonstrate the added value of specialty pharmaceuticals.

These tools also can be used to develop plans of action if a specialty pharmaceutical is not providing the value expected. Until this is done, we will continue to struggle with a fundamental question regarding the value of specialty pharmaceuticals.

1. Medco Health. 2010 Drug Trend Report: Solving the Healthcare Cost/Quality Equation. 2010;12. https://host1.medcohealth.com/art/drug_trend/pdf/DT_ Report_ 2010.pdf. Accessed June 4, 2010.

2. Express Scripts. 2009 Drug Trend Report: Solving for America’s $163 Billion in Pharmacy-related Waste. April 2010. www.express-scripts.com/research/studies/ drugtrendreport/2009/dtrFinal.pdf. Accessed June 4, 2010.

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI

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GENERIC DRUG TRENDS

Impact of 2 Copay Waivers in a Generic Incentive Program Anthony F. Liu, MSCS; Tom Jecklin; Geoffrey Lee; James Hogan

G

eneric copay incentive programs, which incentivize users of brand-name medications to choose lower-cost generic medications, have gained popularity among pharmacy plan sponsors.

Strategies such as these result in a reduction of overall pharmacy costs and a change in plan member behavior.

The goals of this study were to evaluate the impact of a generic copay incentive program on State Farm plan members and to compare the effect on the generic dispensing rate (GDR) for 1 versus 2 generic copay waivers provided by mail.

As an incentive to improve GDR and reduce membersâ&#x20AC;&#x2122; costs, State Farm offered 2 generic copay waivers to their members who use brand-name medications in 52 therapeutic classes. An ongoing process identified brand-name users to receive communications by mail, advising them of the benefits of choosing generic medications.

Targeted brand-name users were given a 6-month period in which to change to a recommended generic medication and receive up to 2 generic copay waivers.

These waivers for targeted members were proactively installed in the CVS Caremark benefit system to avoid the need for physical coupons, and to make it easier for members to take advantage of the offer.

Targeted brand-name users who converted to a generic medication early in the 6-month period received 2 generic copay waivers. Those who delayed their generic conversion until the end of the 6-month period received 1 generic copay waiver.

The study focused on generic adopters who continued therapy after using the generic copay waiver(s).

Continued therapy was defined as a generic adopter having filled at least 1 prescription after the last generic copay waiver was used. Targeted brand-name users continued to receive communications by mail if they did not choose generic medications.

Mr Liu is Advisor, Mr Lee is Manager, and Mr Hogan is Strategic Account Executive at CVS Caremark, Northbrook, IL; Tom Jecklin is Director, Healthcare and Welfare Benefits, State Farm. This article was presented at the annual meeting of the Academy of Managed Care Pharmacy in April 2010 in San Diego, CA.

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The waiver observation period selected for this study was 18 months after the generic copay incentive program began, plus 4 months of trailing claims, for a total of 22 months. Two measures of GDR were evaluated during the study: â&#x20AC;˘ Postconversion GDR, which examined the prescription filled immediately after the last generic copay waiver was used, and measured the percentage of prescriptions that were generic â&#x20AC;˘ Sustained GDR, which examined the last prescription filled within the specified observation period, and measured the percentage of prescriptions that were generic.

Members who received 1 generic copay waiver comprised 45% of all generic adopters; members who received 2 generic copay waivers comprised the remaining 55%. There were 5140 generic adopters during the specified observation period.

Overall, sustained GDR for members who received 2 copay waivers was 88.2% compared with 71.7% for members who received 1 copay waiver, a significant 16.5% difference (P = .05).

Among the leading 4 therapeutic classes (measured according to the number of generic adopters), sustained GDR for members who received 2 copay waivers was higher than for those who received 1 waiver (Table 1), Table 1 Impact of 2 Waivers in a Generic Copay Program: Top-4 Therapeutic Classes Therapeutic class HMG CoA reductase inhibitors (statins) Antihypertensive combinations Proton pump inhibitors Beta-blockers cardioselective

Postconversion Sustained GDR, % GDR, % 1 Waiver 2 Waivers 1 Waiver 2 Waivers 81.0

95.1

78.1

90.4

63.3

81.3

58.8

77.3

69.5

91.7

67.5

87.3

60.5

95.9

59.5

90.7

GDR indicates generic dispensing rate.

www.AHDBonline.com

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Table 2 Impact of 2 Waivers in a Generic Copay Program: Top-10 Branded Drugs Postconversion GDR, % 1 Waiver 2 Waivers

Targeted brand-name drug Toprol XLa Hyzaara Nexiuma Aciphexa Diovan HCT Prevacid Solutaba Prevacida Lipitora Avalide Crestor

Sustained GDR, % 1 Waiver 2 Waivers

Difference in sustained GDR, %

62.7

95.8

61.5

90.5

29.0

53.0

81.1

51.2

77.3

26.1

66.7

89.2

62.9

84.7

21.8

66.1

88.9

61.3

82.2

20.9

68.3

78.3

63.4

80.4

16.9

77.3

96.5

77.3

93.0

15.8

72.0

92.7

72.8

88.2

15.5

81.0

95.9

77.9

91.1

13.2

72.7

77.6

62.7

71.7

9.0

81.5

87.4

79.1

83.7

4.6

a

Sustained GDR is significantly higher with 2 copay waivers than with 1 copay waiver.

GDR indicates generic dispensing rate.

Figure Difference in Sustained GDR: 1 versus 2 Generic Difference in sustained GDR, %

35

31.3

30 25 19.9

18.6

20 15

12.3

10 5 0

HMG CoA Antihypertensive reductase inhibitors combinations (statins)

Proton pump inhibitors

Beta-blockers cardioselective

Drug class GDR indicates generic dispensing rate.

with a 12.3% difference for statins, 18.6% for antihypertensives, and 31.3% for beta-blockers (Figure).

Among the top-10 targeted brand-name drugs (measured according to the number of generic adopters), the impact of 2 generic copay waivers was consistently greater than the impact of 1 single waiver: sustained GDR for 7 of them was significantly higher with the 2 copay waivers than with the 1 copay waiver (Table 2).

During the study period, generic conversions attributed to the generic copay incentive program led to

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approximately $1.6 million in net plan sponsor savings and approximately $1.7 million in plan member savings.

Generic conversions attributed to the generic copay incentive program led to approximately $1.6 million in net plan sponsor savings and approximately $1.7 million in plan member savings.

Conclusion Among the top-4 therapeutic classes, and for most of the top-10 targeted brand-name medications, generic adopters who received 2 copay waivers by mail were more likely to continue taking generic medications than those who received 1 copay waiver by mail.

A longer observation period would have been ideal to determine if the program had a sustained impact on member behavior.

It is possible that if the program was made available to members at a retail pharmacy, a greater participation rate would have been seen among members. However, State Farm chose not to incentivize the use of a more costly delivery channel.

Further research is needed to identify the reasons why members who initially converted to a generic medication may have converted back to a brand-name medication after the copay waivers were used. â&#x2013;

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We Are Forward Thinking.

Developing the generic pharmaceuticals of tomorrow requires vision because it involves a process that begins years before the first shipment ever leaves the manufacturing facility.

At Mylan Pharmaceuticals, we know this process well, as evidenced by our record of successful product introductions and the breadth of our product portfolio.

At every step in the process, from identifying a long-term source for an active pharmaceutical ingredient, to selecting a formulation that will result in a commercially-viable dosage form, to projecting the supply that will be needed to satisfy market demand, a multi-disciplinary team at Mylan guides the product from concept to reality.

So as you look to the future for the products your patients will need in years to come, look to Mylan.

800.RX.MYLAN â&#x20AC;˘ www.mylanpharms.com

Š2010 Mylan Pharmaceuticals Inc.

MYNMKT362A

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Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, hormone regulation and immunomodulators.

We are dedicated to a strong partnership with the oncology community. Together we can make a dramatic impact on cancer therapeutics over the next decade.

To learn more, visit us at millennium.com. ©2010 Millennium Pharmaceuticals, Inc. All rights reserved.

DDW HIGHLIGHTS

New Approaches to Treating HCV Infection

By Caroline Helwick

A

t the 2010 Digestive Disease Week (DDW), several presentations highlighted new approaches to the treatment of hepatitis C virus (HCV) infection. The burden of HCV is rapidly increasing as those infected with the virus years ago are becoming symptomatic. New treatments may soon offer hope where standard treatments have been failing, but the cost is expected to soar. David R. Nelson, MD, Professor of Medicine, University of Florida, Gainesville, suggested that within a few years we could “cure 60% to 80% of HCV patients with these new treatments.”

Treatment for HCV is only offered to about 20% of patients, and most patients are not diagnosed. The standard of care, with pegylated interferon (PEG-IFN) and ribavirin (PEG RBV), is not effective in the most common HCV—genotype 1: up to 50% of these patients do not respond to treatment.

Genetic studies may help select appropriate patients for standard therapies, thereby avoiding the cost and toxicity of treating patients who would not respond. Recent studies have identified a polymorphism on chromosome 19 that is strongly associated with a sustained viral response (SVR) to the regimen. In the landmark IDEAL (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Peg Interferon Therapy) study of 1137 patients, those with the IL28B genotype had 5 times better odds of treatment success. Genetic testing will likely become a key component of HCV management.

Current regimens are also being optimized by other strategies, including response-guided therapy and maximum dosing of ribavirin. With response-guided therapy, patients who demonstrate a rapid viral response are treated for 24 weeks, then treatment is stopped. In the absence of a rapid response, patients are treated for 48 weeks, and those who completely respond then discontinue treatment. Patients who are partial responders are treated for 72 weeks. Nonresponders virtually never attain an SVR and need other approaches. For slow responders, studies are inconsistent as to whether continued treatment will be beneficial.

Protease Inhibitors for HCV First-generation protease inhibitors (PIs) are expected to offer higher SVR rates for treatment-naïve (7%80%) and treatment-experienced (40%-50%) populations when added to standard PEG RBV. But these dramatic gains will be partially offset by challenges with viral resistance and new adverse effects.

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The PI telaprevir, given along with PEG-IFN and RBV, produced high response rates among patients with previous relapse, viral breakthrough, or partial response to standard treatment, according to final results from a “rollover” study of telaprevir.

Andrew J. Muir, MD, of Duke University, Durham, NC, described this open-label study, in which 117 patients who failed to respond to PEG RBV (or relapsed) in phase 2 telaprevir trials were allowed to cross over to the telaprevir arm. Some 37% of patients who were null responders achieved an SVR, as well as 97% of patients who relapsed after standard therapy. In the control arm (patients who never received telaprevir after standard treatment), SVR rates remained low.

“These are very encouraging results,” said Dr Muir. “We are awaiting phase 3 results, and if they are confirmed, we hope to have this drug available in the near future.”

Telaprevir appears to have the ability to help overcome negative host and viral factors, but drug resistance will eventually emerge. To prevent this, the new drugs will need to be given with PEG RBV. “Ribavirin is critical for protease inhibitor combination therapy. SVR rates are reduced by 25% or more when RBV is not part of treatment regimen,” Dr Muir noted.

Boceprevir is another promising PI and is associated with an SVR rate of 100% at 48 weeks when given after 4 weeks of standard therapy.

Promising New Approaches Other promising agents are nucleoside and nonnucleoside RNA-polymerase inhibitors. Early indications are that the nucleoside polymerase inhibitors may have significant activity, regardless of HCV genotype, and may be associated with less resistance than other agents. Although these drugs may be more effective for HCV, they may still require PEG-IFN and RBV, and resistance may become the “new barrier.”

Starting in 2011, the focus of treatment will be triple therapy—pairing a new PI with PEG RBV—with treatment duration guided by response. By 2014, quadruple therapy that adds a nucleoside or non-nucleoside inhibitor may be the standard. The addition of these agents will likely produce more adverse effects, and costs will likely be significant. Interferon-free regimens, and regimens that combine a PI and a polymerase inhibitor without PEG or RBV, are showing good efficacy and safety. As early as 2015, an interferon-free regimen could be available. ■

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ULORIC powerfully lowers serum uric acid levels for long-term control of gout.

