July/August 2011, Vol 4, No 4

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ JULY/AUGUST 2011

VOLUME 4, NUMBER 4

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

PERSPECTIVE

Moving Beyond Medicare’s ACOs to Accountable Care Murali Karamchedu, Sam Muppalla, and Robert Capobianco

BUSINESS

The Business Case for Payer Support of a Community-Based Health Information Exchange: A Humana Pilot Evaluating Its Effectiveness in Cost Control for Plan Members Seeking Emergency Department Care Albert Tzeel, MD, MHSA; Victor Lawnicki, PhD; Kim R. Pemble, MS ™

Stakeholder Perspective by Alberto M. Colombi, MD, MPH CLINICAL

Modeling Costs and Outcomes Associated with a Treatment Algorithm for Problem Bleeding Episodes in Patients with Severe Hemophilia A and High-Titer Inhibitors Patrick Bonnet, PharmD; Alessandro Gringeri, MD; Edward Gomperts, MD; Cindy Anne Leissinger, MD; Roseline d’Oiron, MD; Jerome Teitel, MD; Guy Young, MD; Meg Franklin, PharmD, PhD; Bruce Ewenstein, MD; Erik Berntorp, MD, PhD

Stakeholder Perspective by Hetty A. Lima, RPh, FASHP

Anticoagulation Bridging Therapy Patterns in Patients Undergoing Total Hip or Total Knee Replacement in a US Health Plan: Real-World Observations and Implications Onur Baser, MS, PhD; Dylan Supina, PhD; Nishan Sengupta, PhD; Li Wang, MS, PhD

Stakeholder Perspective by Charles E. Collins, Jr., MS, MBA

◆

Industry Trends

◆

American Diabetes Association Highlights

HIGHLIGHT

©2011 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)

t 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.

Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 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.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE DEXILANT is indicated for: M C74 740;8=6 >5 0;; 6A034B >5 4A>B8E4 4B>?7068C8B 5>A D? C> F44:B M <08=C08=8=6 740;8=6 >5 5>A D? C> <>=C7B 0=3 M C74 CA40C<4=C >5 740AC1DA= 0BB>280C43 F8C7 BH<?C><0C82 =>= 4A>B8E4 60BCA>4B>?70640; A4K DG 38B40B4 ' 5>A F44:B CONTRAINDICATIONS , ! #) 8B 2>=CA08=3820C43 8= ?0C84=CB F8C7 :=>F= 7H?4AB4=B8C8E8CH C> 0=H 2><?>=4=C >5 C74 5>A<D;0C8>= H?4AB4=B8C8E8CH 0=3 0=0?7H;0G8B 70E4 144= A4?>AC43 F8C7 , ! #) DB4 [see Adverse Reactions] WARNINGS AND PRECAUTIONS Gastric Malignancy (H<?C><0C82 A4B?>=B4 F8C7 , ! #) 3>4B =>C ?A42;D34 C74 ?A4B4=24 >5 60BCA82 <0;86=0=2H Bone Fracture (4E4A0; ?D1;8B743 >1B4AE0C8>=0; BCD384B BD664BC C70C ?A>C>= ?D<? 8=7818C>A %% C74A0?H <0H 14 0BB>280C43 F8C7 0= 8=2A40B43 A8B: 5>A >BC4>?>A>B8B A4;0C43 5A02CDA4B >5 C74 78? FA8BC >A B?8=4 )74 A8B: >5 5A02CDA4 F0B 8=2A40B43 8= ?0C84=CB F7> A4248E43 7867 3>B4 34J =43 0B <D;C8?;4 308;H 3>B4B 0=3 ;>=6 C4A< %% C74A0?H 0 H40A >A ;>=64A %0C84=CB B7>D;3 DB4 C74 ;>F4BC 3>B4 0=3 B7>AC4BC 3DA0C8>= >5 %% C74A0?H 0??A>?A80C4 C> C74 2>=38C8>= 148=6 CA40C43 %0C84=CB 0C A8B: 5>A >BC4>?>A>B8B A4;0C43 5A02CDA4B B7>D;3 14 <0=0643 022>A38=6 C> 4BC01;8B743 CA40C<4=C 6D834;8=4B ADVERSE REACTIONS Clinical Trials Experience )74 B054CH >5 , ! #) F0B 4E0;D0C43 8= ?0C84=CB 8= 2>=CA>;;43 0=3 D=2>=CA>;;43 2;8=820; BCD384B 8=2;D38=6 ?0C84=CB CA40C43 5>A 0C ;40BC <>=C7B 0=3

?0C84=CB CA40C43 5>A >=4 H40A %0C84=CB A0=643 8= 064 5A>< C>

H40AB <4380= 064 H40AB F8C7 54<0;4 0D20B80= ;02: B80= 0=3 >C74A A024B (8G A0=3><8I43 2>=CA>;;43 2;8=820; CA80;B F4A4 2>=3D2C43 5>A C74 CA40C<4=C >5 <08=C4=0=24 >5 740;43 0=3 BH<?C><0C82 ' F7827 8=2;D343 ?0C84=CB >= ?;0241> ?0C84=CB >= , ! #) <6

?0C84=CB >= , ! #) <6 0=3 ?0C84=CB >= ;0=B>?A0I>;4 <6 >=24 308;H B 2;8=820; CA80;B 0A4 2>=3D2C43 D=34A F834;H E0AH8=6 2>=38C8>=B 03E4AB4 A402C8>= A0C4B >1B4AE43 8= C74 2;8=820; CA80;B >5 0 3AD6 20==>C 14 38A42C;H 2><?0A43 C> A0C4B 8= C74 2;8=820; CA80;B >5 0=>C74A 3AD6 0=3 <0H =>C A4K 42C C74 A0C4B >1B4AE43 8= ?A02C824 ">BC ><<>=;H '4?>AC43 3E4AB4 '402C8>=B )74 <>BC 2><<>= 03E4AB4 A402C8>=B â&#x2030;Ľ C70C >22DAA43 0C 0 78674A 8=2834=24 5>A , ! #) C70= ?;0241> 8= C74 2>=CA>;;43 BCD384B 0A4 ?A4B4=C43 8= )01;4

Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies %;0241> 3E4AB4 '402C8>= 80AA740

#

DEXILANT

<6 #

DEXILANT

<6 #

DEXILANT !0=B>?A0I>;4

<6 )>C0; # #

13><8=0; %08=

#0DB40

*??4A '4B?8A0C>AH )A02C =542C8>=

+><8C8=6

;0CD;4=24

3E4AB4 '402C8>=B '4BD;C8=6 8= 8B2>=C8=D0C8>= = 2>=CA>;;43 2;8=820; BCD384B C74 <>BC 2><<>= 03E4AB4 A402C8>= ;4038=6 C> 38B2>=C8=D0C8>= 5A>< , ! #) C74A0?H F0B 380AA740

$C74A 3E4AB4 '402C8>=B $C74A 03E4AB4 A402C8>=B C70C F4A4 A4?>AC43 8= 2>=CA>;;43 BCD384B 0C 0= 8=2834=24 >5 ;4BB C70= 0A4 ;8BC43 14;>F 1H 1>3H BHBC4< Blood and Lymphatic System Disorders: 0=4<80 ;H<?7034=>?0C7H Cardiac Disorders: 0=68=0 0AA7HC7<80 1A03H20A380 274BC ?08= 434<0 <H>20A380; 8=50A2C8>= ?0;?8C0C8>= C027H20A380 Ear and Labyrinth Disorders: 40A ?08= C8==8CDB E4AC86> Endocrine Disorders: 6>8C4A Eye Disorders: 4H4 8AA8C0C8>= 4H4 BF4;;8=6 Gastrointestinal Disorders: 013><8=0; 38B2><5>AC 013><8=0; C4=34A=4BB 01=>A<0; 5424B 0=0; 38B2><5>AC 0AA4CC B 4B>?706DB 14I>0A 1>F4; B>D=3B 01=>A<0; 1A40C7 >3>A 2>;8C8B <82A>B2>?82 2>;>=82 ?>;H? 2>=BC8?0C8>= 3AH <>DC7 3D>34=8C8B 3HB?4?B80 3HB?70680 4=C4A8C8B 4AD2C0C8>= 4B>?7068C8B 60BCA82 ?>;H? 60BCA8C8B 60BCA>4=C4A8C8B 60BCA>8=C4BC8=0; 38B>A34AB

60BCA>8=C4BC8=0; 7H?4A<>C8;8CH 38B>A34AB ' D;24AB 0=3 ?4A5>A0C8>= 74<0C4<4B8B 74<0C>274I80 74<>AA7>83B 8<?08A43 60BCA82 4<?CH8=6 8AA8C01;4 1>F4; BH=3A><4 <D2DB BC>>;B =0DB40 0=3 E><8C8=6 >A0; <D2>B0; 1;8BC4A8=6 ?08=5D; 345420C8>= ?A>2C8C8B ?0A4BC74B80 >A0; A42C0; 74<>AA7064 General Disorders and Administration Site Conditions: 03E4AB4 3AD6 A402C8>= 0BC74=80 274BC ?08= 278;;B 544;8=6 01=>A<0; 8=K 0<<0C8>= <D2>B0; 8=K 0<<0C8>= =>3D;4 ?08= ?HA4G80 Hepatobiliary Disorders: 18;80AH 2>;82 27>;4;8C780B8B 74?0C><460;H Immune System Disorders: 7H?4AB4=B8C8E8CH Infections and Infestations: 20=3830 8=542C8>=B 8=K D4=I0 =0B>?70AH=68C8B >A0; 74A?4B ?70AH=68C8B B8=DB8C8B E8A0; 8=542C8>= ED;E> E068=0; 8=542C8>= Injury, Poisoning and Procedural Complications: 50;;B 5A02CDA4B 9>8=C B?A08=B >E4A3>B4 ?A>243DA0; ?08= BD=1DA= Laboratory Investigations: !% 8=2A40B43 !)

8=2A40B43 () 8=2A40B43 18;8AD18= 342A40B43 8=2A40B43 1;>>3 2A40C8=8=4 8=2A40B43 1;>>3 60BCA8= 8=2A40B43 1;>>3 6;D2>B4 8=2A40B43 1;>>3 ?>C0BB8D< 8=2A40B43 ;8E4A 5D=2C8>= C4BC 01=>A<0; ?;0C4;4C 2>D=C 342A40B43 C>C0; ?A>C48= 8=2A40B43 F4867C 8=2A40B4 Metabolism and Nutrition Disorders: 0??4C8C4 270=64B 7H?4A20;24<80 7H?>:0;4<80 Musculoskeletal and Connective Tissue Disorders: 0AC7A0;680 0AC7A8C8B <DB2;4 2A0<?B <DB2D;>B:4;4C0; ?08= <H0;680 Nervous System Disorders: 0;C4A43 C0BC4 2>=ED;B8>= 38II8=4BB 74030274B <86A08=4 <4<>AH 8<?08A<4=C ?0A4BC74B80 ?BH27><>C>A 7H?4A02C8E8CH CA4<>A CA864<8=0; =4DA0;680 Psychiatric Disorders: 01=>A<0; 3A40<B 0=G84CH 34?A4BB8>= 8=B><=80 ;8183> 270=64B Renal and Urinary Disorders: 3HBDA80 <82CDA8C8>= DA64=2H Reproductive System and Breast Disorders: 3HB<4=>AA740 3HB?0A4D=80 <4=>AA70680 <4=BCAD0; 38B>A34A; Respiratory, Thoracic and Mediastinal Disorders: 0B?8A0C8>= 0BC7<0 1A>=278C8B 2>D67 3HB?=>40 7822D?B 7H?4AE4=C8;0C8>= A4B?8A0C>AH CA02C 2>=64BC8>= B>A4 C7A>0C Skin and Subcutaneous Tissue Disorders: 02=4 34A<0C8C8B 4AHC74<0 ?ADA8C8B A0B7 B:8= ;4B8>= DAC820A80 Vascular Disorders: 344? E48= C7A><1>B8B 7>C K DB7 7H?4AC4=B8>= 338C8>=0; 03E4AB4 A402C8>=B C70C F4A4 A4?>AC43 8= 0 ;>=6 C4A< D=2>=CA>;;43 BCD3H 0=3 F4A4 2>=B834A43 A4;0C43 C> , ! #) 1H C74 CA40C8=6 ?7HB8280= 8=2;D343 0=0?7H;0G8B 0D38C>AH 70;;D28=0C8>= 24;; ;H<?7><0 1DAB8C8B 24=CA0; >14B8CH 27>;42HBC8C8B 02DC4 342A40B43 74<>6;>18= 347H3A0C8>= 38014C4B <4;;8CDB 3HB?7>=80 4?8BC0G8B 5>;;82D;8C8B 60BCA>8=C4BC8=0; ?08= 6>DC 74A?4B I>BC4A 7H?4A6;H24<80 7H?4A;8?834<80 7H?>C7HA>838B< 8=2A40B43 =4DCA>?78;B " 342A40B4 =4DCA>?4=80 >A0; B>5C C8BBD4 38B>A34A A42C0; C4=4B<DB A4BC;4BB ;46B BH=3A><4 B><=>;4=24 C7A><1>2HC74<80 C>=B8;;8C8B $C74A 03E4AB4 A402C8>=B =>C >1B4AE43 F8C7 , ! #) 1DC >22DAA8=6 F8C7 C74 A024<0C4 ;0=B>?A0I>;4 20= 14 5>D=3 8= C74 ;0=B>?A0I>;4 ?02:064 8=B4AC + '( ' ) $#( B42C8>= Postmarketing Experience 3E4AB4 A402C8>=B 70E4 144= 834=C8J 43 3DA8=6 ?>BC 0??A>E0; >5 , ! #) B C74B4 A402C8>=B 0A4 A4?>AC43 E>;D=C0A8;H 5A>< 0 ?>?D;0C8>= >5 D=24AC08= B8I4 8C 8B =>C 0;F0HB ?>BB81;4 C> A4;801;H 4BC8<0C4 C748A 5A4@D4=2H >A 4BC01;8B7 0 20DB0; A4;0C8>=B78? C> 3AD6 4G?>BDA4 Eye Disorders 1;DAA43 E8B8>= Gastrointestinal Disorders >A0; 434<0 General Disorders and Administration Site Conditions 50280; 434<0 Immune System Disorders 0=0?7H;02C82 B7>2: A4@D8A8=6 4<4A64=2H 8=C4AE4=C8>= (C4E4=B >7=B>= BH=3A><4 C>G82 4?834A<0; =42A>;HB8B B><4 50C0; Musculoskeletal System DisorderB 1>=4 5A02CDA4 Respiratory, Thoracic and Mediastinal Disorders ?70AH=640; 434<0 C7A>0C C867C=4BB Skin and Subcutaneous Tissue Disorders 64=4A0;8I43 A0B7 ;4D2>2HC>2;0BC82 E0B2D;8C8B DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics , ! #) 20DB4B 8=7818C8>= >5 60BCA82 0283 B42A4C8>= , ! #) 8B ;8:4;H C> BD1BC0=C80;;H 342A40B4 C74 BHBC4<82 2>=24=CA0C8>=B >5 C74 + ?A>C40B4 8=7818C>A 0C0I0=0E8A F7827 8B 34?4=34=C D?>= C74 ?A4B4=24 >5 60BCA82 0283 5>A 01B>A?C8>= 0=3 <0H A4BD;C 8= 0 ;>BB >5 C74A0?4DC82 45542C >5 0C0I0=0E8A 0=3 C74 34E4;>?<4=C >5 + A4B8BC0=24 )74A45>A4 , ! #) B7>D;3 =>C 14 2> 03<8=8BC4A43 F8C7 0C0I0=0E8A C 8B C74>A4C820;;H ?>BB81;4 C70C , ! #) <0H 8=C4A54A4 F8C7 C74 01B>A?C8>= >5 >C74A 3AD6B F74A4 60BCA82 ? 8B 0= 8<?>AC0=C 34C4A<8=0=C >5 >A0; 18>0E08;018;8CH 4 6 0<?828;;8= 4BC4AB 386>G8= 8A>= B0;CB :4C>2>=0I>;4 Warfarin > 03<8=8BCA0C8>= >5 , ! #) <6 0=3 F0A50A8= <6 383 =>C 05542C C74 ?70A<02>:8=4C82B >5 F0A50A8= >A #' >F4E4A C74A4 70E4 144= A4?>ACB >5 8=2A40B43 #' 0=3 ?A>C7A><18= C8<4 8= ?0C84=CB A4248E8=6 %% B 0=3 F0A50A8= 2>=2><8C0=C;H =2A40B4B 8= #' 0=3 ?A>C7A><18= C8<4 <0H ;403 C> 01=>A<0; 1;4438=6 0=3 4E4= 340C7 %0C84=CB CA40C43 F8C7 , ! #) 0=3 F0A50A8= 2>=2><8C0=C;H <0H =443 C> 14 <>=8C>A43 5>A 8=2A40B4B 8= #' 0=3 ?A>C7A><18= C8<4 Tacrolimus >=2><8C0=C 03<8=8BCA0C8>= >5 34G;0=B>?A0I>;4 0=3 C02A>;8<DB <0H 8=2A40B4 F7>;4 1;>>3 ;4E4;B >5 C02A>;8<DB 4B?4280;;H 8= CA0=B?;0=C ?0C84=CB F7> 0A4 8=C4A<4380C4 >A ?>>A <4C01>;8I4AB >5 -%

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed.