In the largest phase 3 study (6 months): • 45% of patients who received ULORIC 40 mg achieved serum uric acid level <6 mg/dL (N=757) compared to 42% of patients who received allopurinol 300 mg (N=755; p=0.233)1 • 67% of patients who received ULORIC 80 mg achieved serum uric acid level <6 mg/dL (N=756) compared to 42% of patients who received allopurinol 300 mg (N=755; p<0.001)1

Indication ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.

Important Safety Information • ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline.

• An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e. - NSAIDs or colchicine) upon initiation of treatment may be beneficial for up to six months.

• Cardiovascular Events: In randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial

For more information, please visit www.ULORIC.com

infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke.

• Liver Enzyme Elevations: In randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively).

No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter.

• Adverse reactions occurring in at least 1% of ULORICtreated patients, and, at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash.

Individual results may vary based on factors such as baseline serum uric acid levels.

Please see brief summary of complete Prescribing Information on adjacent pages.

Reference: 1. ULORIC® (febuxostat) full prescribing information, February 2009.

ULORIC® is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc. ©2009 Takeda Pharmaceuticals North America, Inc. TXF-00321 08/09

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for ULORIC® (febuxostat) tablets INDICATIONS AND USAGE ULORIC® is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout.

ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.

CONTRAINDICATIONS ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Drug Interactions].

WARNINGS AND PRECAUTIONS Gout Flare After initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels resulting in mobilization of urate from tissue deposits.

In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended.

Cardiovascular Events In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see Adverse Reactions]. A causal relationship with ULORIC has not been established.

Monitor for signs and symptoms of myocardial infarction (MI) and stroke.

Liver Enzyme Elevations During randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for r 6 months. For ULORIC 80 mg, 1377 subjects were treated for r 6 months, 674 patients were treated for r 1 year and 515 patients were treated for r 2 years.

Most Common Adverse Reactions In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were 6 to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo.

Table 1: Adverse Reactions Occurring in r 1% of ULORIC-Treated Patients and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies Placebo

Adverse Reactions Liver Function Abnormalities Nausea Arthralgia Rash

ULORIC

allopurinol*

(N=134)

40 mg daily (N=757)

80 mg daily (N=1279)

(N=1277)

0.7%

6.6%

4.6%

4.2%

0.7%

1.1%

1.3%

0.8%

0%

1.1%

0.7%

0.7%

0.7%

0.5%

1.6%

1.6%

*Of the subjects who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment.

The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of allopurinol-treated subjects.

In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC-treated subjects although not at a rate more than 0.5% greater than placebo.

Less Common Adverse Reactions In phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions.

Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia; Cardiac Disorders: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia; Ear and Labyrinth Disorders: deafness, tinnitus, vertigo; Eye Disorders: vision blurred; Gastrointestinal Disorders: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting; General Disorders and Administration Site Conditions: asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst; Hepatobiliary Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly; Immune System Disorder: hypersensitivity; Infections and Infestations: herpes zoster; Procedural Complications: contusion; Metabolism and Nutrition Disorders: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased; Musculoskeletal and Connective Tissue Disorders: arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia; Nervous System Disorders: altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor; Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change; Renal and Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence; Reproductive System and Breast Changes: breast pain, erectile dysfunction, gynecomastia; Respiratory, Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection; Skin and Subcutaneous Tissue Disorders: alopecia, angio edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria; Vascular Disorders: flushing, hot flush, hypertension, hypotension; Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein.

Cardiovascular Safety Cardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists’ Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (95% CI 0.00-1.08), ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53).

In the long-term extension studies, the incidences of adjudicated APTC events were: ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24).

Overall, a higher rate of APTC events was observed in ULORIC than in allopurinoltreated patients. A causal relationship with ULORIC has not been established.

Monitor for signs and symptoms of MI and stroke.

DRUG INTERACTIONS Xanthine Oxidase Substrate Drugs ULORIC is an XO inhibitor. Drug interaction studies of ULORIC with drugs that are metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity [see Clinical Pharmacology].

ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Contraindications].

Cytotoxic Chemotherapy Drugs Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy.

In Vivo Drug Interaction Studies Based on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used concomitantly with these medications.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. ULORIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg (40 and 51 times the human plasma exposure at 80 mg per day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg per kg (40 times the human plasma exposure at 80 mg per day) during organogenesis and through lactation period.

Nursing Mothers Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULORIC is administered to a nursing woman.

Pediatric Use Safety and effectiveness in pediatric patients under 18 years of age have not been established.

Geriatric Use No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16 percent were 65 and over, while 4 percent were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric subjects (r 65 years) were similar to those in younger subjects (18-40 years).

Renal Impairment No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30-89 mL per min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended.

There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL per min); therefore, caution should be exercised in these patients.

Hepatic Impairment No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients.

Secondary Hyperuricemia No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.

OVERDOSAGE ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies. Patients should be managed by symptomatic and supportive care should there be an overdose.

CLINICAL PHARMACOLOGY Pharmacodynamics Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations, and an increase in 24-hour mean serum xanthine concentrations.

In addition, there was a decrease in the total daily urinary uric acid excretion.

Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40% to 55% at the exposure levels of 40 mg and 80 mg daily doses.

Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. ULORIC in doses up to 300 mg daily, at steady state, did not demonstrate an effect on the QTc interval.

Special Populations Renal Impairment: Following multiple 80 mg doses of ULORIC in healthy subjects with mild (Clcr 50-80 mL per min), moderate (Clcr 30-49 mL per min) or severe renal impairment (Clcr 10-29 mL per min), the Cmax of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL per min).

AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for 3 active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).

No dose adjustment is necessary in patients with mild to moderate renal impairment [see Dosage and Administration and Use in Specific Populations].

The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients [see Use in Specific Populations.

ULORIC has not been studied in end stage renal impairment patients who are on dialysis.

Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20-30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg per kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg per day) and 18.75 mg per kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder.

Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells.

Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day (approximately 35 times the human plasma exposure at 80 mg per day) had no effect on fertility and reproductive performance of male and female rats.

Animal Toxicology A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg per kg (approximately 4 times the human plasma exposure at 80 mg per day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg per kg (approximately 35 times the human plasma exposure at 80 mg per day).

PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in the full prescribing information] General Information Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy.

Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered.

Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520.

ULORICŽ is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners Š2009 Takeda Pharmaceuticals America, Inc. February 2009 For more detailed information, see the full prescribing information for ULORIC (febuxostat) tablets (PI1114 R1; February 2009) or contact Takeda Pharmaceuticals America, Inc. at 1.877.825.3327.

PI1114 R1-Brf; February 2009 L-TXF-0209-3

AMERICAN SOCIETY OF HYPERTENSION HIGHLIGHTS

T

he 2010 annual meeting of the American Society of Hypertension (ASH) presented a wealth of newsworthy studies that serve as a reminder for the ongoing struggle to reduce the number of patients with uncontrolled hypertension. The following highlights are but a small sample of new findings presented at the meeting.

Long-Term VA Study Raises the Bar for BP Control In an 8-year study comprised of 15 veteran affairs (VA) medical centers across the country, the use of automated reminders for providers to control patient blood pressure (BP) resulted in an impressive rate of patients reaching adequate BP control.

At the beginning of the study, only 40% to 50% of the approximately 500,000 VA patients had their BP controlled. After 8 years, >70% of the patients had reached BP control, an “astonishingly good” rate, said

Henry Black, MD, of New York University Center for the Prevention of Cardiovascular Disease, NY, and past president of ASH. These results indicate that BP control can be reached by all hypertensive patients, who are often seen as difficult to treat. Providers and payers may need to consider using such tools to increase the rate of BP control, as a way to reduce as the costs associated with elevated BP and its attendant risks for increased morbidity and mortality.

New ARB Outperforms Older Agents Two phase 3 trials presented at ASH suggest that the new angiotensin receptor blocker (ARB) azilsartan, currently under review by the US Food and Drug Administration (FDA), was more effective at its highest dose (80-mg/day) in lowering BP than 2 other ARBs already on the market—olmesartan (Benica) and valsartan (Diovan). The lower doses of azilsartan, 20-mg/day and 40-mg/day, did not outperform olmesartan and valsartan in lowering BP. In addition, results of a late-breaking, 10-week headto-head trial presented at the meeting showed that a fixed-dose combination of azilsartan and the (thiazidelike) diuretic chlorthalidone led to better BP control than the combination of azilsartan plus the diuretic hydrochlorothiazide (HCTZ).

All patients (N = 600) had moderate-to-severe

hypertension and received 40-mg/day of azilsartan alone for 2 weeks. They were then randomized in weeks 3 to 6 to the fixed-dose combination of azilsartan 40-mg/day plus chlorthalidone 12.5-mg/day (n = 302) or azilsartan 40 mg/day with HCTZ 12.5-mg/day (n = 303). In weeks 7 to 10, both diuretics were titrated to 25 mg/day for those who did not reach BP target with the 12.5-mg dose. The fixed-dose combination significantly lowered BP compared with azilsartan plus HCTZ. George Bakris, MD, of the University of Chicago Pritzker School of Medicine, IL, presented the study, predicting that this drug is going to become very popular if, as expected, it receives FDA approval in the near future. This is the first trial to compare the effects of these 2 diuretics in combination with an ARB.

Phase 4 Study Targets Hispanics with Hypertension Hispanics currently comprise 14% of the US population and are the fastest growing ethnic minority group in the country. According to a study presented at ASH, 20% of adult Hispanics have hypertension, and Hispanics also have higher rates of diabetes and obesity compared with American whites, which are known risk factors for hypertension, heart attacks, stroke, and kidney failure.

In this 8-week, randomized, double-blind, placebo controlled dose-titration trial conducted in several centers in the country, 113 Hispanic women and 164 Hispanic men (aged ≥18 years) with stage I-II hyperten-

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sion received either nebivolol (Bystolic) 5-mg/day (n = 141) or placebo (n =136); the dose was titrated at a 2week interval as needed, to a maximum of 40-mg/day.

At the end of the 8 weeks, mean change from baseline in systolic and diastolic BP was –14.1/–11.1 mm Hg for those taking nebivolol compared with –9.3/–7.3 mm Hg for the placebo group, respectively, representing a significant difference.

Discontinuation rate because of adverse events was 0% for the active drug compared with 4.4% for the placebo. The adverse events profile was similar among the 2 groups.

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GIVE YOUR MEMBERS A SUPERIOR DEFENSE Proven branded migraine pain relief Only RELPAX demonstrated superior headache response at 2 and 24 hours vs sumatriptan 100 mg, as shown in 2 double-blind, placebo-controlled studies1-7 A sustained pain-free response was 64% more likely with RELPAX 40 mg than with sumatriptan 100 mg (Odds ratio: 1.64*; P<.05. Data based on a meta-analysis)2 Significantly more patients treated with RELPAX 40 mg experienced a decrease in the incidence of nausea and phonophobia compared with sumatriptan 100 mg1,3 *Odds ratios for clinical response with RELPAX 40 mg vs sumatriptan 100 mg were determined by a logistic regression calculation of data from a meta-analysis of 3 head-to-head studies. An odds ratio of 1.64 indicates that a patient taking RELPAX 40 mg was 64% more likely to have a sustained pain-free response at 24 hours than if the patient had been treated with sumatriptan 100 mg.

Indication RELPAX is indicated for the acute treatment of migraine with or without aura in adults.

Important Safety Information As with other 5-HT1 agonists, it is recommended that RELPAX not be given to patients with known or suspected coronary artery disease, uncontrolled hypertension, peripheral vascular disease, a history of cerebrovascular accident or transient ischemic attack, severe renal impairment, severe hepatic impairment, or concomitant administration of other 5-HT1 agonists.

The maximum recommended single dose of RELPAX is 40 mg. The maximum daily dose should not exceed 80 mg.

RELPAX is metabolized by the CYP3A4 enzyme; RELPAX does not inhibit or induce CYP3A4. RELPAX should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir.

Potentially life-threatening serotonin syndrome may occur with triptans, particularly during combined use with SSRIs or SNRIs. The most common adverse events reported with RELPAX 40 mg compared with placebo were dizziness (6% vs 3%), somnolence (6% vs 4%), asthenia (5% vs 3%), and nausea (5% vs 5%).

RELPAX is generally well tolerated. Most adverse reactions are mild and transient.

For more information, please visit www.RELPAX.com.

References: 1. Mathew NT, Schoenen J, Winner P, Muirhead N, Sikes CR. Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg. Headache. 2003;43:214-222. 2. Diener H-C, Ryan R, Sun W, Hettiarachchi J. The 40-mg dose of eletriptan: comparative efficacy and tolerability versus sumatriptan 100 mg. Eur J Neurol. 2004;11:125-134. 3. Sandrini G, F채rkkil채 M, Burgess G, Forster E, Haughie S, for the Eletriptan Steering Committee. Eletriptan vs sumatriptan: a double-blind, placebo-controlled, multiple migraine attack study. Neurology.

2002;59:1210-1217. 4. Visser WH, Terwindt GM, Reines SA, Jiang K, Lines CR, Ferrari MD, for the Dutch/US Rizatriptan Study Group. Rizatriptan vs sumatriptan in the acute treatment of migraine: a placebo-controlled, dose-ranging study. Arch Neurol. 1996;53:1132-1137.

5. Tfelt-Hansen P, Teall J, Rodriguez F, et al, on behalf of the Rizatriptan 030 Study Group.

Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Headache. 1998;38:748-755. 6. Geraud G, Olesen J, Pfaffenrath V, et al, on behalf of the Study Group. Comparison of the efficacy of zolmitriptan and sumatriptan: issues in migraine trial design. Cephalalgia. 2000;20:30-38. 7. Cabarrocas X, Zayas JM, Suris M, for and on behalf of the Almotriptan Comparative Study Group. Equivalent efficacy of oral almotriptan, a new 5-HT1B/1D agonist, compared with sumatriptan 100 mg. Headache. 1998;38:377-378.

Please see brief summary of Prescribing Information on reverse side.

RELPAX® (eletriptan hydrobromide) Tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE: RELPAX is indicated for the acute treatment of migraine with or without aura in adults. RELPAX is not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and effectiveness of RELPAX Tablets have not been established for cluster headache, which is present in an older, predominantly male population.

CONTRAINDICATIONS: RELPAX Tablets should not be given to patients with ischemic heart disease (e.g., angina pectoris, history of myocardial infarction, or documented silent ischemia) or to patients who have symptoms, or findings consistent with ischemic heart disease, coronary artery vasospasm, including Prinzmetal’s variant angina, or other significant underlying cardiovascular disease (see WARNINGS). RELPAX Tablets should not be given to patients with cerebrovascular syndromes including (but not limited to) strokes of any type as well as transient ischemic attacks (see WARNINGS). RELPAX Tablets should not be given to patients with peripheral vascular disease including (but not limited to) ischemic bowel disease (see WARNINGS).

Because RELPAX Tablets may increase blood pressure, it should not be given to patients with uncontrolled hypertension (see WARNINGS). RELPAX Tablets should not be administered to patients with hemiplegic or basilar migraine. RELPAX Tablets should not be used within 24 hours of treatment with another 5-HT1 agonist, an ergotamine-containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide. RELPAX Tablets should not be used in patients with known hypersensitivity to eletriptan or any of its inactive ingredients. RELPAX Tablets should not be given to patients with severe hepatic impairment.

WARNINGS: RELPAX Tablets should only be used where a clear diagnosis of migraine has been established. CYP3A4 Inhibitors: Eletriptan should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir. Eletriptan should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition and have this potent effect described in the CONTRAINDICATIONS, WARNINGS or PRECAUTIONS sections of their labeling (see CLINICAL PHARMACOLOGY: Drug Interactions and DOSAGE AND ADMINISTRATION). In a coronary angiographic study of rapidly infused intravenous eletriptan to concentrations exceeding those achieved with 80 mg oral eletriptan in the presence of potent CYP3A4 inhibitors, a small dose-related decrease in coronary artery diameter similar to that seen with a 6 mg subcutaneous dose of sumatriptan was observed. Risk of Myocardial Ischemia and/or Infarction and Other Cardiac Events: Because of the potential of 5-HT1 agonists to cause coronary vasospasm, eletriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS).

It is strongly recommended that eletriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, or male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history, electrocardiographic, or other investigations reveal findings indicative of, or consistent with coronary artery vasospasm or myocardial ischemia, eletriptan should not be administered (see CONTRAINDICATIONS). For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of eletriptan take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received eletriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following administration of RELPAX Tablets, in these patients with risk factors. It is recommended that patients who are intermittent long-term users of 5-HT1 agonists including RELPAX Tablets, and who have or acquire risk factors predictive of CAD, as described above, undergo periodic cardiovascular evaluation as they continue to use RELPAX Tablets.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to eletriptan. Cardiac Events and Fatalities: Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of 5-HT1 agonists including RELPAX. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low. Premarketing experience with eletriptan among the 7,143 unique individuals who received eletriptan during pre-marketing clinical trials: In a clinical pharmacology study, in subjects undergoing diagnostic coronary angiography, a subject with a history of angina, hypertension and hypercholesterolemia, receiving intravenous eletriptan (Cmax of 127 ng/mL equivalent to 60 mg oral eletriptan), reported chest tightness and experienced angiographically documented coronary vasospasm with no ECG changes of ischemia. There was also one report of atrial fibrillation in a patient with a past history of atrial fibrillation. Postmarketing experience with eletriptan: Serious cardiovascular events, some resulting in death, have been reported in association with the use of RELPAX. In very rare cases, these events have occurred in the absence of known cardiovascular diseases. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively if the cases were actually caused by eletriptan or to reliably assess causation in individual cases. Cerebrovascular Events and Fatalities Associated With 5-HT1 Agonists: Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, and transient ischemic attack). Other Vasospasm-Related Events: 5-HT1 agonists may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported with 5-HT1 agonists. Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome may occur with triptans, including RELPAX treatment, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with RELPAX and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). (See PRECAUTIONS—DRUG INTERACTIONS). Increase in Blood Pressure: Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasion in patients receiving 5-HT1 agonists with and without a history of hypertension. In clinical pharmacology studies, oral eletriptan (at doses of 60 mg or more) was shown to cause small, transient dose-related increases in blood pressure, predominantly diastolic, consistent with its mechanism of action and with other 5-HT1B/1D agonists. The effect was more pronounced in renally impaired and elderly subjects. A single patient with hepatic cirrhosis received eletriptan 80 mg and experienced a blood pressure of 220/96 mm Hg five hours after dosing. The treatment related event persisted for seven hours. Eletriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS). An 18% increase in mean pulmonary artery pressure was seen following dosing with another 5-HT1 agonist in a study evaluating subjects undergoing cardiac catheterization.

PRECAUTIONS: General: As with other 5-HT1 agonists, sensations of tightness, pain, pressure and heaviness have been reported after treatment with eletriptan in the precordium, throat, and jaw. Events that are localized to the chest, throat, neck and jaw have not been associated with arrhythmias or ischemic ECG changes in clinical trials; in a clinical pharmacology study of subjects undergoing diagnostic coronary angiography, one subject with a history of angina, hypertension and hypercholesterolemia, receiving intravenous eletriptan, reported chest tightness and experienced angiographically documented coronary vasospasm with no ECG changes of ischemia. Because 5-HT1 agonists may cause coronary artery vasospasm, patients who experience signs or symptoms suggestive of angina following dosing should be evaluated for the presence of CAD or a predisposition to Prinzmetal’s variant angina before receiving additional doses of medication, and should be monitored electrocardiographically if dosing is resumed and similar symptoms recur. Similarly, patients who experience other symptoms or signs suggestive of decreased arterial flow, such as ischemic bowel syndrome or Raynaud’s syndrome following the use of any 5-HT1 agonist are candidates for further evaluation (see CONTRAINDICATIONS and WARNINGS).

Hepatically Impaired Patients: The effects of severe hepatic impairment on eletriptan metabolism was not evaluated. Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The Cmax was increased by 18%. Eletriptan should not be used in patients with severe hepatic impairment. No dose adjustment is necessary in mild to moderate impairment (see DOSAGE AND ADMINISTRATION).

Binding to Melanin-Containing Tissues: In rats treated with a single intravenous (3 mg/kg) dose of radiolabeled eletriptan, elimination of radioactivity from the retina was prolonged, suggesting that eletriptan and/or its metabolites may bind to the melanin of the eye. Because there could be accumulation in melanin-rich tissues over time, this raises the possibility that eletriptan could cause toxicity in these tissues after extended use.

Although no systematic monitoring of ophthalmologic function was undertaken in clinical trials, and no specific recommendations for ophthalmologic monitoring are offered, prescribers should be aware of the possibility of long-term ophthalmologic effects. Corneal Opacities: Transient corneal opacities were seen in dogs receiving oral eletriptan at 5 mg/kg and above. They were observed during the first week of treatment, but were not present thereafter despite continued treatment. Exposure at the no-effect dose level of 2.5 mg/kg was approximately equal to that achieved in humans at the maximum recommended daily dose. Information for Patients: Patients should be cautioned about the risk of serotonin syndrome with the use of RELPAX or other triptans, especially during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). Laboratory Tests: No specific laboratory tests are recommended. Drug Interactions: Ergot-containing drugs: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine [DHE] or methysergide) and eletriptan within 24 hours of each other is not recommended (see CONTRAINDICATIONS).

CYP3A4 Inhibitors: Eletriptan is metabolized primarily by CYP3A4 (see WARNINGS regarding use with potent CYP3A4 inhibitors). Monoamine Oxidase Inhibitors: Eletriptan is not a substrate for monoamine oxidase (MAO) enzymes, therefore there is no expectation of an interaction between eletriptan and MAO inhibitors. Propranolol: The Cmax and AUC of eletriptan were increased by 10 and 33% respectively in the presence of propranolol. No interactive increases in blood pressure were observed. No dosage adjustment appears to be needed for patients taking propranolol (see CLINICAL PHARMACOLOGY).

Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans (See WARNINGS). Other 5-HT1 agonists: Concomitant use of other 5-HT1 agonists within 24 hours of RELPAX treatment is not recommended (see CONTRAINDICATIONS). Drug/Laboratory Test Interactions: RELPAX Tablets are not known to interfere with commonly employed clinical laboratory tests. Carcinogenesis: Lifetime carcinogenicity studies, 104 weeks in duration, were carried out in mice and rats by administering eletriptan in the diet. In rats, the incidence of testicular interstitial cell adenomas was increased at the high dose of 75 mg/kg/day. The estimated exposure (AUC) to parent drug at that dose was approximately 6 times that achieved in humans receiving the maximum recommended daily dose (MRDD) of 80 mg, and at the no-effect dose of 15 mg/kg/day it was approximately 2 times the human exposure at the MRDD. In mice, the incidence of hepatocellular adenomas was increased at the high dose of 400 mg/kg/day. The exposure to parent drug (AUC) at that dose was approximately 18 times that achieved in humans receiving the MRDD, and the AUC at the no-effect dose of 90 mg/kg/day was approximately 7 times the human exposure at the MRDD. Mutagenesis: Eletriptan was not mutagenic in bacterial or mammalian cell assays in vitro, testing negative in the Ames reverse mutation test and the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) mutation test in Chinese hamster ovary cells. It was not clastogenic in two in vivo mouse micronucleus assays. Results were equivocal in in vitro human lymphocyte clastogenicity tests, in which the incidence of polyploidy was increased in the absence of metabolic activation (-S9 conditions), but not in the presence of metabolic activation. Impairment of Fertility: In a rat fertility and early embryonic development study, doses tested were 50, 100 and 200 mg/kg/day, resulting in systemic exposures to parent drug in rats, based on AUC, that were 4, 8 and 16 times MRDD, respectively, in males and 7, 14 and 28 times MRDD, respectively, in females. There was a prolongation of the estrous cycle at the 200 mg/kg/day dose due to an increase in duration of estrus, based on vaginal smears. There were also dose-related, statistically significant decreases in mean numbers of corpora lutea per dam at all 3 doses, resulting in decreases in mean numbers of implants and viable fetuses per dam. This suggests a partial inhibition of ovulation by eletriptan. There was no effect on fertility of males and no other effect on