A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9-times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or 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 lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole 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.

Enterochromaffi n-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 human lansoprazole 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 lansoprazole 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 human lansoprazole 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 lansoprazole 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 human lansoprazole 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 human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

PATIENT COUNSELING INFORMATION Information for Patients 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: Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued. Advise your patients to tell you if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes.

DEXILANT is available as a delayed release capsule.

DEXILANT may be taken without regard to food.

DEXILANT should be swallowed whole.

M ;C4A=0C8E4;H , ! #) 20?BD;4B 20= 14 >?4=43 0=3 03<8=8BC4A43 as follows: â&#x20AC;&#x201C; Open capsule; â&#x20AC;&#x201C; Sprinkle intact granules on one tablespoon of applesauce; â&#x20AC;&#x201C; Swallow immediately. Granules should not be chewed. â&#x20AC;&#x201C; Do not store for later use.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. 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.

DEX006 R8-Brf; August 2010 L-LPD-0810-2

Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANT and Dual Delayed Release are trademarks of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.

Š2011Takeda Pharmaceuticals North America, Inc. LPD-01450R1 01/11 Printed in U.S.A.

EDITORIAL BOARD

CLINICAL EDITOR

HEALTH INFORMATION TECHNOLOGY

PHARMACY BENEFIT DESIGN

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

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

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

GOVERNMENT EDITOR

Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson

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

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

David Williams Milliman Health Consultant Windsor, CT AGING AND WELLNESS

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

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

Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta

HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals, Chadds Ford, PA

Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

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

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

POLICY & PUBLIC HEALTH

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

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

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

HEALTH & VALUE PROMOTION

Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Milwaukee

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

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

ENDOCRINOLOGY RESEARCH

MANAGED MARKETS

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

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

Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Associate Scientist, RAND Health

MANAGED CARE & GOVERNMENT AFFAIRS

Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality & biomedical research

EMPLOYERS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care Business Unit, PA

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

Charles E. Collins, Jr, MS, MBA Vice President, Managed Markets Strategy Fusion Medical Communications

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

PATIENT ADVOCACY

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA

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

Vol 4, No 4

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

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

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RESEARCH & DEVELOPMENT

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

PERSONALIZED MEDICINE

EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Vice President, Research Operations Center for Health Research Geisinger Health System, Danville, PA

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

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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

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VOLUME 4, NUMBER 4

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

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FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS PERSPECTIVE

204 Moving Beyond Medicare’s ACOs to Accountable Care Murali Karamchedu; Sam Muppalla; Robert Capobianco

BUSINESS

207 The Business Case for Payer Support of a Community-Based Health Information Exchange: A Humana Pilot Evaluating Its Effectiveness in Cost Control for Plan Members Seeking Emergency Department Care Albert Tzeel, MD, MHSA; Victor Lawnicki, PhD; Kim R. Pemble, MS 215 Stakeholder Perspective by Alberto M. Colombi, MD, MPH

CLINICAL

219 Modeling Costs and Outcomes Associated with a Treatment Algorithm for Problem Bleeding Episodes in Patients with Severe Hemophilia A and High-Titer Inhibitors Patrick Bonnet, PharmD; Alessandro Gringeri, MD; Edward Gomperts, MD; Cindy Anne Leissinger, MD; Roseline d’Oiron, MD; Jerome Teitel, MD; Guy Young, MD; Meg Franklin, PharmD, PhD; Bruce Ewenstein, MD; Erik Berntorp, MD, PhD

Mission Statement

228 Stakeholder Perspective by Hetty A. Lima, RPh, FASHP Continued on page 202

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moving millimeters

NEW EDARBI: Head-to-head efficacy trials versus the highest marketed doses of DIOVAN® (320 mg) and BENICAR® (40 mg) EDARBI 80 mg was statistically superior to DIOVAN® 320 mg and BENICAR® 40 mg in reducing 24-hr mean ambulatory and clinic SBP1 REDUCTIONS IN 24-HR MEAN AMBULATORY SBP AT WEEK 61,2 ▼ Similar results were observed across two other comparator studies: Mean ambulatory baseline: Study 2 vs BENICAR 40 mg and Study 3 vs DIOVAN 320 mg Study 1=144.9 mm Hg ▼ Clinic SBP differences between EDARBI and active comparators STUDY 1 were consistent with mean ambulatory results Study 1 Design: A 6-week, randomized, double-blind, placebo-controlled, forced-titration study in patients (N = 1,291) with clinic SBP ≥150 mm Hg and ≤180 mm Hg and 24-hr mean SBP ≥130 mm Hg and ≤170 mm Hg. The primary endpoint was change in 24-hr mean ambulatory SBP. Placebo lowered 24-hr mean ambulatory SBP by 0.3 mm Hg. Data shown are placebo corrected.

IMPORTANT SAFETY INFORMATION WARNING: AVOID USE IN PREGNANCY

When pregnancy is detected, discontinue EDARBI as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

DIOVAN 320 mg

-10.0 mm Hg BENICAR 40 mg

-11.7 mm Hg EDARBI 80 mg

-14.3 mm Hg P<0.001 vs DIOVAN 320 mg P=0.009 vs BENICAR 40 mg References: 1. EDARBI Prescribing Information. 2. White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension.

2011;57:413-420.

▼ Avoid fetal or neonatal exposure. ▼ Correct volume or salt depletion prior to administration of EDARBI, or start treatment at 40 mg. ▼ Monitor for worsening renal function in patients with renal impairment. ▼ In patients with an activated renin-angiotensin system, as by volume or salt depletion, renin-angiotensin-aldosterone system (RAAS) blockers such as azilsartan medoxomil can cause excessive hypotension. In patients whose renal function may depend on the activity of the renin-angiotensin system, e.g., with renal artery stenosis, treatment with RAAS blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. ▼ Monitor renal function periodically in patients receiving EDARBI and NSAIDs who are also elderly, volume-depleted, or who have compromised renal function. ▼ The most common adverse reaction in adults was diarrhea (2%).

For further information, please see adjacent Brief Summary of Prescribing Information.

INDICATION EDARBI is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension, either alone or in combination with other antihypertensive agents.

EDARBI is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

Trademarks are the property of their respective owners. ©2011 Takeda Pharmaceuticals North America, Inc. All rights reserved. LXA-00331 04/11

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for Edarbi (azilsartan medoxomil) tablets WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue Edarbi as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

INDICATIONS AND USAGE Edarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women during the second and third trimester. When pregnancy is detected, Edarbi should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Edarbi as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system is available. In these rare cases, the mother should be apprised of the potential hazards to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Edarbi should be discontinued unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function.

Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or saltdepleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi. Correct volume or salt depletion prior to administration of Edarbi, or start treatment at 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Impaired Renal Function As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbi. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbi.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of Edarbi in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

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 4814 patients were evaluated for safety when treated with Edarbi at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least 6 months; of these, 588 were treated for at least 1 year.

Treatment with Edarbi was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4% (19/801) for placebo, 2.2% (24/1072) for Edarbi 40 mg, and 2.7% (29/1074) for Edarbi 80 mg. The most common adverse event leading to discontinuation, hypotension/ orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to Edarbi 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo.

Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race.

In placebo controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Edarbi 80 mg daily compared with 0.5% of patients on placebo.

Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of â&#x2030;Ľ0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below: Gastrointestinal Disorders: nausea General Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue Disorders: muscle spasm Nervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: cough Clinical Laboratory Findings In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Edarbi.

Serum creatinine: Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide.

In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases.

Hemoglobin/Hematocrit: Low hemoglobin, hematocrit, and RBC counts were observed in 0.2%, 0.4%, and 0.3% of Edarbi-treated subjects, respectively. None of these abnormalities were reported in the placebo group. Low and high markedly abnormal platelet and WBC counts were observed in <0.1% of subjects.

DRUG INTERACTIONS No clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin. Therefore, Edarbi may be used concomitantly with these medications.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving azilsartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including azilsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C (first trimester) and D (second and third trimesters). There is no clinical experience with the use of Edarbi in pregnant women.

Nursing Mothers It is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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

Geriatric Use No dose adjustment with Edarbi is necessary in elderly patients. Of the total patients in clinical studies with Edarbi, 26% were elderly (65 years of age and older); 5% were 75 years of age and older. Abnormally high serum creatinine values were more likely to be reported for patients age 75 or older. No other differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment Dose adjustment is not required in patients with mild-to-severe renal impairment or end-stage renal disease. Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values.

Hepatic Impairment No dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Edarbi has not been studied in patients with severe hepatic impairment.

OVERDOSAGE Limited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of Edarbi were administered for 7 days and were well tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patientâ&#x20AC;&#x2122;s clinical status.

Azilsartan is not dialyzable.

CLINICAL PHARMACOLOGY Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensinconverting enzymes (ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis.

An AT2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction catalyzed by ACE. Because azilsartan does not inhibit ACE (kinase II), it should not affect bradykinin levels. Whether this difference has clinical relevance is not yet known. Azilsartan does not bind to or block other receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of azilsartan on blood pressure.

Pharmacodynamics Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. An azilsartan single dose equivalent to 32 mg azilsartan medoxomil inhibited the maximal pressor effect by approximately 90% at peak, and approximately 60% at 24 hours. Plasma angiotensin I and II concentrations and plasma renin activity increased while plasma aldosterone concentrations decreased after single and repeated administration of Edarbi to healthy subjects; no clinically significant effects on serum potassium or sodium were observed.

Effect on Cardiac Repolarization: A thorough QT/QTc study was conducted to assess the potential of azilsartan to prolong the QT/QTc interval in healthy subjects. There was no evidence of QT/QTc prolongation at a dose of 320 mg of Edarbi.

Pharmacokinetics Absorption: Azilsartan medoxomil is hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma after oral administration. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing.

The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.

Distribution: The volume of distribution of azilsartan is approximately 16L. Azilsartan is highly bound to human plasma proteins (>99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.

In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier. Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus.

Metabolism and Elimination: Azilsartan is metabolized to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of Edarbi. The major enzyme responsible for azilsartan metabolism is CYP2C9.

Following an oral dose of 14 C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steadystate levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.

Special Populations The effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference). Effects are modest and do not call for dosage adjustment.

Figure 1 Impact of intrinsic factors on the pharmacokinetics of azilsartan Population Description

PK

Fold Change and 90% CI

Recommendation

AGE >65y/18-45y

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

GENDER Females/Males RACE Whites/Blacks RENAL IMPAIRMENT Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

No dose adjustment

Severe/Normal

Cmax AUC

No dose adjustment

ESRD/Normal

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

HEPATIC IMPAIRMENT

No dose adjustment

Severe/Normal

NO EXPERIENCE NO EXPERIENCE

PEDIATRIC

0.5

1.0

1.5

2.0

Change relative to reference

2.5

3.0

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (450 mg azilsartan medoxomil/kg/day in the mouse and 600 mg azilsartan medoxomil/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, 80 mg azilsartan medoxomil/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested (approximately 8000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1000 mg M-II/kg/day (males) and up to 3000 mg M-II/kg/day (females) in the rat) produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD. Mutagenesis: Azilsartan medoxomil, azilsartan, and M-II were positive for structural aberrations in the Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was also positive in this assay during a 24 hr assay without metabolic activation.

Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay.

Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to 1000 mg azilsartan medoxomil/kg/day [6000 mg/m2 (approximately 122 times the MRHD of 80 mg azilsartan medoxomil/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3000 mg M-II/kg/day.

Animal Toxicology and/or Pharmacology Reproductive Toxicology: In peri- and postnatal rat development studies, adverse effects on pup viability, delayed incisor eruption and dilatation of the renal pelvis along with hydronephrosis were seen when azilsartan medoxomil was administered to pregnant and nursing rats at 1.2 times the MRHD on a mg/m2 basis. Reproductive toxicity studies indicated that azilsartan medoxomil was not teratogenic when administered at oral doses up to 1000 mg azilsartan medoxomil/kg/day to pregnant rats (122 times the MRHD on a mg/m2 basis) or up to 50 mg azilsartan medoxomil/ kg/day to pregnant rabbits (12 times the MRHD on a mg/m2 basis). M-II also was not teratogenic in rats or rabbits at doses up to 3000 mg M-II/kg/day. Azilsartan crossed the placenta and was found in the fetuses of pregnant rats and was excreted into the milk of lactating rats.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).

General Information Pregnancy: Female patients of childbearing age should be told that use of drugs like Edarbi that act on the renin-angiotensin system during pregnancy can cause serious problems in the fetus and infant including low blood pressure, poor development of skull bones, kidney failure, and death. These consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Discuss other treatment options with female patients planning to become pregnant.

Women using Edarbi who become pregnant should notify their physicians as soon as possible.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Edarbi is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Š2011 Takeda Pharmaceuticals America, Inc. For more detailed information, see the full prescribing information for Edarbi at www.edarbi.com or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.

AZL074 R1; February 2011 L-LXA-0211-2

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TABLE OF CONTENTS

(Continued)

CLINICAL

240 Anticoagulation Bridging Therapy Patterns in Patients Undergoing Total Hip or Total Knee Replacement in a US Health Plan: Real-World Observations and Implications Onur Baser, MS, PhD; Dylan Supina, PhD; Nishan Sengupta, PhD; Li Wang, MS, PhD 248 Stakeholder Perspective by Charles E. Collins, Jr., MS, MBA

DEPARTMENTS

industry trends 233 economic and Clinical Value of integrating a Clinical Pharmacist into the Care Management team Matthew Zubiller, MBA 251 American diabetes Association Highlights

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PERSPECTIVE

Moving Beyond Medicare’s ACOs to Accountable Care Murali Karamchedu, Sam Muppalla, and Robert Capobianco Mr Karamchedu is Vice President, Healthcare Strategy; Mr Muppalla is Executive Vice President and Chief Strategy and Marketing Officer; and Mr Capobianco is Director of Marketing, Portico Systems, Blue Bell, PA. (Portico Systems was acquired by McKesson Health Solutions in July 2011.)