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fertility of females. Pregnancy: Pregnancy Category C: In reproductive toxicity studies in rats and rabbits, oral administration of eletriptan was associated with developmental toxicity (decreased fetal and pup weights and an increased incidence of fetal structural abnormalities). Effects on fetal and pup weights were observed at doses that were, on a mg/m2 basis, 6 to 12 times greater than the clinical maximum recommended daily dose (MRDD) of 80 mg. The increase in structural alterations occurred in the rat and rabbit at doses that, on a mg/m2 basis, were 12 times greater than (rat) and approximately equal to (rabbit) the MRDD. When pregnant rats were administered eletriptan during the period of organogenesis at doses of 10, 30 or 100 mg/kg/day, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the MRDD on a mg/m2 basis). The 100 mg/kg dose was also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for developmental toxicity in rats exposed during organogenesis was 30 mg/kg, which is approximately 4 times the MRDD on a mg/m2 basis. When doses of 5, 10 or 50 mg/kg/day were given to New Zealand White rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg, which is approximately 12 times the MRDD on a mg/m2 basis. The incidences of fused sternebrae and vena cava deviations were increased in all treated groups. Maternal toxicity was not produced at any dose. A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established, and the 5 mg/kg dose is approximately equal to the MRDD on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women; therefore, eletriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: Eletriptan is excreted in human breast milk. In one study of 8 women given a single dose of 80 mg, the mean total amount of eletriptan in breast milk over 24 hours in this group was approximately 0.02% of the administered dose. The ratio of eletriptan mean concentration in breast milk to plasma was 1:4, but there was great variability. The resulting eletriptan concentration-time profile was similar to that seen in the plasma over 24 hours, with very low concentrations of drug (mean 1.7 ng/mL) still present in the milk 18-24 hours post dose. The N-desmethyl active metabolite was not measured in the breast milk. Caution should be exercised when RELPAX is administered to nursing women. Pediatric Use: Safety and effectiveness of RELPAX Tablets in pediatric patients have not been established; therefore, RELPAX is not recommended for use in patients under 18 years of age. The efficacy of RELPAX Tablets (40 mg) in patients 11-17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs (see CLINICAL STUDIES). Adverse events observed were similar in nature to those reported in clinical trials in adults. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse events that are similar in nature to those reported rarely in adults. Long-term safety of eletriptan was studied in 76 adolescent patients who received treatment for up to one year. A similar profile of adverse events to that of adults was observed. The long-term safety of eletriptan in pediatric patients has not been established. Geriatric Use: Eletriptan has been given to only 50 patients over the age of 65. Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults (see CLINICAL PHARMACOLOGY). In clinical trials, there were no apparent differences in efficacy or the incidence of adverse events between patients under 65 years of age and those 65 and above (n=50). There is a statistically significantly increased half-life (from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age) and younger adult subjects (18 to 45 years of age) (see CLINICAL PHARMACOLOGY).

ADVERSE REACTIONS: Serious cardiac events, including some that have been fatal, have occurred following the use of 5-HT1 agonists including RELPAX. These events are extremely rare and most have been reported in patients with risk factors predictive of CAD. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS). Incidence in Controlled Clinical Trials: Among 4,597 patients who treated the first migraine headache with RELPAX in short-term placebo-controlled trials, the most common adverse events reported with treatment with RELPAX were asthenia, nausea, dizziness, and somnolence. These events appear to be dose related. In long-term open-label studies where patients were allowed to treat multiple migraine attacks for up to 1 year, 128 (8.3%) out of 1,544 patients discontinued treatment due to adverse events. Table 1 lists adverse events that occurred in the subset of 5,125 migraineurs who received eletriptan doses of 20 mg, 40 mg and 80 mg or placebo in worldwide placebo-controlled clinical trials. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, those frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Only adverse events that were more frequent in a RELPAX treatment group compared to the placebo group with an incidence greater than or equal to 2% are included in Table 1.

Table 1: Adverse Experience Incidence in Placebo-Controlled Migraine Clinical Trials: Events Reported by ≥ 2% Patients Treated with RELPAX and More Than Placebo Placebo Adverse Event Type (n=988) ATYPICAL SENSATIONS Paresthesia 2% Flushing/feeling of warmth 2% PAIN AND PRESSURE SENSATIONS Chest – tightness/pain/pressure 1% Abdominal – pain/discomfort/stomach pain/cramps/pressure 1% DIGESTIVE Dry mouth 2% Dyspepsia 1% Dysphagia – throat tightness/difficulty swallowing 0.2% Nausea 5% NEUROLOGICAL Dizziness 3% Somnolence 4% Headache 3% OTHER Asthenia 3%

RELPAX 20 mg (n=431)

RELPAX 40 mg (n=1774)

RELPAX 80 mg (n=1932)

3% 2%

3% 2%

4% 2%

1%

2%

4%

1%

2%

2%

2% 1%

3% 2%

4% 2%

1% 4%

2% 5%

2% 8%

3% 3% 4%

6% 6% 3%

7% 7% 4%

4%

5%

10%

RELPAX is generally well-tolerated. Across all doses, most adverse reactions were mild and transient. The frequency of adverse events in clinical trials did not increase when up to 2 doses of RELPAX were taken within 24 hours. The incidence of adverse events in controlled clinical trials was not affected by gender, age, or race of the patients. Adverse event frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (e.g., SSRIs, beta blockers, calcium channel blockers, tricyclic antidepressants), estrogen replacement therapy and oral contraceptives. Other Events Observed in Association With the Administration of RELPAX Tablets: In the paragraphs that follow, the frequencies of less commonly reported adverse clinical events are presented. Because the reports include events observed in open studies, the role of RELPAX Tablets in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, etc., limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N=4,719) exposed to RELPAX. All reported events are included except those already listed in Table 1, those too general to be informative, and those not reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: 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 and rare adverse events are those occurring in fewer than 1/1000 patients. General: Frequent were back pain, chills and pain. Infrequent were face edema and malaise. Rare were abdomen enlarged, abscess, accidental injury, allergic reaction, fever, flu syndrome, halitosis, hernia, hypothermia, lab test abnormal, moniliasis, rheumatoid arthritis and shock. Cardiovascular: Frequent was palpitation. Infrequent were hypertension, migraine, peripheral vascular disorder and tachycardia. Rare were angina pectoris, arrhythmia, atrial fibrillation, AV block, bradycardia, hypotension, syncope, thrombophlebitis, cerebrovascular disorder, vasospasm and ventricular arrhythmia. Digestive: Infrequent were anorexia, constipation, diarrhea, eructation, esophagitis, flatulence, gastritis, gastrointestinal disorder, glossitis, increased salivation and liver function tests abnormal. Rare were gingivitis, hematemesis, increased appetite, rectal disorder, stomatitis, tongue disorder, tongue edema and tooth disorder. Endocrine: Rare were goiter, thyroid adenoma and thyroiditis.

Hemic and Lymphatic: Rare were anemia, cyanosis, leukopenia, lymphadenopathy, monocytosis and purpura. Metabolic: Infrequent were creatine phosphokinase increased, edema, peripheral edema and thirst. Rare were alkaline phosphatase increased, bilirubinemia, hyperglycemia, weight gain and weight loss. Musculoskeletal: Infrequent were arthralgia, arthritis, arthrosis, bone pain, myalgia and myasthenia. Rare were bone neoplasm, joint disorder, myopathy and tenosynovitis. Neurological: Frequent were hypertonia, hypesthesia and vertigo. Infrequent were abnormal dreams, agitation, anxiety, apathy, ataxia, confusion, depersonalization, depression, emotional lability, euphoria, hyperesthesia, hyperkinesia, incoordination, insomnia, nervousness, speech disorder, stupor, thinking abnormal and tremor. Rare were abnormal gait, amnesia, aphasia, catatonic reaction, dementia, diplopia, dystonia, hallucinations, hemiplegia, hyperalgesia, hypokinesia, hysteria, manic reaction, neuropathy, neurosis, oculogyric crisis, paralysis, psychotic depression, sleep disorder and twitching. Respiratory: Frequent was pharyngitis. Infrequent were asthma, dyspnea, respiratory disorder, respiratory tract infection, rhinitis, voice alteration and yawn. Rare were bronchitis, choking sensation, cough increased, epistaxis, hiccup, hyperventilation, laryngitis, sinusitis and sputum increased. Skin and Appendages: Frequent was sweating. Infrequent were pruritus, rash and skin disorder. Rare were alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, psoriasis, skin discoloration, skin hypertrophy and urticaria. Special Senses: Infrequent was abnormal vision, conjunctivitis, ear pain, eye pain, lacrimation disorder, photophobia, taste perversion and tinnitus. Rare were abnormality of accommodation, dry eyes, ear disorder, eye hemorrhage, otitis media, parosmia and ptosis. Urogenital: Infrequent were impotence, polyuria, urinary frequency and urinary tract disorder. Rare were breast pain, kidney pain, leukorrhea, menorrhagia, menstrual disorder and vaginitis. Other Events Observed During Post-Marketing Use: The following adverse reaction(s) have been identified during postapproval use of RELPAX. 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. Neurological: seizure. Digestive: vomiting. DRUG ABUSE AND DEPENDENCE: Although the abuse potential of RELPAX has not been assessed, no abuse of, tolerance to, withdrawal from, or drug-seeking behavior was observed in patients who received RELPAX in clinical trials or their extensions. The 5-HT1B/1D agonists, as a class, have not been associated with drug abuse. OVERDOSAGE: No significant overdoses in premarketing clinical trials have been reported. Volunteers (N=21) have received single doses of 120 mg without significant adverse effects. Daily doses of 160 mg were commonly employed in Phase III trials. Based on the pharmacology of the 5-HT1B/1D agonists, hypertension or other more serious cardiovascular symptoms could occur on overdose. The elimination half-life of eletriptan is about 4 hours (see CLINICAL PHARMACOLOGY) and therefore monitoring of patients after overdose with eletriptan should continue for at least 20 hours, or longer should symptoms or signs persist. There is no specific antidote to eletriptan. In cases of severe intoxication, intensive care procedures are recommended, including establishing and maintaining a patent airway, ensuring adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentration of eletriptan.

All rights reserved.

Printed in USA/June 2010

AMCP HIGHLIGHTS

Medication Adherence: Effectiveness of Physician Alerts to Resolve Potential Gaps in Pharmacotherapy Joshua N. Liberman, PhD; Janice Moore, MPH; Asif Ally, RPh, MBA; Troyen A. Brennan, JD, MD

This study was presented at the 22nd Annual Meeting of the Academy of Managed Care Pharmacy, April 2010, San Diego, CA. Joshua N. Liberman

P

oor medication adherence is frequently the cause of preventable hospitalizations and patient illness.

Costs to the US healthcare system resulting from nonadherence have been estimated to exceed a staggering $100 billion annually.1 Inpatient clinical decision support systems provide physicians with real-time information to improve clinical practice.2 Typically, outpatient practices do not have access to real-time feedback and patient information. This fact, coupled with the fractured healthcare system, leads to incomplete information and has created an opportunity for pharmacy benefit managers (PBMs) to provide clinically valid feedback to assist physician decision-making.

In a recent commentary, Shrank and colleagues stated that PBMs have “a unique opportunity to promote health and generate value in the healthcare system.”3 To realize this value, CVS Caremark supports numerous outreach efforts to improve adherence to essential therapies. Consensus clinical guidelines recommend standards of pharmacotherapy care for different conditions. PBMs can operationalize these guidelines and identify patients who may benefit from treatment additions.

This present study evaluated changes in care after a fax-based messaging intervention delivered to physicians with a recommendation to add: 1. An osteoporosis-preventive agent for women with long-term glucocorticosteroid use4 2. An angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for adults with diabetes

Dr Liberman is Vice President, Strategic Research, and Mr Ally is Vice President, CVS Caremark, Hunt Valley, MD; Ms Moore is Research Advisor, Strategic Research, CVS Caremark, Northbrook, IL; and Dr Brennan is Executive Vice President and Chief Medical Officer, CVS Caremark, Woonsocket, RI.

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3. A lipid-lowering agent for individuals with diabetes aged ≥30 years.5 A total of 337 employers and health plans representing 5,508,559 individuals, participated in a program that delivered a fax alert to a provider when pharmacy claims indicated the absence of a recommended therapy. From January 1, 2009, to March 30, 2009, a total of 78,768 alerts were sent to providers regarding osteoporosis (n = 1763), ACE/ARB (n = 22,915), and dyslipidemia (n = 54,090).

Consensus clinical guidelines recommend standards of pharmacotherapy care for different conditions. PBMs can operationalize these guidelines and identify patients who may benefit from treatment additions.

Through September 30, 2009, therapy addition rates (“gap closure rate”) occurring within 90 days of the intervention were compared with a control group selected from employers and health plans that did not implement the program.

Adjusted odds ratios were derived by logistic regression, with adjustment for age, sex, previous medication use, and out-of-pocket participant cost-sharing.

Analysis showed that gap closure rates were higher for cases than for the controls: • 23.5% versus 15.1% for osteoporosis (Figure 1) • 13.2% versus 7.7% for ACE/ARB (Figure 2) • 13.6% versus 9.1% for dyslipidemia (Figure 3).

The odds ratios for the addition of therapy by day 90 were significant (P <.001) for each intervention— osteoporosis (1.62), ACE/ARB (1.88), and dyslipidemia (1.46).

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Figure 1 Osteoporosis Preventive Therapy among Glucocorticosteroid Users Figure 2 ACE/ARB Gap Closure Rate among Patients with Diabetes

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ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

Conclusion Fax alerts to providers were an effective mechanism for communicating potential gaps in pharmacotherapy and enhance medication adherence. In 3 months, these 3 fax alerts resulted in a total of 3842 individuals implementing pharmacotherapy in accordance with evidence-based medicine. Future research should focus on the subsequent adherence and the medical value of additive therapy. ■

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References

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Older age and higher risk scores (Pharmacy Risk Group score) were significant predictors of adding the concomitant therapy, whereas member cost-sharing was not significant.

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1. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353: 487-497.

2. Kawamato K, Houlihan CA, Balas A, Lobach DF. Improving clinical practice using clinical decision support systems: a systematic review of trials to identify features critical to success. BMJ. 2005;330:765. Epub 2005 Mar 14.

3. Shrank WH, Porter ME, Jain SH, Choudhry NK. A blueprint for pharmacy benefit managers to increase value. Am J Manag Care. 2009;15:87-93.

4. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum.2001;44: 1496-1503.

5. American Diabetes Association. Standards of medical care in diabetes care— 2009. Diabetes Care. 2009;32(suppl 1):S13-S61.

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AMCP HIGHLIGHTS

A

host of new studies with implications for payers and other healthcare stakeholders were presented at the 2010 Annual Meeting of the Academy of Managed Care Pharmacy (AMCP) in April in San Diego, CA. The following summaries highlight some of the major trends presented at the meeting.

(See also pages 201-202 and 213-214.)

Patient Out-of-Pocket Cost Affects Adherence to Oral Oncology Medications Increasing out-of-pocket (OOP) cost to health plan members above a certain threshold reduces adherence to cancer medications, suggested researchers from Prime Therapeutics, Eagan, MN. Pat Gleason, PharmD, Director of Clinical Outcomes Assessment at Prime Therapeutics, and colleagues analyzed data from a database of 7 million Blue Cross and Blue Shield members in the Midwest and South who were prescribed oral drugs for cancer for the first time between July 2006 and June 2008.

Based on their OOP cost, patients were divided into 4 groups—$0 to $100, $101 to $200, $201 to $500, and >$500. Patients with OOP cost >$200 were 3 times more likely than those with lower OOP cost to stop their drug therapy.

During the study period, of the 1909 members who started therapy with oral oncology medications, 163 (8.5%) stopped taking their drugs. Although 1562 (81.8%) of those patients had an OOP cost of $0 to $100, the next largest group (14%) had a cost-sharing (OOP) >$500. Those with an OOP cost between $201 and >$500 were 3 times more likely to stop their therapy than patients in the lower 2 groups. “The $200-plus group is where things start to change,” said Dr Gleason.

The therapy discontinuation rate was 16.1% for those in the $201 to $500 OOP group and 28.8% for the >$500 OOP group.

Age and sex were not associated with the level of medication adherence.

Cost-Effectiveness Trends for 20 Top-Selling Drugs With increasing healthcare costs and budgetary pressures, payers are focusing on superior efficacy and costeffectiveness as determinants for medication coverage.

The new emphasis on comparative effectiveness research (CER) and the growing focus on cost-effectiveness research in the past 10 and 15 years are further indications that performance and pricing will increasingly determine drug utilization and reimbursement. A team of researchers from PAREXEL Consulting, Waltham, MA, led by Saurabh Agarwal, PhD, investigated the current trends of cost-effectiveness studies for the 20 top-selling drugs worldwide—which collectively generated between $150 billion and $160 billion in worldwide sales in 2008—to see whether these studies can indeed offer the information payers are seeking in their coverage decisions.

The study results showed that despite the growing focus on CER and cost-effectiveness studies, those conducting the research use various methodologies and models that do not coincide, which may impede reaching the conclusions necessary for true comparative

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research. The team analyzed peer-reviewed cost-effectiveness studies published between 1999 and 2008, collecting data on the comparator drugs used in each study, the indication, the incremental cost-effectiveness ratio (ICER), length of study, and the model used, in addition to other study characteristics.

The researchers found a large variability in methodology used by the different groups in modeling costeffectiveness related to the same drugs, especially in terms of study duration and a comparator drug, for different indications, as well as for the same indications.

Different groups selected different comparator drugs, applied different treatment costs in their assessments, and used different time projections for costs, all of which made outcome comparisons difficult.

Primary care drugs had less variability than specialty drugs. Among the 10 top-selling drugs, quetiapine and erythropoietin had the highest variability in study methodologies and ICER. In contrast, atorvastatin, salmeterol/fluticasone, and clopidogrel had the most consistent ICER values across the studies.

Continued

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Effect of Diabetes Medication Adherence on Costs and Outcomes Diabetes is among the key drivers of healthcare costs in the United States, and the prevalence of the disease continues to rise. A team of researchers from Blue Cross and Blue Shield of Nebraska and the University of Nebraska Medical Center investigated the impact of medication adherence and following clinical guidelines on the cost of type 2 diabetes, visits to emergency departments, and hospitalizations.

Using pharmacy and medical claims data, 5573 adult members with type 2 diabetes who were continuously enrolled in a Midwestern managed care health plan from January 1, 2008, to December 31, 2009, were enrolled in this study. A total of 4480 members met the criteria for medical guidelines (screening for hemoglo-

bin [Hb] A1c, lipid panel, cholesterol, and hypertension) in 2008, and 4683 members met the criteria in 2009. Medication adherence was measured by medication possession ratio.

Increased medication adherence resulted in a significant trend toward reduced total, professional, and facility costs for all drug classes—except for statins and sulfonylureas—even though pharmacy costs increased.

Adherence to HbA1c testing reduced emergency department visits during the study period. Inpatient admission trended down from 2008 to 2009 with adherence to cholesterol and lipid testing. In 2009, patients adherent with all of these types of testing had significantly lower costs than nonadherent patients.

Applying Pharmacogenomics in Oncology Care Pharmacogenomics is the study of genetic influences on variations in patients’ response to drug therapy (a variation of personalized medicine). To date, no studies have looked at the application of pharmacogenomics in oncology drug utilization. Researchers from CVS

These findings suggest that payers can use UM practices to ensure appropriateness of therapy, such as requesting copies of pharmacogenomic test results and standardizing test requirements.

Caremark, Northbrook, IL, presented data on the frequency and utilization of pharmacogenomics to determine the appropriateness of oncology treatment within a utilization management (UM) program.

Using pharmacogenomic testing data from July 1, 2009, through December 31, 2009, a total of 801 patients who had such data were categorized into 3 groups, based on UM criteria developed using US Food and Drug Administration–approved and compendia-

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based indications for cancer therapies: • Pharmacogenomic testing performed and patient met UM criteria • Pharmacogenomic testing performed and patient did not meet UM criteria • Pharmacogenomic testing not performed and patient did not meet UM criteria.

Of these 801 patients, 424 patients required pharmacogenomic testing, and 417 (98%) of them underwent testing. Lead researcher Sherry Siegert, PharmD, noted that having such a high percentage of patients receiving testing when needed “may indicate that most oncologists are prescribing in accordance with currently accepted guidelines.”

Despite the small study sample and short duration, these findings suggest that payers can use UM practices to ensure appropriateness of therapy, such as requesting copies of pharmacogenomic test results and standardizing test requirements.

Applying pharmacogenomics is particularly important in cancer care, considering the cost of therapy and the serious implications of inappropriate therapy for this patient population.

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DRUG PIPELINE

Promising New Approaches to Multiple Sclerosis Medications: AAN 2010

By Alice Goodman

A

t the 2010 annual meeting of the American Academy of Neurology (AAN), the largest explosion of new agents in development was for multiple sclerosis (MS), the second most common neurologic disability in young and middle-aged adults.

Oral fingolimod (Galenia), currently under FDA review, is a first-in-class oral agent that represents a new approach to the treatment of MS; it is a sphingosine 1-phosphate receptor (S1P-R) modulator that binds to the S1P-R on circulating lymphocytes, sequestering them in lymph nodes away from the central nervous system. Preliminary evidence suggests that this drug can reduce inflammation and nerve damage, and promote repair of damaged nerve cells.

Two different analyses of data from the large, 2-year, randomized, placebo-controlled, multicenter phase 3 FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) study showed that oral fingolimid was clinically effective and improved magnetic resonance imaging (MRI) scans of patients with relapsing-remitting MS (RRMS).

FREEDOMS enrolled 1272 patients in 22 countries.

Patients were randomized to a low dose of fingolimod (0.5 mg/day), a higher dose of fingolimod (1.25 mg/day), or to placebo and were treated for 2 years. After that, patients could continue on the lower dose of fingolimod for an extension study. Compared with placebo, oral fingolimod significantly reduced annualized relapse rates and slowed progression of disability. In addition, MRI scans of the brain showed evidence of less brain tissue loss and fewer MS-enhancing lesions in the fingolimod group compared with the placebo group.

Because both doses reduced the annualized relapse rate by >50% compared with placebo and prevented disability progression, the manufacturer will seek approval for the lower dose.

Cladribine (Leustatin), the second oral agent in development with a new approach to MS, was effective across a range of clinically important subgroups of patients with RRMS, based on the double-blind, 96week CLARITY (Cladribine Tablets MS Orally) trial.

Reductions in annualized relapse rates of >54% were achieved with 3.5 mg/kg and 5.25 mg/kg of the drug.

An injectable formulation of cladribine is already approved for the treatment of leukemia. The drug is given in short courses over each cycle for a total of 8 to

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10 days annually and results in targeted and sustained immunomodulation. Consistent reductions in MS relapse rates were seen in men and women and with no regard to the use of disease-modifying drugs.

Alemtuzumab (Campath), an investigational MS drug, was superior to standard treatment of RRMS with interferon beta-1a (Rebif), according to 4-year results of the phase 2 CAMMS223 study. Patients taking alemtuzumab were free from clinically active MS twice as often as patients taking interferon beta-1a (71% vs 35%, respectively).

“These data may set a new bar for clinical outcomes in MS,” said lead investigator Omar Khan, MD, Professor of Neurology, Wayne State University School of Medicine, Detroit, MI. Alemtuzumab is a humanized monoclonal antibody approved for use in B-cell chronic lymphocytic leukemia. The drug binds to the CD52 protein on cell surfaces and directs the immune system to destroy those cells. The drug has a safety warning regarding cytopenias, infusion reactions, and infections.

Adverse events reported include infusion-related reactions in patients who received alemtuzumab and flulike symptoms in patients treated with standard therapy.

Infections were more common in the alemtuzumab-treated group, particularly upper respiratory tract infections, but these were mainly mild to moderate in severity.

T-Cell Immunotherapy (Tovaxin) is an individualized autologous irradiated T-cell vaccine prepared by isolating myelin reactive T-cells from a patient’s own blood and expanding the cells ex vivo to a therapeutic dose.

The vaccine has a dual mechanism of action, depleting circulating cells that attack the myelin sheath of nerves and rebalancing the immune system by causing a shift from pathogenic inflammatory T-cells to anti-inflammatory T-cells.

Promising results were seen in the post-hoc analysis of the Tovaxin for Early Relapsing Multiple Sclerosis trial, which included 129 patients who had at least 1 MS relapse during the previous year. Tovaxin reduced the annualized relapse rate by 42% compared with placebo.

At week 52, patients treated with the vaccine had less progression of MS-related disability compared with placebo, and MRI results also favored the vaccine cohort.