O

n March 31, 2011, the Centers for presubmission of member communications to Medicare & Medicaid Services (CMS) CMS. These challenges have dampened the released regulations governing the enthusiasm for establishing Medicare ACOs. establishment of accountable care organizaFor example, the Mayo Clinic, Geisinger tions (ACOs) to mixed reactions from the Health System, the Cleveland Clinic, and provider community. Much of this reaction Intermountain Health have indicated hesitais driven by the governance, risk managetion toward setting up an ACO as proposed ment, and operational complexities of estabby the recent regulations.4 An emerging alternative to provider lishing a Medicare ACO. Murali Karamchedu groups independently establishing ACOs is As proposed by the regulation, provider partnerships between private payers and provider groups would have limited quantifiable performance groups in establishing ACO-like entities. These partfeedback before they assume the associated financial nerships are being designed to combine the payer’s risk.1 CMS would not begin performance analysis until the third quarter of the second year. There would be expertise in administration along with the provider’s significant start-up costs for an ACO, with estimates expertise in care delivery. One recent example of such ranging from $1.7 million, according to the US a partnership is the Pittsburgh-based Highmark’s acquiGovernment Accountability Office,2 to $26.1 million, sition of West Penn Allegheny Health System, as was as estimated by the American Health Association.3 reported in the Wall Street Journal, “With spending on The ACO must continually submit proof of complihealth care spiraling, insurers and health-care providers ance with CMS’s regulations to receive payments, with are looking for ways to cut costs, creating a range of difthe prospect of 25% of the payments withheld, to be ferent relationships in an effort to become more effiadjusted against losses in the third year. Some examples cient. Some health plans are buying clinics, and hospiof proof of compliance are: tals are exploring payment models that increasingly • Proof of development, implementation, monitoring, resemble insurance.”5 Such strategies provide a valuable template for and enforcement of evidence-based clinical guidelines establishing ACOs. Regardless of the approach, estab• Proof of adequate use of information technology to lishing accountable care will require 5 core competensupport the program cies, as described below.

• Proof that at least half of the primary care physicians are “meaningful users” of electronic medical records Core Competencies for Establishing (EMRs) by the end of the first year of participation Accountable Care in an ACO Accountable care represents a systemic and pro• Demonstration of financial ability to repay amounts gram-based approach to unifying several innovations in owed to CMS when shared losses are involved payment, care delivery, and outcomes coordination.

• Demonstration of prior and periodic review by CMS The interdependency among care teams, member outof all marketing and advertisement material used for comes, and provider payments calls for the coordinated shared savings development of the following 5 core competencies: • Ability to notify CMS 30 days before a material • Population risk modeling change of its ACO participants, and the ACO must • Care network design and rollout submit a recalculation of its primary service area.

• Care coordination enablement Additional considerations to traditional provider • Value-based reimbursement groups include the network nonexclusivity provisions, • Productization of accountable care. the impact of retrospective member attribution, and

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Population Risk Modeling Characterizing the risk represented by an ACO’s member population is a key first step. This involves understanding the potential utilization patterns of the diverse risk groups and projecting the financial costs incurred by such utilization.

Effective modeling of the population risk—based on utilization patterns, along with access requirements and other performance criteria—is the basis for determining optimal care networks that are best suited to deliver care.

Traditionally, health plans have had the tools to characterize population risk and have accumulated significant experience in understanding whether the revenues can sustain these risks.

Care Network Design and Rollout Effective population risk modeling provides a rational basis for designing provider networks. Risk modeling provides the number and type of providers required to service the population. This, along with provider performance goals, can be used as the network design criteria.

The resulting network design criteria will govern the participation of providers in the ACO network. The new ACO regulations’ nonexclusivity clauses for network participation are an example of how such network composition may be further affected by regulatory requirements.

Provider groups by themselves are ill-equipped to undertake such analysis. However, this is an area where health plans can offer significant help. Leading health plans have already been on a path to implement such criteria-based network designs. They can bring significant capabilities to enable a prospective ACO in designing and maintaining these care networks.

Care Coordination Enablement The ACO regulations place significant emphasis on patient-centeredness in care delivery.1 The 8-part definition of patient-centeredness guidelines in the regulations draw significant attention to enabling care coordination. It calls for beneficiary “experience of care” surveys, care coordinators, and care coordination technologies to electronically exchange clinical summary information during care transitions, medical records access, and communication of clinical and evidencebased knowledge to beneficiaries.1 Care coordination enablement requires clinical data integration, secure messaging with all stakeholders, and a longitudinal view of the patient across all care encounters. In addition, coordination also needs access to clinical workflow automation tools, such as EMRs, e-prescriptions, and e-laboratories. Development of care coordination platforms requires the cooperation of health plans and providers to avoid fragmentation.

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In the payer–provider partnerships, provider groups can leverage their existing clinical information technology infrastructure (eg, EMRs) while health plans enable the integration of patient data across all stakeholders.

Plans can also facilitate communication across all care delivery teams to ensure continuity of care and timely interventions. Such coordination is particularly important to populations with chronic conditions.

Value-Based Reimbursement Accountable care incorporates a shift from volumebased reimbursement to outcomes-based (ie, valuebased) provider reimbursement. It also incorporates risk sharing to incentivize the achievement of high-quality outcomes. The performance of providers is measured against specific financial and quality goals. The right mix of payment strategies is leveraged to incentivize the desired performance. Bundled payments and shared savings are a typical part of this approach. However, they introduce complexity in payment partitioning among the different providers in a care network. Effective decision support needs the description of the details of reimbursement partitioning in a single source of truth.

Although ACOs are likely to be reimbursed through shared-savings models, they may have to reimburse their providers through fee-for-service, episodic care, or other payment arrangements. Efficient reconciliation of this paradox will be key to the financial success of each ACO and the approach to accountable care.

Once again, a health plan’s experience with such complex reimbursement scenarios is increasingly seen as an argument favoring a partnership between health plans and provider groups. However, existing health plan claims pricing competencies will need to be augmented to deal with value-based reimbursement. A key component of payments in accountable care is the continual demonstration of compliance with performance guidelines. Provider groups will need to facilitate access to performance data to enable the application of appropriate payment.

Productization of Accountable Care Productization of accountable care—namely, the incorporation of accountable care into existing products—will be crucial to the commercial success of accountable care. Accountable care offers the prospect of designing products with lower premiums and improved outcomes. ACO products will need to include benefit designs that steer members to the ACO as the preferred provider.

Employers are increasingly demanding such customized benefit designs that better serve their employee populations. Employers see this as the basis for contain-

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ing premium growth. Although health plans have addressed these needs for select employers, expansion across the customer base introduces significant administrative costs.

Productization of accountable care is an area where a health plan can demonstrate significant leadership. A partnership with provider groups will foster the adoption of accountable care products with employers.

Critical Success Factors for Accountable Care Alignment of Network, Product, Care Model, and Reimbursement Design The alignment of network, product, care model, and reimbursement design is critical to balancing the value of care to insured members (eg, reduced premiums and high quality of care) against the value to the ACO (eg, revenue, expenses, and provider satisfaction). The proper design of care networks is critical to this alignment.

Network designs perform several functions. They create effective steerage targets for product benefits. Network designs ensure high quality of care through care team design. Network reimbursement policies drive provider reimbursement to incent the desired outcomes.

Administrative Simplification through Integrated Systems The complexity of payer–provider ACO partnerships brings the prospect of significant administrative costs.

Some of these costs stem from the existing disconnected nature of administrative processes and systems.

Mitigating this issue and simplifying the administrative challenges requires the integration of key systems.

Currently, health plans’ provider management and claims systems are poorly connected to several key business functions, such as utilization management, contracting, and financial planning.

Such disconnectedness renders basic decision support ineffective. As an example, many organizations routinely struggle to answer 2 critical questions: “Which providers are covered by a particular contract?” and “What are the diverse arrangements that cover a particular provider?”

A patchwork of ad hoc solutions often serves these tactical needs. This is inadequate in the face of increasingly complex, overlapping payment arrangements implicit in the ACO regulations. Support of tailored ACO products will increase the burden on these disconnected and inflexible systems. The complex demands of provider network performance-related payments will increase the risk of information leakage, payment errors, and performance misreporting.

These daunting challenges call for an integrated approach to provider management. This approach will

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integrate network, reimbursement, and clinical systems and would establish a connected platform that not only reduces administrative complexity, but offers a platform for informed decision-making and transparency.

Buy-In through Provider and Member Transparency Measuring and reporting provider performance are key components of the ACO initiative. Participating providers will legitimately demand to know what payment rules and performance measures influenced their individual payments. Members will demand the quality outcomes of their care teams and the details of their medical expenses. This demands a dynamic and flexible reporting capability. The reporting capabilities need to enable transparency across all stakeholders, by presenting a consistent rationale for the different constituents: members, participating providers, the government, and the employers.

Conclusion Although the Medicare ACO regulations are being contested, the spirit behind ACOs to promote valuebased designs and payments is being embraced. Many aspects of the incentives and challenges are still undergoing serious reexamination. Ultimately, the promise of accountable care depends on the intelligent alignment of products, networks, care models, and reimbursement designs. A look at the history of healthcare evolution ensures us that although the acronyms may change, our pursuit of accountable, affordable, and high-quality care will continue. The investment in the areas described here are critical in this iteration of our healthcare journey and the next one that is sure to follow.

Author Disclosure Statement Mr Karamchedu, Mr Muppalla, and Mr Capobianco have reported no conflicts of interest.

References 1. US Department of Health and Human Services, Centers for Medicare & Medicaid Services. Medicare shared savings program: accountable care organizations. Timing and process for evaluating shared savings. Docket No. CMS-1345-P; RIN 0938– AQ22. Federal Register. 2011;76:19527-19654. http://edocket.access.gpo.gov/2011/ pdf/2011-7880.pdf. Accessed June 27, 2011.

2. Department of Government Relations, American Psychiatric Association.

Accountable care organizations. www.psych.org/MainMenu/AdvocacyGovernment Relations/GovernmentRelations/HealthCareReform/ACOs.aspx?FT=.pdf. Accessed June 27, 2011.

3. American Hospital Association. New study finds the start up costs of establishing an ACO to be significant. Press release. May 13, 2011. www.aha.org/aha/pressrelease/2011/110513-pr-aco.html. Accessed June 27, 2011.

4. Page L. Mayo, Geisinger, Cleveland Clinic may not participate in ACOs. May 10, 2011. www.beckershospitalreview.com/hospital-physician-relationships/mayo-geisingercleveland-clinic-may-not-participate-in-acos.html. Accessed June 27, 2011.

5. Mathews AW. Insurer’s cost-cut plan: buy hospitals. WSJ. June 29, 2011. http:// online.wsj.com/article/SB10001424052702303627104576413580875856442.html.

Accessed July 22, 2011.

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viibryd: Approved to treat Major Depressive Disorder (MDD) in adults

Important Safety Information WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of VIIBRYD or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. VIIBRYD is not approved for use in pediatric patients.

Contraindications • VIIBRYD must not be used concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. Allow at least 14 days after stopping VIIBRYD before starting an MAOI. Warnings and Precautions • All patients treated with antidepressants should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment and when changing the dose.

Consider changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, or suicidality that are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Families and caregivers of patients being treated with antidepressants should be alerted about the need to monitor patients daily.

Prescriptions for VIIBRYD should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

• The development of potentially life-threatening serotonin syndrome

or Neuroleptic Malignant Syndrome (NMS)-like reactions has been reported with antidepressants alone, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Symptoms of serotonin syndrome were noted in 0.1% of patients treated with VIIBRYD. Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms while treated with VIIBRYD. • Like other antidepressants, VIIBRYD should be prescribed with caution in patients with a seizure disorder.

• The use of drugs that interfere with serotonin reuptake, including VIIBRYD, may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of VIIBRYD and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation or bleeding.

Please also see additional Important Safety Information and brief summary of Prescribing Information on following pages.

Please also see full Prescribing Information at www.viibryd.com.

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The first and only SSRI and 5-HT1A receptor partial agonist1 • While the MOA is not fully understood, it is thought to be related to enhancement of serotonergic activity • The role of 5-HT1A partial agonist activity on serotonergic transmission and antidepressant effect is unknown

Proven efficacy in adults with MDD1–4 • Significant improvement vs placebo in Montgomery-Asberg Depression Rating Scale (MADRS) total score in

two 8-week, randomized and controlled studies (P<0.01) – At week 8, least squares (LS) mean difference from placebo in change from baseline in MADRS total score was -2.5 in Khan et al and -3.2 in Rickels et al

MADRS mean total score reduction from baseline at week 82-4 Rickels et al

Placebo (n=232)

LS MEAN CHANGE FROM BASELINE

LS MEAN CHANGE FROM BASELINE

Khan et al VIIBRYD (n=231) 0 -2

42% change from baseline vs 34% for placebo2,4

-4 -6 -8 -10

-10.8

-12 -14

-13.3*

*P=0.009 vs placebo

-16

Baseline values: 31.9 for VIIBRYD and 32.0 for placebo

VIIBRYD (n=198)

Placebo (n=199)

0 -2

42% change from baseline vs 31% for placebo3,4

-4 -6 -8 -10

-9.6

-12 -14

-12.9

†

†

P=0.001 vs placebo

-16

Baseline values: 30.8 for VIIBRYD and 30.7 for placebo

Randomized, double-blind, placebo-controlled, multicenter, 8-week clinical trials to determine the efficacy and safety of VIIBRYD in adults aged 18 to 70 years in Khan et al, and in adults aged 18 to 65 years in Rickels et al, who were diagnosed with MDD. Patients were randomized to receive VIIBRYD (n=231) or placebo (n=232) in Khan et al, and VIIBRYD (n=198) or placebo (n=199) in Rickels et al. Last observation carried forward analysis shown.1-3 The primary efficacy endpoint was the change from baseline in MADRS total score to week 8 (ITT population).

The LS mean difference (95% confidence interval) from placebo in change from baseline in MADRS total score was -2.5 (-4.4, -0.6) in Khan et al and -3.2 (-5.2, -1.3) in Rickels et al.

VIIBRYD treatment was initiated once daily at 10 mg for 7 days, followed by 20 mg for another 7 days, and 40 mg thereafter until the end of week 8. VIIBRYD was administered with food.1-3

Important Safety Information (continued) Warnings and Precautions • Symptoms of mania/hypomania were noted in 0.1% of patients treated with VIIBRYD in clinical studies. As with all antidepressants, VIIBRYD should be used cautiously in patients with a history or family history of bipolar disorder, mania or hypomania.

• Prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder. VIIBRYD is not approved for use in treating bipolar depression.

• Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as VIIBRYD. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible.

Monitor patients when discontinuing VIIBRYD. If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate.

• Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking VIIBRYD. Although no cases of hyponatremia resulting from VIIBRYD treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. Discontinuation of VIIBRYD in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

VIIBRYD is a trademark of Forest Laboratories, Inc. © 2011 Forest Laboratories, Inc. 47-12000115-PI

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Adverse Reactions

• The most commonly observed adverse reactions in MDD patients treated with VIIBRYD in placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were: diarrhea (28% vs 9%), nausea (23% vs 5%), insomnia (6% vs 2%), and vomiting (5% vs 1%).

References: 1. Viibryd (vilazodone HCl) [package insert]. St Louis, MO: Forest Pharmaceuticals, Inc.; 2011. 2. Khan A, Cutler AJ, Kajdasz DK, et al. A randomized, double-blind, placebocontrolled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. J Clin Psychiatry. 2011;72:441-447. 3. Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR. Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial.

J Clin Psychiatry. 2009;70:326-333. 4. Data on file. Forest Laboratories, Inc.

Please also see brief summary of Prescribing Information on following pages and full Prescribing Information at www.viibryd.com.

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VIIBRYD (vilazodone HCl) Tablets for oral administration Brief Summary of full Prescribing Information Initial U.S. Approval: 2011

Rx Only

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of VIIBRYD or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. VIIBRYD is not approved for use in pediatric patients [see Warnings and Precautions, Use in Specific Populations, and Patient Counseling Information] INDICATIONS AND USAGE: VIIBRYD is indicated for the treatment of major depressive disorder (MDD).