The only adverse events reported with the vaccine were mild-to-moderate injection-site reactions. ■

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SIMPONITM is indicated for the treatment of 1: Rheumatoid Arthritis • Moderately to severely active RA in adults, in combination with methotrexate

Psoriatic Arthritis • Active PsA in adults, alone or in combination with methotrexate

A once-monthly subcutaneous anti–TNF-α agent

Ankylosing Spondylitis • Active AS in adults

Recommended dosing1 SIMPONI™ is administered by 50 mg subcutaneous injection once a month • SIMPONI™ is intended for use under the guidance and supervision of a physician.

Patients may self-inject with SIMPONI™ after physician approval and training • There is no loading dose with SIMPONI™

Serious and sometimes fatal side effects have been reported with SIMPONI™, including infections due to tuberculosis, invasive fungal infections (eg, histoplasmosis), bacterial, viral, or other opportunistic pathogens. Prior to initiating SIMPONI™ and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection. Lymphoma and other malignancies, some fatal, can occur in adults and children. Other serious risks include hepatitis B reactivation, heart failure and demyelinating disorders.

Please see related and other Important Safety Information on next page.

Two delivery options1 • 50 mg/0.5 mL single dose prefilled syringe • 50 mg/0.5 mL single dose SmartJect™ autoinjector

www.simponi.com

Reference: 1. SIMPONI TM (golimumab) Prescribing Information. Centocor Ortho Biotech Inc.

IMPORTANT SAFETY INFORMATION FOR SIMPONI™ (golimumab) SERIOUS INFECTIONS Patients treated with SIMPONI™ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue SIMPONI™ if a patient develops a serious infection.

HEPATITIS B REACTIVATION The use of TNF-blocking agents including SIMPONI™ has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

Reported infections include:

Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating SIMPONI™. Exercise caution when prescribing SIMPONI™ for patients identified as carriers of HBV and closely monitor for active HBV infection during and following termination of therapy with SIMPONI™. Discontinue SIMPONI™ in patients who develop HBV reactivation, and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of SIMPONI™, and monitor patients closely.

• Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before SIMPONI™ use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI™ use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with SIMPONI™ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Do not start SIMPONI™ in patients with clinically important active infections, including localized infections. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI™, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Other serious infections observed in patients treated with SIMPONI™ included sepsis, pneumonia, cellulitis, abscess and hepatitis B infection.

MALIGNANCIES Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers of which SIMPONI™ is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children or adolescents. Malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

In the controlled portions of clinical trials of all TNF-blocking agents including SIMPONI™, more cases of lymphoma have been observed among patients receiving TNF-blocking treatment compared with control patients.

In clinical trials, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI™ group compared with an incidence of 0 (95% CI: 0, 0.96) in the placebo group. In clinical trials, the incidence of malignancies other than lymphoma was not increased with exposure to SIMPONI™ and was similar to what would be expected in the general population. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. The risks and benefits of TNF-blocker therapy should be considered prior to initiating therapy in patients with a known malignancy or who develop a malignancy.

HEART FAILURE Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers. Exercise caution and monitor patients with heart failure. Discontinue SIMPONI™ if new or worsening symptoms of heart failure appear.

DEMYELINATING DISORDERS TNF-blocking agents have been associated with cases of new-onset or exacerbation of central nervous system demyelinating disorders, including multiple sclerosis. Exercise caution in considering the use of SIMPONI™ in patients with central nervous system demyelinating disorders.

HEMATOLOGIC CYTOPENIAS There have been postmarketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF blockers. Exercise caution when using SIMPONI™ in patients with significant cytopenias.

USE WITH OTHER DRUGS The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections, therefore the use of SIMPONI™ in combination with these products is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. People receiving SIMPONI™ can receive vaccinations, except for live vaccines.

ADVERSE REACTIONS The most serious adverse reactions were serious infections and malignancies.

Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 trials through Week 16, occurring in 7% and 6% of patients treated with SIMPONI™ as compared with 6% and 5% of patients in the control group, respectively. The rate of injection-site reactions was 6% with patients treated with SIMPONI™ compared with 2% of patients in the control group.

Cases of new-onset psoriasis, including pustular and palmoplantar, or exacerbation of pre-existing psoriasis have been reported with the use of TNF blockers, including SIMPONI™. Some of these patients required hospitalization. Most patients had improvement following discontinuation of the TNF blocker. Discontinuation of SIMPONI™ should be considered for severe cases and those that do not improve or that worsen despite topical treatments.

Please see brief summary of Full Prescribing Information on the following pages.

Representing the products of

©2010 Centocor Ortho Biotech Services, LLC

25GL10019

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SIMPONI™ (golimumab) Injection, solution for subcutaneous use See package insert for Full Prescribing Information.

WARNING SERIOUS INFECTIONS Patients treated with SIMPONI™ are at increased risk for developing serious infections that may lead to hospitalization or death (see Warnings and Precautions). Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. SIMPONI™ should be discontinued if a patient develops a serious infection.

Reported infections include: • Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before SIMPONI™ use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI™ use.

• Invasive fungal infections, including histoplasmosis, coccidioidomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with SIMPONI™ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI™, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy (See Warning and Precautions).

MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI is a member.

INDICATIONS AND USAGE: Rheumatoid Arthritis SIMPONI™, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis. Psoriatic Arthritis SIMPONI™, alone or in combination with methotrexate, is indicated for the treatment of adult patients with active psoriatic arthritis.

Ankylosing Spondylitis SIMPONI™ is indicated for the treatment of adult patients with active ankylosing spondylitis. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS (see Boxed WARNINGS): Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving TNF-blockers including SIMPONI™. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of SIMPONI™ and these biologic products is not recommended (see Warning and Precautions and Drug Interactions). Treatment with SIMPONI™ should not be initiated in patients with an active infection, including clinically important localized infections. The risks and benefits of treatment should be considered prior to initiating SIMPONI™ in patients: with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or with underlying conditions that may predispose them to infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI™. SIMPONI™ should be discontinued if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with SIMPONI™ should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored. In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, serious infections were observed in 1.4% of SIMPONI™-treated patients and 1.3% of control-treated patients. In the controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, the incidence of serious infections per 100 patient-years of follow-up was 5.4 (95% CI: 4.0, 7.2) for the SIMPONI™ group and 5.3 (95% CI: 3.1, 8.7) for the placebo group. Serious infections observed in SIMPONI™-treated patients included sepsis, pneumonia, cellulitis, abscess, tuberculosis, invasive fungal infections, and hepatitis B infection. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating SIMPONI™ and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating SIMPONI™, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). Anti-tuberculosis therapy should also be considered prior to initiation of SIMPONI™ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating antituberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tuberculosis should be strongly considered in patients who develop a new infection during SIMPONI™ treatment, especially in patients who have previously or recently traveled to countries with

a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. In the controlled and uncontrolled portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence of active TB was 0.23 and 0 per 100 patient-years in 2347 SIMPONI™-treated patients and 674 placebo-treated patients, respectively. Cases of TB included pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases occured in countries with a high incidence rate of TB. Invasive Fungal Infections For SIMPONI™-treated patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness.

Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Hepatitis B Virus Reactivation The use of TNF-blockers including SIMPONI™ has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI™, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely. Malignancies Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNFblocking agents (initiation of therapy ≤ 18 years of age), of which SIMPONI is a member.

Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy.

Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. The risks and benefits of TNF-blocker treatment including SIMPONI™ should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy. In the controlled portions of clinical trials of TNF-blockers including SIMPONI™, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the Phase 2 trials in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patientyears of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI™ group compared with an incidence of 0 (95% CI: 0., 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2347 SIMPONI™-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined SIMPONI™ group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in SIMPONI™treated patients was similar to that expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).1 In controlled trials of other TNFblockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener’s granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory 1-year clinical trial evaluating the use of 50, 100 and 200 mg of SIMPONI™ in 309 patients with severe persistent asthma, 6 patients developed malignancies other than NMSC in the SIMPONI™ groups compared to none in the control group. Three of the 6 patients were in the 200-mg SIMPONI™ group. Congestive Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNFblockers. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI™ has not been studied in patients with a history of CHF and SIMPONI™ should be used with caution in patients with CHF. If a decision is made to administer SIMPONI™ to patients with CHF, these patients should be closely monitored during therapy, and SIMPONI™ should be discontinued if new or worsening symptoms of CHF appear. Demyelinating Disorders Use of TNF-blockers has been associated with cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS). While no trials have been performed evaluating SIMPONI™ in the treatment of patients with MS, another TNF-blocker was associated with increased disease activity in patients with MS. Therefore, prescribers should exercise caution in considering the use of TNF-blockers including SIMPONI™ in patients with CNS demyelinating disorders including MS. Use with Abatacept In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the

combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI™ and abatacept is not recommended (see Drug Interactions). Use with Anakinra Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI™, is not recommended (see Drug Interactions). Hematologic Cytopenias There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. Although, there were no cases of severe cytopenias seen in the SIMPONI™ clinical trials, caution should be exercised when using TNF-blockers, including SIMPONI™, in patients who have significant cytopenias. Vaccinations Patients treated with SIMPONI™ may receive vaccinations, except for live vaccines. No data are available on the response to live vaccination or the risk of infection, or transmission of infection after the administration of live vaccines to patients receiving SIMPONI™. In the Phase 3 PsA study, after pneumococcal vaccination, a similar proportion of SIMPONI™-treated and placebotreated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both SIMPONI™treated and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving MTX compared with patients not receiving MTX. The data suggest that SIMPONI™ does not suppress the humoral immune response to the pneumococcal vaccine. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Studies Experience The safety data described below are based on 5 pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Studies RA-1, RA-2, RA-3, PsA and AS). These 5 trials included 639 control-treated patients and 1659 SIMPONI™-treated patients including 1089 with RA, 292 with PsA, and 277 with AS. The proportion of patients who discontinued treatment due to adverse reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS was 2% for SIMPONI™-treated patients and 3% for placebo-treated patients. The most common adverse reactions leading to discontinuation of SIMPONI™ in the controlled Phase 3 trials through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%). The most serious adverse reactions were: Serious Infections; Malignancies. Upper respiratory tract infection and nasopharyngitis, were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials through Week 16, occurring in 7% and 6% of SIMPONI™-treated patients as compared with 6% and 5% of control-treated patients, respectively. Infections In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of SIMPONI™-treated patients compared to 25% of control-treated patients. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of SIMPONI™ in patients with RA, PsA, and AS through Week 16, ALT elevations ≥5 x ULN occurred in 0.2% of control-treated patients and 0.7% of SIMPONI™-treated patients, and ALT elevations ≥3 x ULN occurred in 2% of control-treated patients and 2% of SIMPONI™-treated patients. Since many of the patients in the Phase 3 trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDs, MTX), the relationship between golimumab and liver elevation is not clear. Autoimmune Disorders and Autoantibodies The use of TNF-blockers has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In the controlled Phase 3 trials in patients with RA, PsA, and AS through Week 14, there was no association of SIMPONI™ treatment and the development of newly positive anti-dsDNA antibodies.

Injection Site Reactions In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6% of SIMPONI™ treated patients had injection site reactions compared with 2% of controltreated patients. The majority of the injection site reactions were mild and the most frequent manifestation was injection site erythema. In controlled Phase 2 and 3 trials in RA, PsA, and AS, no patients treated with SIMPONI™ developed anaphylactic reactions. Psoriasis: NewOnset and Exacerbations Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, have been reported with the use of TNF-blockers, including SIMPONI. Cases of exacerbation of pre-existing psoriasis have also been reported with the use of TNF-blockers. Many of these patients were taking concomitant immunosuppressants (e.g., MTX, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of SIMPONI™ should be considered for severe cases and those that do not improve or that worsen despite topical treatments. Immunogenicity Antibodies to SIMPONI™ were detected in 57 (4%) of SIMPONI™-treated patients across the Phase 3 RA, PsA and AS trials through Week 24. Similar rates were observed in each of the 3 indications. Patients who received SIMPONI™ with concomitant MTX had a lower proportion of antibodies to SIMPONI™ than patients who received SIMPONI™ without MTX (approximately 2% versus 7%, respectively). Of the patients with a positive antibody response to SIMPONI™ in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to SIMPONI™ limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. The data above reflect the percentage of patients whose test results were considered positive for antibodies to SIMPONI™ in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SIMPONI™ with the incidence of antibodies to other products may be misleading. Other Adverse Reactions The adverse drug reactions that occurred at a rate of at least 1% in the combined SIMPONI™ groups during the controlled period of the 5 pooled Phase 3 trials through Week 16 in patients with RA, PsA, and AS are summarized below. Patients may have taken concomitant MTX, sulfasalazine, hydroxychloroquine, low-dose corticosteroids (≤10 mg of prednisone/day or equivalent), and/or NSAIDs during the trials. The numbers (percentages) of adverse drug reactions for Placebo ± DMARDS-treated patients (n=639) and SIMPONI™ ± DMARDS-treated patients (n=1659), respectively, were:

Upper respiratory tract infection Nasopharyngitis Alanine aminotransferase increased Injection site erythema Hypertension Aspartate aminotransferase increased Bronchitis Dizziness Sinusitis Influenza Pharyngitis Rhinitis Pyrexia Oral herpes Paraesthesia

Placebo ± DMARDS 37 (6%) 31 (5%) 18 (3%) 6 (1%) 9 (1%) 10 (2%) 9 (1%) 7 (1%) 7 (1%) 7 (1%) 8 (1%) 4 (< 1%) 4 (< 1%) 2 (< 1%) 2 (< 1%)

SIMPONI™ ± DMARDS 120 (7%) 91 (6%) 58 (4%) 56 (3%) 48 (3%) 44 (3%) 31 (2%) 32 (2%) 7 (2%) 25 (2%) 22 (1%) 20 (1%) 20 (1%) 16 (1%) 16 (1%)

DRUG INTERACTIONS: Methotrexate. For the treatment of RA, SIMPONI™ should be used with MTX. Since the presence or absence of concomitant MTX did not appear to influence the efficacy or safety of SIMPONI™ in the treatment of PsA or AS, SIMPONI™ can be used with or without MTX in the treatment of PsA and AS. Biologic Products for RA, PsA, and/or AS An increased risk of serious infections has been seen in clinical RA studies of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI™ with abatacept or anakinra is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. There is insufficient information to provide recommendations regarding the concomitant use of SIMPONI™ and other biologic products approved to treat RA, PsA, or AS. Live Vaccines Live vaccines should not be given concurrently with SIMPONI™. Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI™ in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B – There are no adequate and well-controlled studies of SIMPONI™ in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether SIMPONI™ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI™ should be used during pregnancy only if clearly needed. An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (360 times greater than the maximum recommended human dose-MHRD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus. A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times and 310 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates.

Golimumab was present in the neonatal serum from the time of birth and for up to 6 months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants. Nursing Mothers It is not known whether SIMPONI™ is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from SIMPONI™, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400fold lower than the maternal serum concentrations. Pediatric Use Safety and effectiveness of SIMPONI™ in patients less than 18 years of age have not been established. Geriatric Use In the Phase 3 trials in RA, PsA, and AS, there were no overall differences in SAEs, serious infections, and AEs in SIMPONI™-treated patients ages 65 or older (N=155) compared with younger SIMPONI™-treated patients. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with SIMPONI™. OVERDOSAGE In a clinical study, 5 patients received protocol-directed single infusions of 10 mg/kg of intravenous SIMPONI™ without serious adverse reactions or other significant reactions. The highest weight patient was 100 kg, and therefore received a single intravenous infusion of 1000 mg of SIMPONI™. There were no SIMPONI™ overdoses in the clinical studies. PATIENT COUNSELING INFORMATION Patient Counseling Patients should be advised of the potential benefits and risks of SIMPONI™. Physicians should instruct their patients to read the Medication Guide before starting SIMPONI™ therapy and to read it each time the prescription is renewed. Infections Inform patients that SIMPONI™ may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and hepatitis B reactivation. Malignancies Patients should be counseled about the risk of lymphoma and other malignancies while receiving SIMPONI™. Allergic Reactions Advise latex-sensitive patients that the needle cover on the prefilled syringe as well as the prefilled syringe in the prefilled SmartJect™ autoinjector contains dry natural rubber (a derivative of latex). Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, demyelinating disorders, autoimmune diseases, liver disease, cytopenias, or psoriasis.

References: 1. SEER [database online]. U.S. Population Data—1969-2004. Bethesda, MD; National Cancer Institute. Release date: January 3, 2007. Available at: http://www.seer.cancer.gov/popdata.

©2009 Centocor Ortho Biotech Inc. Horsham, PA 19044, US 1-800-457-6399

License No. 1821 November 2009 25GL09427

BUSINESS

Health Benefit Coverage, Reimbursement, and Influences on Traditional Pharmaceutical Channels F. Randy Vogenberg, RPh, PhD Pharmaceutical manufacturers face a product-use dilemma in the US marketplace for patent expiration and biotechnology products. Current business transaction platforms, such as health insurance plans, have created different barriers to the entry of products and to their routine use that traditional pharmaceutical marketing has yet to effectively address.

Health benefit coverage decision makers are disrupting the traditional pharmaceutical channel, emphasizing the absence of a compelling pharmaceutical value proposition to the buyer (ie, patient and benefits community), while exposing a critical weakness for managed market coverage and utilization. Despite manufacturers’ efforts in traditional channels to achieve sales or market share, the current managed market channels can eliminate a product’s marketplace value within weeks. In addition to research and development investment, harnessing 21st-century technologies and a better understanding of the new healthcare customer channels may prove to be the best investment a manufacturer can make.

[AHDB. 2010;3(3):225-230.]

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harmaceutical manufacturers face an increasing drug utilization dilemma—not related to formulary acceptance—in the US marketplace regarding patent expiration, new-entry pharmaceuticals, and biotechnology products. Influencers of health plan reimbursement program decision makers (eg, benefit managers, consultants, consumer advocates) and reimbursement transaction platforms need more attention from pharmaceutical marketers and senior executives in relation to their current and emerging product pipeline.

This is because of the current exchange of dollars in the controlled managed market flow, which will continue to constrict sales of pipeline products that are already drying up. As the pharmaceutical industry turns its attention increasingly to biotechnology or specialty pharmacy products, the managed market channel problem changes, but is not solved. The 2010 health insurance reform legislation underscores this point, because the anticipated healthcare system changes will likely further complicate the managed market.

Today we have a healthcare market that is focused on medical practices and regulatory oversight, where the majority of the healthcare system efforts reside in rewarding reactive management or delivery of services.

Dr Vogenberg is Principal, Institute for Integrated Healthcare, Sharon, MA, and Senior Fellow, Jefferson School of Population Health, Thomas Jefferson University, Philadelphia, PA.

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For example, we have populations of patients with cardiovascular disease or diabetes who are at risk for a heart attack or a glycemic event, but are generally not screened for these events or often not detected in the current healthcare system.1 In contrast, better screening and detection programs can identify people for inclusion in drug and nondrug therapies to facilitate the prevention of a potentially serious illness and costly hospitalization.

This represents a true value proposition opportunity not only for health plan payers or sponsors but also for influencers in the US healthcare system, such as patients and providers. In fact, true value-based offerings supported by pharmaceutical manufacturers may deliver the opportunity for alignment of interests for improving health in contrast to the current pharmacy distribution channel’s focus and health plan coverage in the marketplace (Figure 1).

The Value Proposition in Current Healthcare Another difficulty in the current healthcare system is understanding what aspect of the drug product is of value, and to whom, and what determines value. There is no single definition of value consistently used in the marketplace or in the literature to date. Furthermore, the use of value in combination with various applications (eg, value-based purchasing, value-based benefits, value-based insurance design, and quality-adjusted life-

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The healthcare market today is focused on medical practices and regulatory oversight, rewarding reactive management/delivery of services.

Reimbursement decision makers should be considered by pharmaceutical manufacturers with regard to their product pipeline.

The absence of a compelling value proposition to healthcare buyers, including patients and payers, is a significant weakness for product coverage and utilization.

Successfully implementing a new market-channel strategy necessitates a well-orchestrated approach to integrating the manufacturer’s marketing issues.

Drug manufacturers are beginning to address disease states and drug classes/categories from an employer’s or a buyer’s perspective.

Those in charge of benefit design and their influencers are currently disrupting the traditional pharmaceutical sales and distribution channels that are still relying on traditional physician-focused marketing efforts.

The price for failing to implement change in addressing new channels can be more costly than the investment toward facilitating change.

Figure 1 View of the Marketplace

Information or business transaction platform tie channels together

Channels driving decisions on coverage include: • Manufacturer • Distributor • Dispenser (pharmacy)/administering professional (eg, Medical Director) • Patient, purchaser (employer, government, union), and payer (health plan, PBM)

PBM indicates pharmacy benefit manager.

year analysis) has contributed to increased confusion among stakeholders seeking to find a common ground.

Fundamental to the understanding of value is the relationship between economic value and the individual stakeholder perspective. Key stakeholders include patients, physicians, health plans, and plan sponsors (eg, employers, union trusts).

Various value-driven product coverage or utilization decisions have been emerging from the traditional costonly (unifactorial) decision system as a result of finally recognizing that multiple factors are responsible for driving up the total cost of healthcare, including more

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sophisticated medical treatments and an aging population that will consume ever-more services. Consequently, even modest savings from this new value-based benefit design strategy can be significant for struggling employers, municipalities, and patients who are the key payers in our economically strained modern healthcare system.

Value-based benefit design incorporates cost-efficiency with alignment of corporate business goals and objectives that should be reflective in the company’s health plan (Figure 2).

The continuing absence of a compelling value proposition to the buyer (ie, patients and the health benefits payer community) has exposed a significant weakness for product coverage and utilization, despite some modifications to traditional pharmaceutical marketing practices.

As seen in the October 2008 congressional votes authorizing “bail out” funding toward solving the economic crisis, Congress members could not fail to address the changes through funds that can lead efforts toward restoring the economy.

In the healthcare marketplace, the price for failure to change product-marketing efforts by addressing new drug distribution decision-making channels is going to be more costly than the relatively modest investment toward facilitating change to achieve marketplace success.

System Dysfunction versus Cost-Efficiency Affordability and effectiveness are 2 components of value for health insurance payers. As an example, employers have used value-based purchasing strategies for many disparate services over the years, akin to the collective purchasing power by hospitals, health plans, and even pharmacy chains. This represents a unit cost–focused decision approach similar to cost minimization in pharmacoeconomic terms. However, a November 2007 survey of employers showed that as a whole, employers do not appear to be implementing healthrelated programs in line with value-based purchasing ideals that include affordability and cost-effectiveness.2 Even when using available health plan level quality information—such as HEDIS (Healthcare Effectiveness Data and Information Set) and eValue8—the information is used by less than two thirds of benefit design decision makers and less than one quarter of medical providers.3,4 However, existing sources of quality data, with their inherent limitations or usefulness, are not factored into many pay-for-performance programs and decisions.

This gap stems from the difficulty in executing a fully electronic exchange of patient-centered information at the time of service, along with traditional reimbursement programs that are not incented to align across different areas of coverage. For example, medical and pharmacy

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services are typically handled under different benefit design and coverage rules, making it difficult for providers to treat a patient independent of what service or product may be covered under their area of the benefit design.

For pharmaceutical product coverage and purchasing decisions in the traditional pharmacy channel, misaligned incentives between quality (ie, performance) and cost means that key decisions for branded products with (an actual or perceived) low or marginal health improvement could be placed in a higher copayment or coinsurance tier, or not be covered without prior approval. Therefore, quality outcomes that are researched in the absence of economic impacts may fail to influence actual physician prescribing, plan coverage, or use by patients.

Different industry, accounting, and benefit consulting organizations indicate that although employers as a whole are not ready to adopt even value-based purchasing, such a strategy has the potential to lower costs and improve quality. For example, despite a 2001 report from the RAND Corporation that healthcare spending could be reduced by nearly 30% without adversely affecting health,5 as well as evidence from the health literature from the past 20 years, employers still maintain their deep-rooted ambivalence regarding the reality that value-based purchasing is limited in its potential to contain healthcare costs.

The importance of these emerging trends for pharmaceutical marketers and executives is in the rapidly evolving need to better align the value proposition of a drug product with all stakeholders and influencers. Such an approach requires looking beyond any perceived clinical need, US Food and Drug Administration (FDA) approval, or drug price to address the issues of the payer or consumer as buyer in a product’s value proposition.