The efficacy of VIIBRYD was established in two 8-week, randomized, double-blind, placebo-controlled trials in adult patients with a diagnosis of MDD [see Clinical Studies]. Major depressive disorder consists of one or more major depressive episodes. A major depressive episode (DSM-IV-TR) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.

CONTRAINDICATIONS: Monoamine Oxidase Inhibitors - VIIBRYD must not be used concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Allow at least 14 days after stopping VIIBRYD before starting an MAOI [see Drug Interactions].

WARNINGS AND PRECAUTIONS: Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. There were 14 additional cases reported in patients under the age of 18, while 5 additional cases were reported in patients between 18 and 24 years of age. Patients between 25 and 64 years of age reported 1 fewer case of suicidality, while patients 65 years of age and over reported 6 fewer cases. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions and Dosage and Administration]. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for VIIBRYD should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose [see also Patient Counseling Information]. Screening patients for bipolar disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above

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represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that VIIBRYD is not approved for use in treating bipolar depression. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)like Reactions - The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions has been reported with antidepressants alone, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs that impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Symptoms of serotonin syndrome were noted in 0.1% of patients treated with VIIBRYD. 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). Serotonin syndrome, in its most severe form can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of VIIBRYD with MAOIs intended to treat depression is contraindicated [see Contraindications]. If concomitant treatment of VIIBRYD with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions]. The concomitant use of VIIBRYD with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions]. Treatment with VIIBRYD and any concomitant serotonergic (SSRI, serotonin–norepinephrine reuptake inhibitor [SNRI], triptan, buspirone, tramadol, etc.) or antidopaminergic drugs, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Seizures - VIIBRYD has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Like other antidepressants, VIIBRYD should be prescribed with caution in patients with a seizure disorder. Abnormal Bleeding - The use of drugs that interfere with serotonin reuptake inhibition, including VIIBRYD, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), warfarin, and other anticoagulants 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 have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of VIIBRYD and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Activation of Mania/Hypomania - Symptoms of mania/hypomania were reported in 0.1% of patients treated with VIIBRYD in clinical studies.

Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use VIIBRYD cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. Discontinuation of Treatment with VIIBRYD - There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Monitor patients for these symptoms when discontinuing VIIBRYD. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate [see Dosage and Administration]. Hyponatremia - Although no cases of hyponatremia resulting from VIIBRYD treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of VIIBRYD in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

ADVERSE REACTIONS: Clinical Studies Experience - The most commonly observed adverse reactions in VIIBRYD-treated MDD patients in placebo-controlled studies (incidence ≥5% and at least twice the rate of placebo) were: diarrhea, nausea, vomiting, and insomnia. Patient Exposure - The safety of VIIBRYD was evaluated in 2,177 patients (18-70 years of age) diagnosed with MDD who participated in clinical studies, representing 552 patient-years of exposure. In an open-label 52 week study at 40 mg daily, 599 patients were exposed to VIIBRYD for a total of 348 patient-years. The information presented in these sections was derived from studies of VIIBRYD 40 mg daily in major depressive disorder including: 1) 2 placebo-controlled 8-week studies in 861 patients, including 436 receiving vilazodone; and 2) an open-label 52-week study of 599 patients. These studies included a titration period of 10 mg daily for 7 days followed by 20 mg daily for 7 days. In these clinical trials, VIIBRYD was administered with food. Because clinical trials are conducted under widely varying conditions and varying lengths of time, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in practice. Adverse reactions reported as reasons for discontinuation of treatment - In the placebo-controlled studies of MDD there was no single adverse reaction leading to discontinuation in > 1% of the patients. Overall, 7.1% of the patients who received VIIBRYD discontinued treatment due to an adverse reaction, compared with 3.2% of placebo-treated patients in these studies. Common adverse reactions in placebo-controlled MDD studies - Table 2 shows the incidence of common adverse reactions that occurred in ≥2% of VIIBRYDtreated MDD patients (and greater than in placebo-treated patients) in the placebo-controlled studies.

The first value displays the number of patients exhibiting the adverse reaction while receiving VIIBRYD 40 mg/day (N = 436) and the second value is the number of patients exhibiting the adverse reaction while receiving Placebo (N = 433). Gastrointestinal disorders: Diarrhea (28, 9); Nausea (23, 5); Dry mouth (8, 5); Vomiting (5, 1); Dyspepsia (3, 2); Flatulence (3, 2); Gastroenteritis (3, <1); Nervous system disorders: Dizziness (9, 5); Somnolence (3, 2); Paresthesia (3, 1); Tremor (2, 0); Psychiatric disorders: Insomnia (6, 2); Abnormal dreams (4, 1); Libido decreased (4, <1); Restlessness* (3, <1); Orgasm abnormal** (3, 0); General disorders: Fatigue (4, 3); Feeling jittery (2, <1); Cardiac disorders: Palpitations (2, <1); Musculoskeletal and connective tissue disorders: Arthralgia (3, 2); Reproductive system and breast disorders: Delayed ejaculation*** (2, 0); Erectile dysfunction*** (2, 1); Metabolism and nutrition disorders: Increased appetite (2, 1). *Includes restlessness, akathisia, and restless legs syndrome; **Includes orgasm abnormal and anorgasmia; ***Male patients only (Placebo n=182; VIIBRYD n=170). Table 3 shows the percentages of Sexual Adverse Reactions in the Placebo-Controlled Studies. The first grouping shows the percentages in Males with VIIBRYD (N=170) and Placebo (N=182).

The second grouping shows the percentages in Females with VIIBRYD (N=266) and Placebo (N = 251).

Decreased libido (5,0)/(3,<1); Abnormal orgasm* (4,0)/(2,0); Delayed ejaculation (2,0)/(−,−); Erectile dysfunction (2,1)/(−,−); Sexual dysfunction (2,0)/(<1,<1). − Not applicable; *Includes

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anorgasmia. Laboratory Tests - VIIBRYD has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (including liver function tests), hematology and urinalysis, as measured in placebo-controlled studies. These studies include analysis of (1) mean change from baseline and (2) the proportion of patients meeting criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. ECG - VIIBRYD has not been associated with any clinically significant effect on ECG parameters, including QT, QTc, PR and QRS intervals, or with any arrhythmogenic potential. ECGs were evaluated in a thorough QTc study at doses up to 80 mg daily with food and in the placebo-controlled studies [see Clinical Pharmacology]. Vital Signs - VIIBRYD has not been associated with any clinically significant effect on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies. These studies included analyses of (1) change from baseline, and (2) the proportion of patients meeting criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies. Weight - VIIBRYD had no effect on body weight as measured by the mean change from baseline in the 8-week, placebo-controlled studies. The mean changes in weight were +0.16 kg in the VIIBRYD group and +0.18 kg in the placebo group. The proportions of patients with a weight gain ≥7% were 0.9% in the VIIBRYD group and 1.2% in the placebo group.The proportions of patients with a weight decrease ≥7% were 1.4% in the VIIBRYD group and 1.4% in the placebo group. Other adverse reactions observed in clinical studies - The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients; Cardiac disorders: infrequent: ventricular extrasystoles; Eye disorders: frequent: vision blurred, dry eye; infrequent: cataracts; General disorders: infrequent: feeling abnormal; Metabolism and nutrition disorders: frequent: decreased appetite; Nervous System: frequent: sedation, migraine; infrequent: dysgeusia; Psychiatric disorders: infrequent: panic attack, mania; Renal and Urinary disorder: infrequent: pollakiuria; Skin and subcutaneous tissue disorders: frequent: hyperhidrosis, night sweats DRUG INTERACTIONS: Central Nervous System (CNS)-Active Agents - The risk of using VIIBRYD in combination with other CNS-active drugs has not been systematically evaluated. Consequently, use caution when VIIBRYD is prescribed in combination with other CNS-active drugs. Monoamine Oxidase Inhibitors (MAOI) - Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on antidepressant(s) with pharmacological properties similar to VIIBRYD (e.g. SSRIs), or who have recently had SSRI therapy discontinued prior to initiation of an MAOI. Do not prescribe VIIBRYD concomitantly with an MAOI or within 14 days of discontinuing or starting an MAOI [see Contraindications]. Serotonergic Drugs - Based on the mechanism of action of VIIBRYD and the potential for serotonin toxicity, also known as serotonin syndrome, caution is advised when VIIBRYD is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., MAOI, SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.) [see Warnings and Precautions]. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when VIIBRYD is initiated or discontinued [see Warnings and Precautions]. Potential for Other Drugs to Affect Vilazodone Figure 1. Impact of Other Drugs on Vilazodone PK

Inhibitors of CYP3A4 - Metabolism by CYP3A4 is a major elimination pathway for vilazodone. Concomitant use of VIIBRYD and strong inhibitors of CYP3A4 (e.g., ketoconazole) can increase vilazodone plasma concentrations by approximately 50% (see Figure 1). The VIIBRYD dose should be reduced to 20 mg if co-administered with a strong inhibitor of CYP3A4. During co-administration with moderate inhibitors of CYP3A4 (e.g., erythromycin), the VIIBRYD dose should be reduced to 20 mg for patients with intolerable adverse events. No dose adjustment is recommended when VIIBRYD is co-administered with mild inhibitors of CYP3A4 (e.g., cimetidine). Inducers of CYP3A4 - Concomitant use of VIIBRYD with inducers of CYP3A4 has the potential to reduce vilazodone systemic exposure. However, the effect of CYP3A4 inducers on vilazodone plasma concentrations has not been evaluated. Inhibitors of other CYP enzymes - Concomitant administration of VIIBRYD with inhibitors of CYP2C19 and CYP2D6 is not expected to alter plasma concentrations of vilazodone. These isoforms are minor elimination pathways in the metabolism of vilazodone. In vitro studies have shown that CYP1A2, CYP2A6, CYP2C9 and CYP2E1 have minimal contribution to the metabolism of vilazodone. Potential for Vilazodone to Affect Other Drugs - Drugs metabolized by CYP1A2, CYP2C9, CYP2D6, CYP3A4 or CYP2C19. Coadministration of VIIBRYD with substrates for CYP1A2, CYP2C9, CYP3A4, or CYP2D6 is unlikely to result in clinically significant changes in the concentrations of the CYP substrates. A study in healthy subjects found that VIIBRYD (20 mg/day for 8-10 days) had no effect on the pharmacokinetics of caffeine, flurbiprofen, nifedipine or debrisoquine, probes for CYP1A2, CYP2C9, CYP3A4, and CYP2D6, respectively. VIIBRYD coadministration with mephenytoin to healthy subjects resulted in a small (11%) increase in mephenytoin biotransformation, suggestive of a minor induction of CYP2C19. In vitro studies have shown that VIIBRYD is a moderate inhibitor of CYP2C19 and CYP2D6. Drugs metabolized by CYP2C8 - Coadministration of VIIBRYD with a CYP2C8 substrate may lead to an increase in concentration of the other drug. In vitro studies suggest that VIIBRYD may inhibit the biotransformation of substrates of CYP2C8. The effect of VIIBRYD on CYP2C8 activity has not been tested in vivo. Induction of CYP isoforms - VIIBRYD did not induce CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 or 3A5 in an in vitro study in cultured human hepatocytes. Chronic administration of vilazodone is unlikely to induce the metabolism of drugs metabolized by these major CYP isoforms. Drugs Highly Bound to Plasma Protein - The interaction between vilazodone and other highly protein-bound drugs has not been evaluated. Because vilazodone is highly bound to plasma protein, administration of VIIBRYD to a

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patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug.

USE IN SPECIFIC POPULATIONS: Pregnancy, Teratogenic Effects - Pregnancy Category C - Vilazodone caused some developmental toxicity in rats, but was not teratogenic in rats or rabbits. There are no adequate and well-controlled studies of VIIBRYD in pregnant women. When treating pregnant women with VIIBRYD, carefully consider whether the potential benefits outweigh the potential risks of treatment.

No teratogenic effects were observed when vilazodone was given to pregnant rats or rabbits during the period of organogenesis at oral doses up to 200 and 36 mg/kg/day, respectively. These doses are 48 and 17 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 40 mg on a mg/m2 basis. Fetal body weight gain was reduced, and skeletal ossification was delayed in both rats and rabbits at these doses; these effects were not observed at doses up to 10 times the MRHD in rats or 4 times the MRHD in rabbits. When vilazodone was administered to pregnant rats at an oral dose of 30 times the MRHD during the period of organogenesis and throughout pregnancy and lactation, the number of live born pups was decreased. There was an increase in early postnatal pup mortality, and among surviving pups there was decreased body weight, delayed maturation, and decreased fertility in adulthood. There was some maternal toxicity at this dose. These effects were not seen at 6 times the MRHD. Nonteratogenic Effects - Neonates exposed to serotonergic antidepressants 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 serotonergic antidepressants 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]. Labor and Delivery - The effect of VIIBRYD on labor and delivery in humans is unknown. VIIBRYD should be used during labor and delivery only if the potential benefit outweighs the potential risk. Nursing Mothers - Vilazodone is excreted into the milk of lactating rats. The effect of VIIBRYD on lactation and nursing in humans is unknown. Breast feeding in women treated with VIIBRYD should be considered only if the potential benefit outweighs the potential risk to the child. Pediatric Use - Clinical studies on the use of VIIBRYD in pediatric patients have not been conducted; therefore, the safety and effectiveness of VIIBRYD in the pediatric population have not been established. VIIBRYD is not approved for use in pediatric patients [see Boxed Warning and Warnings and Precautions]. Geriatric Use - No dose adjustment is recommended on the basis of age (see Figure 2). Results from a single-dose (20 mg) pharmacokinetic study in elderly (> 65 years-old) vs. young (24-55 years-old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2177 patients in clinical studies with VIIBRYD, 37 (1.7%) were 65 years of age or older, and 272 (12.5%) were 55 to 64 years of age. Greater sensitivity of some older individuals cannot be ruled out [see Dosage and Administration]. Serotonergic antidepressants 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]. Hepatic Impairment - Vilazodone is eliminated primarily by hepatic metabolism. In mild and moderate hepatic impairment, no dose adjustment is necessary (see Figure 2). VIIBRYD has not been studied in patients with severe hepatic impairment [see Dosage and Administration]. Renal Impairment - In mild, moderate, and severe renal impairment, no dose adjustment is necessary (see Figure 2 below) [see Dosage and Administration]. Gender Effect - After adjustment for body weight, the systemic exposures between males and females are similar (see Figure 2) [see Dosage and Administration].

Figure 2. Impact of Intrinsic Factors on Vilazodone PK

OVERDOSAGE: Human Experience - There is limited clinical experience regarding human overdosage with VIIBRYD. Four patients and 1 patient’s child experienced an overdose of VIIBRYD; all recovered.

The adverse reactions associated with overdose of VIIBRYD at doses of 200-280 mg as observed in clinical trials included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation.

Management of Overdose - Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference® (PDR). No specific antidotes for vilazodone are known. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be considered. Removal of vilazodone by dialysis has not been studied; however, the high volume of distribution of vilazodone suggests that dialysis will not be effective in reducing vilazodone plasma concentrations.

Distributed by Licensed from Merck KGaA, Forest Pharmaceuticals, Inc. Darmstadt, Germany Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA VIIBRYD™ is a trademark of Forest Laboratories, Inc. © 2011 Forest Laboratories, Inc. Rev April 2011 47-1020722-BS-A-APR11 Please also see full Prescribing Information at www.viibryd.com.

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BUSINESS

ORIGINAL RESEARCH

The Business Case for Payer Support of a Community-Based Health Information Exchange: A Humana Pilot Evaluating Its Effectiveness in Cost Control for Plan Members Seeking Emergency Department Care Albert Tzeel, MD, MHSA; Victor Lawnicki, PhD; Kim R. Pemble, MS Background: As emergency department utilization continues to increase, health plans must limit their cost exposure, which may be driven by duplicate testing and a lack of medical history at the point of care. Based on previous studies, health information exchanges (HIEs) can potentially provide health plans with the ability to address this need.

Objective: To assess the effectiveness of a community-based HIE in controlling plan costs arising from emergency department care for a health plan’s members.

Methods: The study design was observational, with an eligible population (N = 1482) of fully insured plan members who sought emergency department care on at least 2 occasions during the study period, from December 2008 through March 2010. Cost and utilization data, obtained from member claims, were matched to a list of persons utilizing the emergency department where HIE querying could have occurred. Eligible members underwent propensity score matching to create a test group (N = 326) in which the HIE database was queried in all emergency department visits, and a control group (N = 325) in which the HIE database was not queried in any emergency department visit.

Results: Post–propensity matching analysis showed that the test group achieved an average savings of $29 per emergency department visit compared with the control group. Decreased utilization of imaging procedures and diagnostic tests drove this cost-savings.

Conclusions: When clinicians utilize HIE in the care of patients who present to the emergency department, the costs borne by a health plan providing coverage for these patients decrease. Although many factors can play a role in this finding, it is likely that HIEs obviate unnecessary service utilization through provision of historical medical information regarding specific patients at the point of care.

Albert Tzeel

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2011;4(4):207-216 www.AHDBonline.com Disclosures are at end of text

“Information should follow the patient, and artificial obstacles—technical, business related, bureaucratic—should not get in the way.”1 —David Blumenthal, MD, MPP

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owhere is this caveat from David Blumenthal, MD, MPP, the former National Coordinator for Health Information Technology, more applicable than in the emergency department setting. Although originally designed as the section of a hospital where Dr Tzeel is National Medical Director, HumanaOne, and Clinical Leadership & Policy Development, Humana, Milwaukee, WI; Dr Lawnicki is Econometrician, Business Intelligence & Informatics Competency Center, Humana, Louisville, KY; Mr Pemble is Executive Director/CEO, Wisconsin Health Information Exchange, Mequon, WI.

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only the most acutely ill persons should seek care for their maladies, the emergency department has become much more than that. It now serves as the primary care provider for many who have no such physician outside the emergency department.2,3 In addition, the emergency department provides a triage function for nonemergent cases that have no reason to be seen in the emergency department yet continue to increase in number.4,5 Finally, the emergency department coordinates care for individuals who have chronic medical conditions.6-8 Such emergency department care results in increased

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KEY POINTS ➤

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The use of the emergency department for nonemergent cases is prevalent, resulting in diminished quality of care and increased expenditures to health plans.

Health information exchanges (HIEs) can allow clinicians to access a patient’s medical history to reduce duplicate testing in the emergency department and lower unnecessary expenses.

In a previous preliminary study, HIE querying reduced the time spent gathering data and the time to disposition decision.

In 2008, Humana in southeast Wisconsin became one of the first health plans in the country to provide a financial incentive to the local HIE for promoting the querying of a clinical database by emergency department clinicians.

In this pilot study, the use of HIEs resulted in an average savings to the health plan of $29 per emergency care event.

Findings from this study suggest that substantial change in outcomes that matter is clinically important, regardless of statistical significance; improving provider performance has cost-saving implications for a health plan and the community at large.

emergency department expenditures and in diminished quality of care.9 Many of the increased expenditures may be directly traced to redundant diagnostic testing.10 Moreover, it is costly for health plans: emergency department care makes up 7% of a health plan’s budget.11 Given that individuals with health insurance drive the increasing use of the emergency department, this issue will continue to be problematic for health plans.12 For these reasons, many tout health information exchanges (HIEs)—where clinical data are exchanged between hospitals, providers, public health administrators, and, potentially, payers—as a method of addressing emergency department overutilization.13 Payer participation in HIEs can promote care coordination and cost control for the end user—the plan’s members—as well as create value for the plan’s customers—the employers. Moreover, because HIEs tend to view payers as receiving the greatest benefit from HIE, many believe that payer support of the exchanges provides a path toward sustainability.14 For payers to invest in HIE voluntarily, they must see the business case for doing so.15 Yet, up to now, only scant evaluations of measured HIE benefits can be found.16 Ultimately, assessing the effectiveness of HIE between multiple facilities in a community can show payers the rationale for having such an exchange from the individ-

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ual health, population health, and financial perspective.

A positive evaluation helps to promote the business case for continued support of these exchanges.17 This was the purpose of the present study.

Study Background Beginning in December 2008, Humana in southeast Wisconsin became the first local health plan—and one of the first in the nation—to provide a financial incentive to the local HIE for promoting the querying of a clinical database by emergency department clinicians (as a part of their workflow) for our fully insured members who present to the emergency department for care.18 The Wisconsin Health Information Exchange (WHIE; www.whie.org) serves as the vehicle for linking disparate emergency departments across 5 competitive health systems in Milwaukee County.19 The WHIE Emergency Department Linking program provides clinicians access to comprehensive encounter history data including: patient demographics, encounter location, date and time, chief complaint, allergy and reaction, primary care provider, and diagnosis. (In addition, these Medicaid patient data include details on procedures performed and prescription fills.) These encounter data guide providers toward the specific information they need to manage patients. Providers may also post messages related to patient-specific care coordination and encounters. These messages become part of the patient’s history and are available to other providers in the course of patient care.

Evaluating the effectiveness of using the WHIE (or any HIE, for that matter) is challenging, because “the economic value is diffuse, accrues over time, and is difficult to measure.”20 Yet, to determine if Humana receives “value” for its investment, and to promote the business case for a continued investment in WHIE sustainability, Humana analyzed WHIE’s effectiveness in controlling costs for our members who sought emergency care, as described in this article. If the Humana–WHIE relationship demonstrates mutual benefit, then this study could serve to encourage other plans toward an additional investment in HIE, which will advance HIE sustainability, and to embrace HIE standards and services.21 Methods Study Design: Developing the Sample Population for Evaluation There is no way for a health plan to know which of its members will seek emergency department care and where. Planning this evaluation to address such concerns served as a focal point of discussion as this proposal advanced to approval through the Humana version of an institutional review board—the clinical “stage gate

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process.” The planned evaluation presumed an observational and retrospective analysis, with the appropriate statistical techniques, such as propensity scoring methodology, for addressing such a quasi-experimental design.

In developing the member pool from which to draw the evaluation population, Humana and the WHIE had agreed in advance that the plan would provide to the WHIE a financial incentive to cover their costs for promoting emergency department clinicians’ querying of the WHIE database for eligible Humana members who presented to the emergency department for care.22 WHIE encouraged emergency department clinicians to make querying the WHIE database a standard part of the emergency department workflow for all patients seeking emergency department care, but, for the purposes of this pilot study, Humana provided the incentive only in cases where a query occurred for an eligible Humana member.

Eligible members were commercial, fully insured members. Self-funded group members were specifically excluded, because we could not ensure savings before the analysis and did not want these groups to assume more financial risk than necessary. Therefore, any non–fully insured members or members otherwise covered by public programs (eg, Medicare or Medicaid) would be ineligible for this study.

WHIE provided Humana, on a quarterly basis, specified data about each health plan member who was fully insured by Humana and who sought emergency department care, as well as when the emergency department clinician accessed the WHIE database for that patient and at which emergency department/facility. The data included the last 4 digits of the Social Security number if known, date/time of emergency department registration, group number, group name, policy number if known, and facility (eg, hospital).

In contrast to the clinical data provided to the emergency department clinicians, WHIE provided no clinical data to Humana for each member, except for such data as would appear on a claim related to the clinical encounter. All communications were compliant with the Health Insurance Portability and Accountability Act and used encrypted files.

The information provided allowed Humana to match emergency department claims data received from providers with the emergency department encounter by date of service and facility. Once we matched member claims for emergency department services with the WHIE file, we then looked at specific procedures and associated costs for an individual member’s given encounter.

In working with claims data, we needed to stipulate explicit parameters for member inclusion in the evaluation sample. Inclusion criteria were:

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1. All members included in the evaluation must have had at least 12 months of continuous coverage with our health plan 2. Members would be excluded from the evaluation if they had either less than 6 months of coverage before the start of the program or less than 3 months of coverage after the start of the program 3. Because plan cost would be the key parameter of evaluation, we excluded potential outliers from the analysis.

An “outlier” was defined as someone who had exceeded $10,000 in claims during a single emergency department visit. This exclusion prevented potential skewing of the data by a member who might have been held as a “24-hour observation” in the emergency department rather than admitted to the hospital (where the emergency department costs roll into the total admission cost and would not be included in our analysis). If the member were not admitted and not held as a “24-hour observation,” our data showed that such an individual did not exceed $10,000 in claims for a single emergency department encounter.

Study Design: Criteria for the Test Group and the Control Group We identified members who were seen in the emergency department when the WHIE database was queried as eligible for the test group; members who were seen in the emergency department where the WHIE database was not queried (because the facility had not yet provided WHIE access at that time) were identified as eligible for the control group.

For the test group, there were 428 plan members presenting for emergency department care with a WHIE database query in both a first emergency department visit and any subsequent emergency department visit.

Alternatively, in the control group, there were 1054 plan members who presented for emergency department care without a WHIE database query in either a first emergency department visit or any subsequent emergency department visit.

In addition, for this observational and retrospective study, propensity scoring afforded the best way to match members and minimize bias. Propensity scoring provides “the conditional probability of receiving the treatment given the observed covariates.”23 For our purposes, a member for whom WHIE database querying occurred at the point of care would have a dependent variable in the logistic regression of “y = 1,” whereas a member whose care did not include WHIE database querying would have a dependent variable of “y = 0.”

In their seminal article, Rosenbaum and Rubin showed that the “adjustment for the scalar propensity score is sufficient to remove bias due to all observed

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covariates.”24 Furthermore, propensity scoring has been found to yield estimates that are not substantially different from typical multivariable methods.25,26 For the logistic regression analysis, we used all the following combinations of cost-related and demographic variables to match the 2 groups—age, gender, medical net costs paid per participant per month (PPPM), net prescription costs paid PPPM, medical plus net prescription costs paid PPPM, medical inpatient net costs paid PPPM, medical outpatient net costs paid PPPM, emergency department net costs paid PPPM, and medical physician net costs paid PPPM. With the exception of age and gender, all these variables represent dollar values, because not only were those the outcomes of interest, but they were also unrelated to the specific dependent variable (WHIE database querying). Simulation studies have shown that one should always include “variables that are unrelated to the exposure but related to the outcome” in a propensity scoring model.27 The econometrician among us, coauthor Victor Lawnicki, PhD, developed the propensity scores with which we matched the participants using the nearest neighbor algorithm. Matching allows for “sampling from a large reservoir of potential controls to produce a control group of modest size in which the distribution of covariates is similar to the distribution in the treated group.”24 MATLAB version 7.0.1.1 was used for member matching.28

Data Analysis Once we completed matching 325 pairs of individuals for the test and control groups, we analyzed the 2 groups for differences in the metrics of interest. SAS Enterprise Guide version 4.2 was used for descriptive, matched-pair t-tests and other statistics.29 We compared claims for the 2 groups for a time period beginning 1 year before an individual’s first emergency department visit to an end date of 1 year after that first emergency department visit:

therefore, each individual’s length of time in the pilot was 1 full year. The pilot ran from December 2008 through March 2010.

To assess total emergency department costs for an individual emergency department visit, we used allowed claims dollars to evaluate if the test group achieved savings for second and subsequent emergency department visits compared with the control group.

We also assessed procedure utilization through billed Current Procedural Terminology codes, including imaging studies, laboratory studies, and therapies, to see how changes in utilization potentially affected emergency department costs per visit. In these analyses we compared the differences in emergency department claims dollars or number of emergency department services rendered between a first and subsequent emergency department visit for the 2 populations of interest after adjustment for the trend between the 2 time periods (which would be a factor if fee schedules at a given facility changed between the 2 emergency department visits).

Results Descriptive results before matching for all eligible control population and test population members are shown in Table 1. These preliminary, unadjusted results show that in the aggregate, the total emergency department cost differences for all members in the test group candidate pool (where querying of the WHIE database occurred for the initial and subsequent emergency department visits) decreased by $186 per emergency department visit compared with the cost differences noted for all members representing the control group candidate pool.

After propensity score matching, Table 2 shows that after a first emergency department visit, the test population has higher costs in nearly all subcategories contributing to the net dollars paid PPPM. This could imply that the test population requires higher intensity care on

Table 1 Descriptive Results for All Study-Eligible Members, Prematching and by Potential Group Assignment Period 1st ED visit

2nd & subsequent ED visits

Potential group participation status

Members, N

Age, yrs

Gender, % female

Paid per ED visit, $

Control

1054

42.0

56.5

1043

Test

428

41.1

53.5

1068

Control

1054

42.0

56.5

1157

Test

428

41.1

53.5

999

NOTE: Decrease for test group in dollars paid by the plan per ED visit = 1068 ⳯ (1157/1043) – 999 = $186.

ED indicates emergency department.

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a total claims dollar basis; it is possible to consider them a “sicker” population based on claims. Second, none of the differences in dollars spent for the test group are significant ( = .05), except for “medical physician” and “emergency department.”

These differences imply that utilizing HIE in the emergency department affects the costs for some care taking place in the emergency department, including physician costs and emergency department facility costs. However, HIE use in the emergency department may not impact medical costs outside the emergency department.

The emergency department subgroup comparison looks at emergency department costs for participants for all services provided during a single emergency department encounter (Table 3). Those results show that Humana achieved an average savings of $29 for each emergency department visit where the WHIE was queried.

Given that the test group experienced higher overall claim costs than the control group, any dollar impact reducing costs becomes important.

Potential drivers of the $29-per-emergency-department visit savings when the WHIE was queried are shown in Table 4. For the top 5 emergency department–based procedures, which are shown in Table 4, we found definitive decreases in the test group for 4 of them.

These decreases in test redundancy help to mitigate waste and control costs.

Such findings bear out that substantial change in outcomes that matter is “clinically important,” regardless of statistical significance.30

Discussion The overarching goal of this study was to evaluate the WHIE’s effectiveness as a means of cost control for Humana members seeking emergency care. A secondary, albeit important, goal involved the assessment of overall value to Humana: if the business case for a health plan’s investment in HIE can be supported, then this study could validate the literature in proposing that health plans promote HIE sustainability.

Review of these results reveals several interesting points. Consistent with our hypothesis, we found that when the WHIE was queried, our health plan achieved an average savings of $29 per emergency department visit. We believe that the savings are driven by 2 factors—(1) the availability of medical history at the point of care, and (2) a decrease in redundant diagnostic testing resulting from the availability of that medical history.

For physicians, the ability to care for a patient in the emergency department has long been limited by the availability of information. As Cory Wilson, MD, Chair

Net cost PPPM, $

Table 2 Comparison of Net Cost per Participant per Month: Matched Control and Test Group after Propensity Matching Cost Test group Control group differences at 2nd & at 2nd & for test group subsequent ED subsequent ED vs control visits, $ visits, $ group,a $ P value

Category

Test group at 1st ED visit, $

Control group at 1st ED visit, $

Medical

697

633

1860

1116

–631 (test)

.077

Prescriptions

64

50

78

59

–2 (test)

.207

Medical + prescriptions

762

683

1938

1175

–628 (test)

.071

Medical inpatient

155

149

788

268

–510 (test)

.160

Medical outpatient

266

245

488

467

19 (control)

.556

Medical physician

233

200

506

328

–123 (test)

.007

ED

85

88

228

180

–48 (test)

.030

NOTE: After the first ED visit, test group members had higher net paid PPPM costs in all subcategories except one. a Higher cost group in parentheses.

ED indicates emergency department; PPPM, per participant per month.