Rethinking the Process One approach would be to look to the marketplace to address how pharmaceutical manufacturers, especially biotechnology-based companies, establish a value proposition to stakeholders beyond just clinical data and rethinking the traditional pharmaceutical strategic planning process (situational analysis, strategic development and planning, implementation). Several examples during the past 2 years have been reported in business and industry publications, suggesting that pharmaceutical industry executives, including GlaxoSmithKline Chief Executive Officer Andrew Witty, have held product pipeline meetings with insurance carrier payers and European regulators to gain feedback on marketplace needs as well as issues related to new or future product acceptance.6,7 Expanding the individual situational analysis to the broader marketplace perspective requires a translational

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Figure 2 Health Benefit Market Influencers and Coverage Decision Relationships Relationship Matrix TPA Vendors

PBM Stop loss Disease management

Brokers

Buyers • Employers • Unions • Purchasing groups

Health and wellness

Consultants (health benefit consultants)

PBM indicates pharmacy benefit manager; TPA, third-party administrator.

Used with permission of the author.

utilization (ie, applying data such as comparative effectiveness research into benefit decisions) of traditional differentiating drug data. For example, when developing a new drug, the developer considers clinical parameters toward the FDA approval requirement and provider

Validation and strategy refinement in working with buyer segments, such as employers, need to be accomplished before consideration of a new product launch. acceptance, whereas benefit plan managers are looking for the product’s value in their covered population and to their operational bottom line. Including the perspectives of the new buyers and influencers of buying decisions, such as employers or unions, in strategic planning and implementation requires a more robust understanding of all those stakeholders, along with the different drivers influencing their decision making for health benefits coverage.

Validation and strategy refinement in working with buyer segments, such as employers, need to be accomplished before consideration of a new product launch.

For example, what is the impact of managing a condition with the various medical, surgical, pharmacologic, and

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nonpharmacologic treatments that are available to cover in a benefits program? Among drug choices, even with a single-source brand-name product, the relative value to the employer could be evaluated according to the most appropriate level of coverage in the benefit design rather than according to a national standard.

When drug alternatives are available, outcomes beyond clinical therapeutics alone could be evaluated to determine the best overall economic fit to an individual employer-based benefit program.

Implementing New Market Strategies Successfully implementing a new market-channel strategy necessitates a well-orchestrated approach in dealing with the tactical integration issues within the manufacturer’s marketing and sales organization.

Defining a value for the new marketplace buyer of drugs requires a broader medical business perspective that has yet to be accomplished by manufacturers. Establishing a high-performing team that can deliver a meaningful value proposition for this new buyer market is a higherstakes business scenario than was dealing with disparate managed care entities in the past.

Companies are beginning to address disease states and classes or categories of drugs from an employer’s or a buyer’s perspective.

Buyer-specific tools, models, and materials require more of an outsourced and independent business solution.

Companies are beginning to address disease states and classes or categories of drugs from an employer’s or a buyer’s perspective. Buyer-specific tools, models, and materials require more of an outsourced and independent business solution, because of the negative perceptions or distrust that commercial plan sponsors (including employers, unions, and municipalities) have of manufacturer-supplied programs. Benefit decision makers are skeptical of manufacturer-driven or -developed programs and instead tend to rely on their trusted network of consultants or brokers for their benefit design and formulary decisions.

In addition, adequate development budgets are needed for entry into the employer markets, because there is currently a dearth of independently developed tools for these commercial buyers of healthcare services. Traditional efforts by manufacturers have focused on physician organizations and health plans, yet it is the commercial plan sponsors along with government programs (ie, Medicare, Medicaid) that are becoming

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increasingly important in driving demand for preventive and new products that will improve health. This effort goes along with established patient advocacy trends, direct-to-consumer campaigns, and recognizing a changing business environment. Overall, realigning resources (ie, field and research personnel and funding), tools, models, and nonbranded support materials needs to be included when addressing this (ie, employers) market channel.

The Emerging 21st-Century Technology The emergence of the human genome, and the resultant biologic- or biotechnology-based diagnostic and medication products is a cutting-edge 21st-century product technology. Manufacturers need to look beyond vendors in the marketplace—such as pharmacy benefit managers (PBMs) and health plans/managed care—and the current vendor-only business model(s) for manufacturers to sell their product. Current influencers on a buyer’s decision makers that are invisible to manufacturers include health benefit consultants and brokers. Of more interest for successful market behavior change are the reimbursement platform technology and money flows that have not changed since the past century.

To date, drug manufacturers maintain their traditional channel focus on access (ie, formulary acceptance) or copay modifications through managed care vendor relationships to include expensive rebates to intermediary health plans. These efforts that focus solely on product costs ignore the marketplace need for vendors in providing value to buyers, and do not offer an improved transaction platform or money flow that could be used to create a winning business-to-business product solution to buyers (ie, patients and providers) that would allow opportunities such as creating brand value beyond a product’s patent life.

For pharmaceutical marketers, not establishing a money-flow product value proposition to buyers in a new business transaction environment can result in market share losses to evolving benefit design policy decisions. For example, the allergic rhinitis drug category represents a large pharmacy cost, but more significantly, an important asset in the management of a disease that represents a high-frequency and high-spending category for buyers.

Managed care plans to date have focused on generic substitution by default as a way to control costs, because of the obvious benefit influencers (ie, PBMs, health plans) and money-flow managers (including healthcare providers) who gain the most from that practice.

However, generic substitution alone is a self-limiting value proposition from an employer total-cost management perspective and ignores the bigger value proposi-

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Influences on Traditional Pharmaceutical Channels

tion of managing a disease risk for a buyer, which is where the manufacturer and employer are in alignment.

In addition, a new electronic communication platform for evolving information transactions can lead to more effectively addressing adherence that can amortize investment costs made but lost through patient behavior or market forces.

Disrupting Channels Contemporary health benefit design decision makers and their influencers are disrupting the traditional pharmaceutical sales and distribution channels, along with demand control, whereas manufacturers are still relying on traditional physician-focused marketing efforts for demand creation, with little focus on utilization or product pull-through. Several limitations to changing healthcare decisions exist, including, for example, patient or employee confidentiality, union-negotiated restrictions on benefit changes, and specified services contracts. In addition, health benefit brokers who represent vendors, or benefit consultants who represent purchasers, may not be the solution for manufacturers seeking advocacy as a result of conflicts of interest.

Further exacerbating product use problems are the current managed market coverage and reimbursement platforms that have created ever-changing or varying barriers to product entry and utilization. This is what pharmaceutical marketing and senior sales executives continue to find difficult to understand or to successfully address.

Conclusion To date, the lack of a compelling value proposition to patients and to the health benefits payer community exposes a weakness for product coverage and utilization, despite talk of changing from traditional pharmaceutical marketing practices. As seen in the banking and finance industry, the cost for failure to implement change in addressing new channels can be more costly than the

investment toward facilitating change. For some pharmaceutical companies, the risk may be no less than failure of the product or the failure to survive as a business.

Contemporary health benefit design decision makers and their influencers are disrupting the traditional pharmaceutical sales and distribution channels, along with demand control.

Despite the best efforts in traditional market channels by marketers and their vendors to achieve sales goals or market share, the new buyer channels for pharmaceuticals can effectively neutralize potential gains and eliminate a productâ&#x20AC;&#x2122;s clinical value in the marketplace. The new road map for success will require systems, processes, and tools that are aligned with the customers in the marketplace. Training and development of personnel also require a change, to implement, sustain, and hold onto marketplace achievements. Harnessing 21st-century technologies, and better understanding new customer channels, may prove to be the best investment by a manufacturer aside from applied research. â&#x2013;

References 1. Collins AJ, Vassalotti JA, Wang C, et al. Who should be targeted for CKD screening? Impact of diabetes, hypertension, and cardiovascular disease. Am J Kidney Dis. 2009;53(3 suppl 3):S71-S77.

2. Rosenthal MB, Landon BE, Normand SL, et al. Employeesâ&#x20AC;&#x2122; use of value-based purchasing strategies. JAMA. 2007;298:2281-2288.

3. National Business Coalition on Healthcare. eValue8 2009: measuring progress toward value-based purchasing. 2009. www.nbch.org/NBCH/files/ccLibraryFiles/ Filename/000000000640/Evalue8%202009%20Annual%20Report.pdf. Accessed May 17, 2010.

4. Survey reveals employers rethinking health care benefit offerings. Workforce Management. February 23, 2010. www.workforce.com/archive/article/27/02/07.php?ht=.

Accessed May 17, 2010.

5. Garber A, Goldman DP, Jena AB. The promise of health care cost containment.

Health Aff (Millwood). 2007;26:1545-1547.

6. Whalen J. Glaxo seeks guidance from health systems. Wall Street Journal. July 7, 2008. http://online.wsj.com/article/SB121538798154831045.html?mod=2_1566_ leftbox. Accessed May 18, 2010.

7. Taylor P. GSK opens pipeline up for comment. Outsourcing-pharma.com. July 7, 2008. www.outsourcing-pharma.com/Clinical-Development/GSK-opens-pipelineup-for-comment. Accessed May 18, 2010.

STAKEHOLDER PERSPECTIVE The Many Challenges of Pay-for-Performance Programs In his article, Dr Vogenberg challenges pharmaceutical manufacturers to consider new strategic approaches to the marketplace. Acknowledging the leverage that managed care organizations (MCOs) and pharmacy benefit managers (PBMs) can have in the marketplace, Dr Vogenberg challenges pharmaceutical manufacturers to think about the multiple

stakeholders in healthcare and how a new product will be perceived by those different stakeholders. In other words, new pharmaceutical products will be judged and accepted based on the clinical and economic value they may bring to health plans, patients, employers, and physicians.

From the managed care perspective, we continue to Continued

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STAKEHOLDER PERSPECTIVE (Continued) struggle to manage the rising costs of medical care, and pharmaceutical products continue to be an area of major focus. According to an Associated Press article from April 1, 2010, “Growth in US sales of pharmaceuticals bounced back last year, as rebates and lowcost generic drugs drove an increase in the number of prescriptions filled, according to data tracking firm IMS Health.”1 In addition, US drug sales “climbed 5.1 percent to $300.3 billion in 2009, after two prior years of slower growth.”1 The report also notes that generic drug sales “made up 75 percent of all prescriptions filled last year,” compared with 57% of all sales in 2004.1 On May 18, 2010, the AARP reported that “manufacturer prices for brand-name drugs widely used by Medicare enrollees rose 9.7 percent in the 12 months that ended in March….The increase was the largest twelve-month spike since AARP began tracking drug prices in 2002.”2 With the cost of pharmaceuticals still a concern for their customers, MCOs are looking for ways to actively manage their drug benefit and to narrow formularies in categories where there are valid generic options or where there are choices of clinically equivalent branded options. Pharmacy & Therapeutics (P&T) committees are increasingly looking to find true innovation in the products they review. Such things as combinations of existing generic agents remarketed as

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a branded agent, new longer-acting formulations of existing products, and branded agents in the “me-too” category are coming under intense review by P&T committees; often the discussion revolves not only around what clinical value does this product bring to the market, but on what is the economic value, and how does the new medication bring additional value to the specific MCO and its clients.

As Dr Vogenberg points out so accurately in his article, failure to recognize this dynamic, and failure to demonstrate this value to the MCO or the PBM client can result in an unsuccessful product launch. From the MCO perspective, I agree with Dr Vogenberg that going forward, manufacturers must understand what the value equation is for the MCOs, and they must also understand the unmet needs in the MCO marketplace early in the drug development cycle to have successful product launches in the future.

1. Associated Press. US drug sales growth bounced back in 2009. www.chicago breakingbusiness.com/2010/04/us-drug-sales-growth-bounced-back-in-2009. html. April 1, 2010. Accessed June 3, 2010.

2. Reichard J. AARP reports biggest 12-month spike in brand-name prices since 2002. The Commonwealth Fund. May 17, 2010. www.commonwealthfund.org/ Content/Newsletters/Washington-Health-Policy-in-Review/2010/May/May24-2010/Biggest-Spike-in-Brand-Name-Drug-Prices-Since-2002.aspx?view= print. Accessed June 3, 2010.

Gary M. Owens, MD President, Gary Owens Associates Philadelphia, PA

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