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of Emergency Medicine at St. Francis Hospital in Milwaukee, WI, states in a video about the WHIE, “it [the WHIE] gives us immediate information that we can use at the bedside, and information, for an emergency physician, is gold.”31 Preliminary survey results of emergency department physicians utilizing the WHIE at the point of care for patient management demonstrated that workup or treatment of the patient was altered 42% of the time.32 Furthermore, the time spent gathering data decreased by 42% and the time to the disposition decision decreased approximately 50% of the time.32 An analysis performed by the Agency for Healthcare Research and Quality highlighted the impact that the availability of electronic information can have on patient care; it can improve provider performance when the data are readily accessible.33 From the health plan business case perspective, improving provider performance has a cost-savings implication as well.34 The cost-savings health plans accrue are important for several reasons. First, if health plans save money when

their members seek emergency department services, the plan can, among many options, share those savings with providers (both physicians and HIEs) to support HIE utilization and sustainability. In fact, early HIE adopters, such as the California Regional Health Information Organization, created a “shared savings” model whereby providers and payers would share the savings attained through quality improvements and cost reductions.35 Within the initial context of HIE, early national costsavings projections were estimated at $78 billion annually once implemented.36 Estimates of local HIE cost-savings may serve as more appropriate comparators to what our results showed. Overhage and colleagues published data in 2002 from the Indiana Health Information Exchange, which estimated that clinical information shared between facilities saved $26 per emergency department visit by eliminating duplicate tests and other unnecessary activities.37,38 More recently, Daniel and colleagues concluded that the utilization of a payer-based electronic health record in an emergency department resulted in a mean cost-sav-

Comparison of Emergency Department Claims Cost Differences: Matched Control and Test Groups for Table 3 Identified Emergency Department Visits after Propensity Matching Period 1st ED visit

2nd & subsequent ED visits

Group assignment

Members, N

Age, yrs

Gender, % female

Cost per ED visit, $

Control

325

42.5

55.2

930

Test

326

42.7

55.8

1005

Control

325

42.5

55.2

925

Test

326

42.7

55.8

971

NOTE: Decrease for test group in dollars paid by plan per ED visit = 1005 ⳯ (925/930) – 971 = $29.

ED indicates emergency department.

Table 4 Comparison of the Top 5 Emergency Department Procedures for Matched Control and Test Groups for Identified Visits after Propensity Matching Test group at 1st ED visit, N

Control group at 1st ED visit, N

Test group at 2nd & subsequent ED visits, N

Control group at 2nd & subsequent ED visits, N

Decrease in procedures in test group, N

624

819

423

630

57

187

247

156

252

35

IV therapy

87

113

104

112

–18

CT scans

63

50

50

60

26

ECGs

48

60

32

42

2

Procedure Procedure Laboratory testing counts Diagnostic radiology

CT indicates computed tomography; ECGs, electrocardiograms; ED, emergency department; IV, intravenous.

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ings of $1560 for each emergency department encounter that led to an admission compared with admissions from the emergency department with no electronic health record access.39 Even cost reductions of as little as $10 per emergency department visit could yield substantial savings for health plans.40 Based on these examples, there is definite potential for health plans to save money by promoting HIE’s sustainability and its use in the emergency department. Such a finding may also help to explain why, after Humana’s promotion of this effort, other national payers have started to support local HIE efforts.41 Second, we theorize that the cost-savings attained relate to decreased ordering of specific tests performed in the emergency department. Overhage and colleagues, along with Frisse and Holmes, noted that operational metrics that eliminate redundancies and reduce costs, such as duplicate imaging and lab tests, specifically decreased when emergency department physicians used HIEs.37,40 Anecdotal evidence before our study had even shown that querying the WHIE avoided the ordering of unnecessary ultrasounds, computed tomography scans, and, in 1 case, an angiogram.42 Moreover, for the top 5 emergency department–based procedures identified in our study, the test group experienced decreases in 4 of them; for the fifth, we hypothesize that because many individuals arrive in the emergency department via ambulance, or because of their chief complaint, they require intravenous (IV) access for potential medication, the fact that IV therapy was seen more frequently in the test group during an emergency department visit may not be a complete surprise for a higher-cost population.

Limitations We need to account for several potential limitations to this study. First, with respect to “internal validity,” although the use of propensity scoring methods to create test and control groups should minimize bias, any time data manipulation occurs, new risks from potential bias must be acknowledged. Although it would have seemed ideal to use emergency department visits from the same individual on a “pretest/posttest” basis, this too is fraught with problems. There is no guarantee that the same member may be seen for the same condition in the emergency department each time; “internal validity” may improve but “external validity” is sacrificed.43 In addition to potential internal validity issues, there are potential external validity issues. In previous studies of community health information networks, Wisconsin had experienced cost-savings, whereas other community health information networks had not.44,45 It is possible that outcomes found in Wisconsin may not transfer else-

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where. Furthermore, although Daniel and colleagues had found cost-savings for patients admitted from the emergency department, they did not find any cost-savings for patients discharged from the emergency department.39 This study, however, looked at HIE using clinical data rather than Daniel and colleagues’ payer-based data.

Second, we used a commercial, fully insured population in Milwaukee, WI. It is possible that similar costsavings may not be achieved for a self-funded population, a Medicaid population, or a Medicare population.

Contractual reimbursement rates for these differing products may play a role. Nonetheless, in comparing “like” groups through propensity scoring, reimbursement amounts for similar products should, in theory, cancel out. Moreover, because we know that the Indiana HIE experienced cost-savings similar to ours, one could view any savings as functionally related to the use of HIE rather than to extraneous factors.

Finally, when it comes to addressing the financial arrangements between payers and HIEs, the details of such arrangements must be established on a case-by-case basis. In our case, the cost-savings Humana realized in the pilot study exceeded the incentive Humana paid to the WHIE. We have choosen not to state the exact incentive amount, because doing so may compromise current or future stakeholders’ ability to adjust their administrative costs for future obligations.

Still, although we are pleased to report that our return on investment was better than 2:1, the acknowledged point is that the basic “value” realized is greater than the financial commitment: not only do providers and patients benefit, but payers do realize a true return on their investment. Pilot programs from health plans in collaboration with HIEs in other markets may serve to substantiate this point further.

Conclusions This study demonstrates that using a communitybased HIE in the emergency department can yield costsavings for health plans; the premise of HIE as a cost minimizer and care enhancer is reinforced, whether savings ensue from decreased service utilization or through the provision of historical medical information. Health plan savings allow this model to develop into a potential revenue stream for HIEs, which helps to ensure HIE sustainability in the absence of public funding. From Humana’s perspective, these positive results encourage us to play a leadership role in other community HIEs as they arise in areas where we have a business presence.

Ultimately, such assessments of community-based HIEs in emergency department care have significant benefits. They provide evidence of cost-savings, service

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utilization efficiency, and financial value. More important, these partnerships help to improve the health of the whole community as they address the continuing proliferation of emergency department use by the insured—a predicament that is not going away anytime soon.12 When it comes to addressing the balance between service and sustainability for HIEs, one may ask what factor makes community-based HIEs a necessity. The answer is simple—“a compelling mission whose clinical and economic value is widely acknowledged and measurably demonstrated.”46 We plan to continue the collaboration between Humana and the WHIE; our study demonstrated that we gained an economic value. We found that as payers invest in HIEs, they receive a positive financial return on their investment. Although these cost-savings realized by the health plan may be used in a number of ways, one option allows health plans to invest in HIE funding, thereby improving HIE sustainability.

Such decisions can benefit the community at large in addition to the plan itself. Morrissey perhaps expressed it best, “To put it short and sweet, health information exchange makes business sense now.”47 ■ Acknowledgments The authors wish to acknowledge and thank the following individuals for their advocacy and support during the development, implementation, and evaluation of this project—Marcia James, Karen McClay, Andrew Osterman, and Dr Michael Sherman from Humana’s Clinical Leadership & Policy Development organization; Chunmei Wang from Humana’s Business Intelligence and Informatics Competency Center; and members of the Milwaukee Health Care Partnership, the Wisconsin Department of Health Services, and the Wisconsin Hospital Association, as well as other members of the Board of Advisors from the WHIE. Without the support of these individuals, their employers, and the groups they represent, this project could have never come to fruition.

The authors also wish to thank Humana, Louisville, KY, for its financial support for this project.

Author Disclosure Statement Dr Tzeel is employed by and owns stock in Humana and is a nonpaid member of the WHIE Board of Advisors, as well as a volunteer member of the WHIE Sustainability Committee; Dr Lawnicki is an employee and shareholder at Humana; Mr Pemble is employed by the National Institute for Medical Informatics/WHIE.

References 1. Blumenthal D. The HITECH Foundation for Information Exchange, a message from Dr. David Blumenthal, National Coordinator for Health Information Technology. Update #4. US Department of Health & Human Services, Office of the

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National Coordinator for Health Information Technology. November 12, 2009. http://healthit.hhs.gov/portal/server.pt?open=512&objID=1406&parentname=Com munityPage&parentid=6&mode=2&in_hi_userid=10741&cached=true. Accessed April 15, 2010.

2. Glick DF, Thompson KM. Analysis of emergency room use for primary care needs.

Nurs Econ. 1997;15:42-49.

3. Grumbach K, Keane D, Bindman A. Primary care and public emergency department overcrowding. Am J Public Health. 1993;83:372-378.

4. Young GP, Wagner MB, Kellerman AL, et al. Ambulatory visits to hospital emergency departments. Patterns and reasons for use. 24 hours in the ED Study Group.

JAMA. 1996;276:460-465.

5. Tufts Managed Care Institute. Emergency department utilization: trends and management. Nov-Dec 2001. www.thci.org/downloads/topic1112_01.pdf. Accessed July 7, 2010.

6. Mollica RL, Gillespie J. Care coordination for people with chronic conditions.

Partnership for Solutions. January 2003. www.partnershipforsolutions.org/DMS/files/ Care_coordination.pdf. Accessed April 14, 2010.

7. Kulkarni R, Pell F, Agocs-Holler EJ, D’Onofrio G. 227: Care coordination in the emergency department: avoiding inappropriate hospital admissions. Ann Emerg Med. 2007;50(suppl):S71-S72.

8. Brigham and Women’s Hospital. Care coordination. www.brighamandwomens. org/Patients_Visitors/pcs/carecoordination/default.aspx. Accessed May 1, 2010.

9. Laborers Health and Safety Fund of North America. Emergency room care: slow, questionable and costly. Lifelines Online. Vol 3, No 2. July 2006. www.lhsfna.org/index. cfm?objectID=120F0D19-D56F-E6FA-9384F31044F34810. Accessed April 14, 2010.

10. van Walraven C, Raymond M. Population-based study of repeat laboratory testing. Clin Chem. 2003;49:1997-2005.

11. Page L. Patients bypassing primary doctors for emergency care. American Medical News. February 12, 2001. www.ama-assn.org/amednews/2001/02/12/bil10212.htm.

Accessed April 14, 2010.

12. DeLia D, Cantor J. Research Synthesis Report No. 17: emergency department utilization and capacity. Robert Wood Johnson Foundation. July 2009. www.rwjf.org/ files/research/072109policysynthesis17.emergencyutilization.pdf. Accessed November 10, 2010.

13. Community Health Integrated Partnership. Emergency Department OverUtilization: A New Paradigm? May 27, 2009. www.dhmh.state.md.us/mma/pdf/2009/ jun09/Emergency_Department_Usage_052209.pdf. Accessed July 14, 2011.

14. Goedert J. The payer role in HIEs. Health Data Management Magazine. June 1, 2009. www.healthdatamanagement.com/issues/2009_67/-28270-1.html?pg=1.

Accessed April 14, 2010.

15. Vest JR, Gamm LD. Health information exchange: persistent challenges and new strategies. J Am Med Inform Assoc. 2010;17:288-294.

16. Hripcsak G, Kaushal R, Johnson KB, et al. The United Hospital Fund meeting on evaluating health information exchange. J Biomed Inform. 2007;40(suppl 6):S3-S10.

17. Veryard R. Making the business case. SCIPIO. February 10, 1999. www.users.globalnet.co.uk/~rxv/scipio/swpbc.pdf. Accessed April 14, 2010.

18. Neupert P. Re-charting healthcare: innovations to drive a new delivery model for tomorrow’s health system. In: Merritt D, ed. Paper Kills 2.0: How Health IT Can Help Save Your Life and Your Money. Washington, DC: Center for Health Transformation Press;2010:15.

19. Wisconsin Health Information Exchange. Information exchange service links emergency departments and community health centers. 2009. www.whie.org/ edlink.php. Accessed April 14, 2010.

20. Ozanich GW, Chrisman K, Jones Dolen R, et al. State health information exchange: factors shaping sustainability and value. J Healthc Inf Manag. 2011;25:48-55.

21. Dixon BE, Zafar A, Overhage JM. A framework for evaluating the costs, effort, and value of nationwide health information exchange. J Am Med Inform Assoc.

2010;17:295-301.

22. Humana to partner with WHIE on emergency department data exchange.

Wisconsin Technology Network News. January 29, 2009. http://wistechnology.com/ articles/5432/. Accessed April 14, 2010.

23. Rosenbaum PR. Observational Studies. 2nd edition. New York, NY: SpringerVerlag; 2002:296.

24. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41-55.

25. Shah BR, Laupacis A, Hux JE, Austin PC. Propensity score methods gave similar results to traditional regression modeling in observational studies: a systematic review. J Clin Epidemiol. 2005;58:550-559.

26. Stürmer T, Joshi M, Glynn RJ, et al. A review of the application of propensity score methods yielded increasing use, advantages in specific settings, but not substantially different estimates compared with conventional multivariable methods. J Clin Epidemiol. 2006;59:437-447.

27. Brookhart MA, Schneeweis S, Rothman KJ, et al. Variable selection for propensity score models. Am J Epidemiol. 2006;163:1149-1156.

28. MathWorks. MATLAB – The language of technical computing. www.mathworks. com/products/matlab/. Accessed June 18, 2010.

29. SAS Institute. SAS enterprise guide, a graphical user interface for deploying the power of SAS analytics. www.sas.com/technologies/bi/query_reporting/guide/.

Accessed June 18, 2010.

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30. American College of Physicians-American Society of Internal Medicine.

Primer on statistical significance and P values. Eff Clin Pract. 2001;4:183-184.

31. Microsoft Showcase. Wisconsin Health Information Exchange [video]. 2008. www.microsoft.com/showcase/en/US/details/ab8cd114-583c-472f-87ac791 ebf531938. Accessed April 14, 2010.

32. Kolbasuk McGee M. Health information exchange enhances decision making.

June 16, 2010. InformationWeek. www.informationweek.com/story/showArticle. jhtml?articleID=225700387. Accessed June 15, 2011.

33. Shekelle PG, Morton SC, Keeler EB. Costs and Benefits of Health Information Technology. Evidence Report/Technology Assessment No. 132. Agency for Healthcare Research and Quality Publication No. 06-E006. Rockville, MD: Agency for Healthcare Research and Quality. April 2006.

34. American Medical Association. Terminology used in physician profiling. 2009. www.ama-assn.org/ama1/pub/upload/mm/368/profiling-terminology.pdf. Accessed April 14, 2010.

35. CalRHIO disbands, in lieu of new ARRA-funded statewide HIE. January 13, 2010. www.healthimaging.com/index.php?option=com_articles&view=article& id=20182:calrhio-disbands-in-lieu-of-new-arra-funded-statewide-hie. Accessed April 14, 2010.

36. Walker J, Pan E, Johnston D, et al. The value of health care information exchange and interoperability. Health Aff (Millwood). 2005;Suppl web exclusives: W5-10-W5-18.

37. Overhage JM, Dexter PR, Perkins SM, et al. A randomized, controlled trial of clinical information shared from another institution. Ann Emerg Med. 2002;39:14-23.

38. Patton S. Sharing data, saving lives. CIO. 2005;18:64-68.

39. Daniel GW, Ewen E, Willey VJ, et al. Efficiency and economic benefits of a payer-based electronic health record in an emergency department. Acad Emerg Med. 2010;17:824-833.

40. Frisse ME, Holmes RL. Estimated financial savings associated with health information exchange and ambulatory care referral. J Biomed Inform. 2007;40(6 suppl): S27-S32.

41. UnitedHealthcare. UnitedHealthcare partners with CalRHIO to expand health information statewide. May 20, 2009. www.uhc.com/news_room/2009_news_ release_archive/unitedhealthcare_partners_with_calrhio.htm. Accessed April 14, 2010.

42. Langreth R. Wiring medicine. Forbes. 2009;183:40-42.

43. Shuttleworth M. Pretest-posttest designs. 2009. www.experiment-resources.com/ pretest-posttest-designs.html. Accessed May 23, 2010.

44. Lassila KS, Pemble KR, DuPont LA, Cheng RH. Assessing the impact of community health information networks: a multisite field study of the Wisconsin Health Information Network. Top Health Inf Manage. 1997;18:64-76.

45. Soper P. Realizing the Potential of Community Health Informaton Networks for Improved Quality and Efficiency Through the Continuum of Care: A Case Study of the HRSA Community Access Program and the Nebraska Panhandle Partnership for Health and Human Services. Scientific Technologies Corporation. December 2001. www.stchome.com/media/white_papers/WHP023A.pdf. Accessed April 14, 2010.

46. Krohn R. The socially responsible HIE: finding the optimal mix of service and sustainability. J Healthc Inf Manag. 2011;25:12-13.

47. Morrissey J. HIE health information exchange. Hospitals Health Networks.

February 2011. www.hhnmag.com/hhnmag_app/jsp/articledisplay.jsp?dcrpath= HHNMAG/Article/data/02FEB2011/0211HHN_Coverstory&domain=HHNMAG. Accessed April 14, 2011.

STAKEHOLDER PERSPECTIVE Health as a Sustainability Strategy: We Need a Healthcare System Focused on Keeping People Healthy Rather than Adding Layers to the Already Too Long, Fragmented Supply Chain POLICYMAKERS: If we apply science and evidence to US healthcare, we would inevitably acknowledge it as the most inefficient among the developed countries. Alas, ideology and prejudice prevent a dispassionate assessment. When the World Health Organization last reviewed it (in 2000), the United States spent more than double what other developed countries spend on healthcare, while its health indicators remained low, with life expectancy and infant mortality trailing behind all the G7 countries.1 In 2007, the Congressional Research Service reported that the country spends more money on healthcare than any of the 30 democracies within the Organization for Economic Cooperation and Development (OECD).2 In 2011, the OECD confirmed that health spending rises faster than economic growth, and US health spending continued to outspend OECD countries as share of the gross domestic product (GDP) by an average of 17.4% versus 9.5%, with spending per capita at $7960—2.5 times more than any OECD country.3 Many causes can be invoked for high prices and little efficiency in the system. One is the imbalance between aggressive catastrophic care and timid primary care, with most of the spending applied to the

former. Another is pricing. For example, US hospital spending per discharge is $17,000 versus $4600 in France and Germany.4 Although health indicators are mediocre relative to spending, the supply side is large, removing queuing for care, but with much waste and many inefficiencies.

This relates to 2 key issues—the role of general practitioners (GPs) and the disparity in primary care availability. In England and France, GPs are considered specialists and are remunerated accordingly, through evidence-based pay-for-performance. GPs are the first point of contact for patients and act as gatekeepers for accessing secondary services. In the United States, there are primary care deserts. If a medical home is the backbone of providing primary care, then too many US patients are medically “homeless.”

EMPLOYERS: Why should employers care? The United States does not have a “health system” but rather a variety of private and public institutions and programs that regulate, finance, and deliver care.

Employers provide insurance to slightly more than 50% of the population, roughly 25% is covered through public programs, 5% pay their own insurance, and 15% have no insurance. Employers care for Continued

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STAKEHOLDER PERSPECTIVE (Continued) the quality and quantity of services they are purchasing on behalf of their employees, as well as the quality of the healthcare communities in which their operations are located.

There is mounting evidence that overuse of emergency departments (EDs) is a result of lack of care coordination and lack of primary care availability in the community.5 This is also true for employed populations.6 More money would be saved by addressing the lack of primary care than the lack of information in the ED. HEALTH PLANS: This brings us to the present article. The thesis of the article is appropriate in that access to health information reduces duplication of services, but this introduces another layer of intermediation (ie, information exchanges), where the putative and modest savings are not redistributed to the patients or to those who purchase care on their behalf.

In France, those who participate in the national healthcare system are given a “smart card” that carries a microchip with their medical history, without adding another layer of intermediation and cost. It would be quite inappropriate to blame the authors for not “saving the world,” but because the authors discuss costsavings, an economic argument could be made here.

And economic arguments are essentially moral.

The authors correctly identify some of the reasons for ED misuse, including that EDs are surrogates for lack of care coordination and for lack of primary care.

If we agree with this analysis, the solution should be more care coordination and more primary care. We need more discussion on how to establish care coordination rather than on the rearrangement of the current status quo.

To talk about saving money by exchanging information at the ED point of service is noble and logical. But based on this study, it appears to save money for the health plan only. Does it save cost for patients and for society at large? This merits a discussion.

Talking about intra-ED savings without the current economic context and without acknowledging primary care inequality is like questioning how to better pay for drinks on the deck of the proverbial Titanic, knowing that not all passengers will have the same fate.

The recession is exacerbating an already uneven playing field, and the debt restructuring gripping most of the OECD countries, including the United States, will not be without consequences to healthcare. It is an accepted notion that healthcare is the most recession-

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proof arena, because people always get sick. But it is impossible to separate the economy from healthcare, because the latter is 17% of our GDP, the largest sector of the economy.

Consequently, primary and preventive care will likely be delayed and people with high deductibles will delay payments on care received. In 2010, 20% of US adults had major problems paying medical bills versus 2% in England and 9% in France.7 The United States is the only country in which 20% of adults report serious problems paying healthcare bills.7 Deep in the recession, many who took pay cuts or lost jobs ended up delaying medical care.8 The healthcare reform law was meant to use Medicaid to insure about 15 million more Americans, but debt restructuring through cuts to state budgets will most likely decimate Medicaid and other programs.9 This is not just a “bleeding heart” matter, but also a matter of corporate sustainability. Investment in health systems feeds into sustained benefits in economic growth by reducing future demand on these systems.10 Ultimately, health is wealth. This holds true for individuals, nations, and corporations. To achieve this, we need a system that prioritizes keeping a nation and its individuals healthy. ■ 1. World Health Organization. World Health Organization assesses the world’s health systems. World Health Report 2000: Press release. June 21, 2000. https://apps. who.int/whr/2001/archives/2000/en/press_release.htm. Accessed August 6, 2011.

2. Peterson CL, Burton R. Congressional Research Service Report for Congress: US health care spending: comparison with other OECD countries. September 17, 2007. http://assets.opencrs.com/rpts/RL34175_20070917.pdf. Accessed August 10, 2011.

3. OECD Health Data 2011. June 30, 2011. www.oecd.org/health/healthdata.

Accessed August 6, 2011.

4. The Commonwealth Fund. International profiles of health care systems. June 2010. www.commonwealthfund.org/~/media/Files/Publications/Fund%20Report/ 2010/Jun/1417_Squires_Intl_Profiles_622.pdf. Accessed August 10, 2011.

5. County Health Rankings. Access to care. www.countyhealthrankings.org/healthfactors/access-care. Accessed August 10, 2011.

6. Colombi AM. Medical homelessness and emergency department utilization: economic and moral implications. Am Health Drug Benefits. 2010;3:255-256.

7. Schoen C, Osborn R, Squires D, et al. How health insurance design affects access to care and costs, by income, in eleven countries. Health Aff (Millwood).

2010;29:2323-2334.

8. Martin A, Lassman D, Whittle L, et al. Recession contributes to slowest annual rate of increase in health spending in five decades. Health Aff (Millwood). 2011; 30:11-22.

9. The Henry J. Kaiser Family Foundation. The uninsured: a primer. Key facts about Americans without health insurance. December 2010. www.kff.org/uninsured/ upload/7451-06.pdf. Accessed August 10, 2011.

10. World Health Organization. European Ministerial Conference on Health Systems: health systems, health and wealth. Tallinn, Estonia; June 25-27, 2008. www.euro.who.int/__data/assets/pdf_file/0006/78918/E92150.pdf. Accessed August 10, 2011.

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Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

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NOW APPROVED

Visit www.zytiga.com

Contact your Centocor Ortho Biotech Sales Representative for more information.

Š Centocor Ortho Biotech Inc. 2011 4/11 08A11076

CALL FOR PAPERS American Health & Drug Benefits offers an open forum for all healthcare participants to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Evaluators, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers.

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being, the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest Include: • Health Economics Research • Health Plan Initiatives • Health Information Technology • Industry Trends • Innovations in Healthcare • Literature Reviews • Medicare/Medicaid

• Adherence Concerns • Benefit Design • Case Studies • Comparative Effectiveness Research • Cost Analyses • Decision-Making Tools • Ethics in Medicine

• Patient Advocacy/Patient Care • Pharmacoeconomics • Policy Issues • Prevention Initiatives • Reimbursement Strategies • Survey Results • Wellness Programs

NOTE TO AUTHORS: AHDB is a member of the Committee on Publication Ethics (COPE). Membership in COPE indicates that this journal upholds COPE’s Code of Conduct standards and intends to take appropriate action in cases of possible misconduct, such as plagiarism, attempted or actual redundant publication, any attempts to pass off fraudulent data, unethical research, or breaches of confidentiality.

Clinical Topics of Interest Include: AGING/DEMENTIA—With the aging of the US population there is a growing need for early implementation of outcomebased preventive and therapeutic strategies for older people.

ALLERGIES—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Undertreatment and lack of adherence are common obstacles to patient management.

ARTHRITIS—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated.

Comparing new and available therapies is a key target for improving patient outcomes and reducing costs.

CANCER CARE—The growing focus on biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management.

CARDIOVASCULAR DISEASE—Original, outcomesbased research on appropriate therapies, cost comparisons, emerging prevention strategies, and comparative effectiveness of best practices will enhance readers’ decision-making.

DIABETES, OBESITY—The increasing comorbid epidemics of these twin conditions mandates a thorough examination of best therapies, adherence issues, access, and prevention strategies. We invite articles that will address how to improve patient outcomes and best patient care.

GASTROINTESTINAL CONDITIONS—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, or inflammatory bowel disorder, remains a challenge.

INFECTIOUS DISEASES—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance.

MENTAL DISORDERS—Depression and bipolar disorder and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, best practices, and reimbursement.

PAIN MANAGEMENT—Chronic pain is associated with a slew of complicated medical disorders and an enormous economic burden, yet pain medications are still underused.

Manuscripts should follow the Manuscript Instructions for Authors (available at www.AHDBonline.com).

Submit articles to editorial @AHDBonline.com. For more information, call 732-992-1892.

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ORIGINAL RESEARCH

Modeling Costs and Outcomes Associated with a Treatment Algorithm for Problem Bleeding Episodes in Patients with Severe Hemophilia A and High-Titer Inhibitors Patrick Bonnet, PharmD; Alessandro Gringeri, MD; Edward Gomperts, MD; Cindy Anne Leissinger, MD; Roseline d’Oiron, MD; Jerome Teitel, MD; Guy Young, MD; Meg Franklin, PharmD, PhD; Bruce Ewenstein, MD; Erik Berntorp, MD, PhD Background: No evidence-based treatment guidelines are currently available for the treatment of problem bleedings in patients with hemophilia who develop clotting factor inhibitors.

A treatment algorithm was developed previously to help providers optimize the approach to the treatment of this patient population. The algorithm provides the specific intervals between treatments; however, it does not specify dosing recommendations and does not offer insights into the likelihood of outcome improvements at each time interval.

Objective: To develop a model to analyze the impact on patient outcomes and costs of adhering to a current treatment algorithm for the 2 available clotting therapies to treat bleeding episodes in patients with hemophilia who develop clotting factor inhibitors.

Methods: A simulation model was developed using a modified Delphi method approach based on a consensus opinion of an expert panel. The model was used to analyze the impact of following the available treatment algorithm on patient outcomes and costs. Treatment patterns and the likelihood of a resolved bleeding episode associated with following the treatment algorithm (ie, adherence) were compared with not following the algorithm (ie, nonadherence).

This model assumed 2 scenarios in which treatment was initiated with each of the 2 bypassing agents currently available, and clinical and economic outcomes were mapped for adhering to and not adhering to the consensus treatment algorithm.

Results: The simulation model shows that adhering to the treatment algorithm would result in 74.4% of patients improving at 72 hours compared with only 56.7% of patients when not adhering to the algorithm. According to this model, regardless of the bypassing agent used at initiation, adherence to the treatment algorithm would result in fewer patients requiring combined sequential therapy with the 2 bypassing agents for 3 days. In addition, using this analytic model, reducing the percentage of patients with hemophilia who required combined sequential therapy by 17.6% resulted in an average cost-savings of $16,305 per patient.

Conclusion: Adherence to an algorithm in which treatment is altered at regular intervals based on a patient’s clinical response has the potential to improve patient outcomes and reduce the number of nonresponsive patients requiring sequential therapy in patients with hemophilia who have clotting factor inhibitors and are experiencing problem bleeding episodes.

Adherence to the algorithm would also result in reduced costs to patients and payers.

Stakeholder Perspective, page 228

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2011;4(4):219-229 www.AHDBonline.com Disclosures are at end of text

Dr Bonnet is a Health Economist working in the Medical Outcomes Research and Economics Group at Baxter Healthcare Corporation, Westlake Village, CA; Dr Gringeri is Professor of Internal Medicine, Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico and University of Milan, Italy; Dr Gomperts is Director, Clinical Research, Children’s Hospital Los Angeles, CA; Dr Leissinger is Professor of Medicine), Louisiana Center for Bleeding and Clotting Disorders, Tulane University School of Medicine, New Orleans; Dr d’Oiron is a Practicing Physician, Centre de traitement pour Hémophiles Hôpital Bicêtre, Université Paris XI, Le KremlinBicetre, France; Dr Teitel is Professor of Medicine, University of Toronto Division of Hematology and Oncology, St. Michael’s Hospital, ON; Dr Young is Director, Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, CA; Dr Franklin is Associate Professor of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC; Dr Ewenstein is Vice President, Clinical Affairs, Baxter Healthcare, Westlake Village, CA; Dr Berntorp is Professor, Lund University, Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Sweden.

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KEY POINTS Factor replacement therapy is the standard treatment for hemophilia, but many patients develop clotting factor inhibitors, which can lead to increased mortality. ➤ No evidence-based treatment guidelines are available for this patient population; a treatment algorithm has previously been developed, but it does not specify dosing recommendations or provide insights into the likelihood of improvements at each time interval. ➤ In this study, a simulation model was developed based on a consensus opinion of an expert panel to assess the clinical and economic impact of adhering to the treatment algorithm. ➤ Adhering to this algorithm would result in 74.4% of patients improving at 72 hours compared with only 56.7% of patients when not adhering to the algorithm; in addition, fewer patients would require combined sequential therapy. ➤ Reducing the percentage of patients who required combined sequential therapy by 17.6% resulted in an average cost-savings of $16,305 per patient. ➤ This model shows that adherence to the treatment algorithm, regardless of the bypassing agent used, improves clinical outcomes and reduces costs. ➤ In the absence of studies assessing the impact of guideline adherence on clinical and economic outcomes in this patient population, these data provide the best available estimate for those outcomes. ➤

Factor replacement therapy is the standard treatment for hemophilia. However, some patients with hemophilia develop inhibitors (alloantibodies) against the clotting factor administered. The development of these clotting inhibitors may render replacement therapy ineffective and, consequently, increase morbidity because of the inability to control or prevent hemorrhages. Inhibitor development has been reported to occur in as many as 33% of patients with hemophilia A, and as many as 7.5% of patients with hemophilia B.1-3 Currently, 2 bypassing agents are available for use in patients who develop clotting factor inhibitors: 1. Factor VIII inhibitor bypassing activity, an activated prothrombin complex concentrate (aPCC), also known as anti-inhibitor coagulant complex4 2. A recombinant activated factor VII (rFVIIa).5 The ability of these agents to control bleeding episodes has been documented, with success rates ranging from 80% to 93%.6-9 However, responses can vary between patients,10-12 as well as within the same patient during the course of a single bleeding episode.13

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Therefore, making appropriate adjustments to therapeutic regimens is critical for controlling problem bleedings in this patient population.14,15

Treatment Algorithm, Definitions Systematic approaches to treating hemorrhagic episodes can potentially guide the most appropriate pharmacologic decisions for patients with hemophilia who develop clotting inhibitors. To date, there are no approved treatment guidelines for such patients who are experiencing problem bleeding episodes.

In the present study, problem bleeding is based on the definition by Teitel and colleagues, who have published a consensus algorithm addressing the treatment of problem bleedings (specifically iliopsoas muscle hematoma as the archetypal limb-threatening bleeding and intracerebral hemorrhage as the archetypal lifethreatening bleeding) in this population (Figure 1).14 Teitel and colleagues have defined problem bleeding as bleeding unresponsive to initial therapy with a single agent within a reasonable time (8-12 hours for non– life-threatening bleedings and 2-4 hours for life-threatening bleedings).14 The goal of the treatment algorithm was to aid physicians in determining the appropriate timing for treatment approaches to optimize patient outcomes.

This algorithm includes the designation of time intervals between assessments, to allow for more effective treatment changes or dosage adjustments based on individual responses, in an effort to facilitate faster responses and improved outcomes.14 Although the algorithm specifies intervals and general recommendations for the treatment of problem bleedings (eg, increasing a dose or increasing the frequency of doses), it does not give specific dose recommendations or provide insight into the likelihood of improvement for patients at each interval. The lack of readily available clinical data precludes a direct comparison of outcomes and costs associated with adherence versus nonadherence to the consensus treatment algorithm.

Methods: Developing a Simulation Model To circumvent the absence of data for this patient population, a simulation model was developed, informed by expert opinion, to estimate the likely outcomes and costs in relation to the treatment algorithm.

Outcomes and costs were modeled for following the treatment algorithm (ie, adherence) and for not following it (ie, nonadherence) for each of these scenarios and for each of the 2 bypassing agents (ie, aPCC and rFVIIa). The present article describes the development of this simulation model and its benefits in evaluating outcomes and costs in this patient population.

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Model Structure The structure of the model was constructed from a consensus algorithm previously developed for controlling limb-threatening muscle bleedings in patients who have severe hemophilia A and high-titer inhibitors.14 Using the algorithm as a foundation, the new model allowed the investigators to assess the impact of guideline adherence on outcomes and costs, assuming therapy would be initiated with either an aPCC or an rFVIIa. Treatment patterns (ie, dosing and frequency) and the likelihood of a successful clinical outcome (defined as improvement in bleeding status at specific time points) associated with guideline adherence versus nonadherence were analyzed in this study based on the consensus opinion of an expert panel.

A decision-analytic model was used to evaluate the clinical and economic impact of adherence to the algorithm.

Panel members developed the model to assess improvement at 12, 24, 48, and 72 hours after bleeding onset.

According to the treatment algorithm, after initial treatment, the dose or frequency of administration of both bypassing agents should be increased in patients

who do not improve after 12 hours. If no improvement is observed after the specified adjustment at 24 hours, the algorithm suggests switching to the other bypassing agent. If no improvement has occurred at 48 hours, the dose or frequency of administration of the new agent should be increased.

Finally, the algorithm specifies that patients not improving after 72 hours should receive combined sequential therapy with aPCC and rFVIIa for 3 days.

Combined sequential therapy consists of aPCC 50 units/kg administered every 12 hours (for a total of 7 doses in 3 days), with rFVIIa 90 mcg/kg (12 doses in 3 days) given between the aPCC doses. It is further assumed that after 3 days of sequential therapy, all bleeding episodes would be resolved and treatment stopped.

A corresponding scenario assuming nonadherence to the treatment algorithm has also been constructed in the present model. In that scenario, patients who did not improve at 12 hours would continue at the same dose and frequency for another 12 hours, thereby delaying the increase in dose or frequency of administration to 24 hours and the switch in agents to 48 hours.

Figure 1 Managing Limb-Threatening Bleeding Episodes in Patients with High-Titer Inhibitors Muscle hematoma (iliopsoas bleed) Time

Begin initial bypassing treatment as soon as possible

Period 0

➤ ➤

Continue

➤

Decrease

➤

Continue

➤

Decrease

➤

Continue

➤

Decrease

➤

Continue

➤

Decrease

➤

Continue

➤

Decrease

0-12 ha ➤

➤

➤

Increase dose of frequency

Period 1 12 h

➤

➤

➤

Switch products

Period 2

Period 3

➤

➤

➤

24 h

Increase dose or frequency

24 h ➤

➤

➤

Period 4

Combination sequential therapy

24 h ➤

➤

➤

➤

Period 5

Improvement Worsening

Other salvage therapy

a

Hemostatic evaluation periods may be shortened, depending on patient status.

Reprinted with permission from Teitel J, et al. A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors. Haemophilia. 2007;13:256-263.

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The model assumed 2 possibilities: one in which treatment was initiated with aPCC and one in which treatment was initiated with rFVIIa. Within each treatment possibility, clinical outcomes and costs were mapped for following (ie, adherence) and not following (ie, nonadherence) the algorithm. Outcomes evaluated included resolution of bleedings at 72 hours, the need for combined sequential therapy, and treatment cost, which were compared for adherence and nonadherence to the algorithm.

Total drug costs were calculated according to the 2008 Medicare Part B allowance payment limits for aPCC and rFVIIa, considered to be $1.48/U for aPCC and $1.23/mcg for rFVIIa. One-way sensitivity analyses

were performed to determine if the results were affected by changes in dosing or in drug pricing.

Expert Panel and Delphi Methodology No evidence-based guidelines have been validated for the treatment of problem bleedings, and clinical studies have not been conducted to establish guidelines. Therefore, we used a modified Delphi approach16 in conjunction with the consensus algorithm to populate the parameters in the decision-analytic model. The Delphi method is a systematic interactive process led by a facilitator who relies on a panel of experts to anonymously answer questions during 2 or more rounds of discussion.16

Figure 2 Treatment Algorithm with aPCC as Initial Agent 12 h

24 h

48 h Improved, stop therapy

Dose: 130 units Improved, decrease dose

0.000

Dose: 81 units Improved, continue dose

0.150

0.730

Dose: 204 units Improved, continue dose Dose: 204 units Not improved, increase dose 0.114

0.580

Dose: 1067 mcg Not improved, switch 0.420

Dose: 81 units aPCC adherence

Dose: 130 units Improved, decrease dose Dose: 300 units Improved,a continue dose 0.623

0.836

Dose: 1067 mcg Not improved, switch

Dose: 150 units Not improved, increase dose

0.164

0.270

Dose: 1067 mcg Improved, continue dose a

Dose: 1067 mcg Not improved,a switch 0.377

Improved 1.000

0.850 Dose: 300 units Not improved, increase dose

0.886

72 h

0.612 Dose: 2066 mcg Not improved, increase dose 0.388

Improved 0.580 Sequential therapy 0.420 Improved 0.836 Sequential therapy 0.164 Improved 0.612 Sequential therapy 0.388 Improved 0.850 Sequential therapy 0.150 Improved 0.612 Sequential therapy 0.388 Improved 0.816 Sequential therapy 0.184 Improved 0.669 Sequential therapy 0.331

P = 0.550 P = 0.000

P = 0.056 P = 0.041

P = 0.040 P = 0.008

P = 0.021 P = 0.014

P = 0.120 P = 0.021

P = 0.017 P = 0.011

P = 0.051 P = 0.011

P = 0.026 P = 0.013

NOTE: The first 2 nodes represent 12-hour intervals. The subsequent nodes represent 24-hour intervals. The probability of improving/not improving is provided for each chance node, and overall probabilities for each path are provided at the terminal nodes. a Indicates that consensus was not reached on probability of improving or on dosage amount, as indicated by placement. aPCC indicates activated prothrombin complex concentrate.

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After each round, a summary of responses or forecasts is presented, and panelists reevaluate their answers in light of the replies. During this process, the range of answers becomes smaller as the group converges on consensus. The process is repeated until a predefined stop criterion is reached. The average scores of the final round determine the end result.16,17 Consensus groups have been utilized previously to address the treatment of hemophilia.12,14 In addition, the Delphi method has been used in other complex disease states, such as asthma and epilepsy.18,19 To obtain model parameters for input, a modified Delphi methodology was used. Given the specialized nature of hemophilia, 7 international physician experts

with experience in treating hemophilia in patients with clotting inhibitors convened in person to form the panel. An audience response system allowed panelists to respond anonymously to questions using a numeric keypad and displayed the results immediately. A moderator facilitated the questions and subsequent discussion for each question addressed to the panel.

A consensus was considered to be reached when the standard deviation of the responses divided by the mean response was less than 0.25. If a consensus was not achieved, a panel discussion would ensue, followed by a revote. Because this was a modified approach, as many as 3 revotes were allowed per question. Input was provided on the number of doses, average dose in U/kg

Figure 3 Nonadherence to Algorithm with aPCC as Initial Agent 12 h

24 h

48 h

Dose: 130 units Improved, decrease dose

72 h

Improved, stop therapy 0.850

0.000 Dose: 130 units Not improved, continue dose

0.886 Dose: 81 units Improved, continue dose

0.150

0.730 Dose: 162 units Not improved, continue dose 0.114 Dose: 81 units aPCC nonadherence

Dose: 162 units Improved,a continue dose 0.204 Dose: 300 units Not improved,a increase dose 0.796

Dose: 130 units Improved, decrease dose Dose: 162 units Improved, continue dose

0.836 Dose: 300 units Not improved, increase dose

0.204 Dose: 81 units Not improved, continue dose

0.164

0.270 Dose: 300 units Not improved, increase dose 0.796

Improved 1.000

Dose: 300 units Improved,a continue dose 0.200 Dose: 1067 mcg Not improved,a switch

Improved 0.204 Sequential therapy 0.796 Improved 0.836 Sequential therapy 0.164 Improved 0.200 Sequential therapy 0.800 Improved 0.850 Sequential therapy 0.150 Improved 0.580 Sequential therapy 0.420 Improved 0.836 Sequential therapy 0.164 Improved 0.612 Sequential therapy 0.388

0.800

P = 0.550 P = 0.000

P = 0.020 P = 0.077

P = 0.014 P = 0.003

P = 0.013 P = 0.053

P = 0.039 P = 0.007

P = 0.005 P = 0.004

P = 0.036 P = 0.007

P = 0.105 P = 0.067

NOTE: The first 2 nodes represent 12-hour intervals. The subsequent nodes represent 24-hour intervals. The probability of improving/not improving is provided for each chance node, and overall probabilities for each path are provided at the terminal nodes. a Indicates that consensus was not reached on probability of improving or on dosage amount, as indicated by placement. aPCC indicates activated prothrombin complex concentrate.

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or mcg/kg, and probability of improvement for each agent at specified intervals (12, 24, and 48 hours) separately for aPCC and for rFVIIa. For example, panelists were initially asked how many doses they would administer during the interval from 0 hours to 12 hours. After panelists responded to the question the first time, discussion ensued, and after the question was asked again, a consensus was reached on the number of doses initially administered.

Questioning continued to further delineate the dosing strength until all dosing parameters were established.

Because clinical data are not readily available, an approach similar to what was used to get dosing information from the physicians was used to determine the

likelihood of improvement in bleedings based on the panelists’ own experience. No specific parameters were established for determining clinical improvement, because there is currently no standardized routine laboratory assay available,14 and improvement status would ultimately be up to each physician’s evaluation of a patient’s response.

The general assumption provided to the panelists regarding improvement was based on the criteria established for the timing algorithm by Teitel and colleagues: treatment should continue until the bleeding resolves, as indicated by the functional recovery of the muscle.14 Questioning ensued for both aPCC and rFVIIa for the adherence and nonadherence algorithm

Figure 4 Algorithm with rFVIIa as Initial Agent 12 h

24 h

48 h

Improved, stop therapy Dose: 899 mcg Improved, decrease dose 0.816

0.000 Dose: 2066 mcg Not improved, increase dose 0.139

0.716

Dose: 1693 mcg Improved, continue dose

0.184

0.616

Dose: 151 units Not improved, switch 0.384

Dose: 590 mcg rFVIIa adherence

Dose: 899 mcg Improved, decrease dose Dose: 2066 mcg Improved, continue dose

0.800

0.669

Dose: 151 units Not improved, switch

Dose: 1033 mcg Not improved, increase dose

0.200

0.284

Dose: 151 units Improved, continue dose Dose: 151 units Not improved, switch 0.331

Improveda 1.000

0.861

Dose: 590 mcg Improved, continue dose

Dose: 1693 mcg Not improved, increase dose

72 h

0.609 Dose: 302 units Not improved, increase dose 0.391

Improved 0.616 Sequential therapy 0.384 Improved 0.800 Sequential therapy 0.200 Improved 0.609 Sequential therapy 0.391 Improved 0.861 Sequential therapy 0.139 Improved 0.609 Sequential therapy 0.391 Improved 0.886 Sequential therapy 0.114 Improved 0.623 Sequential therapy 0.377

P = 0.503 P = 0.000

P = 0.050 P = 0.031

P = 0.065 P = 0.016

P = 0.031 P = 0.020

P = 0.131 P = 0.021

P = 0.023 P = 0.015

P = 0.051 P = 0.007

P = 0.023 P = 0.014

NOTE: The first 2 nodes represent 12-hour intervals. The subsequent nodes represent 24-hour intervals. The probability of improving/not improving is provided for each chance node, and overall probabilities for each path are provided at the terminal nodes. a Indicates that consensus was not reached on probability of improving or on dosage amount, as indicated by placement. rFVIIa indicates recombinant activated factor VII.

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situations. Specific questions posed to the panelists are listed in Appendices A and B (available at www.AHDB online.com).

Results Figures 2, 3, 4, and 5 (pages 222-225) show the treatment algorithm chosen by the panel. Results of the modified Delphi process regarding the dosing, switching patterns, and likelihood of bleeding improvement are provided in Appendices A and B. Consensus was achieved for approximately 70% of the questions. Data obtained from questions for which consensus was not reached were still used in the model; however, these are indicated in Figures 2, 3, 4,

and 5 by a superscript â&#x20AC;&#x153;a.â&#x20AC;? None of the 4 pathways modeled had 100% consensus for dosing/frequency or likelihood of improvement.

The total dosing for each interval, as well as the likelihood for improvement, are provided for each time interval. Of note, the dosing displayed in the figures is reflective of the total dose for each time interval. For example, in the algorithm with aPCC as the initial agent, a patient who improves at 12 hours and at 24 hours should receive a decreased dose. Initially, this patient would have received 81 units in the first 12 hours and 81 units in the next 12 hours but would receive 130 units total during the next 24 hours (assuming 2 doses of 65 units).

Figure 5 Nonadherence to Algorithm with rFVIIa as Initial Agent 12 h

24 h

48 h

Dose: 899 mcga Improved, decrease dose 0.816 a

Dose: 590 mcg Improved, continue dose

72 h

Improved 1.000

Improved, stop therapy 0.861

0.000 Dose: 899 mcg Not improved, continue dose

Improved 0.278 Sequential therapy 0.722

0.139

0.716 Dose: 1179 mcg Not improved, continue dose 0.184 Dose: 590 mcg rFVIIa nonadherence

Dose: 1179 mcg Improved, continue dose

Improved 0.750 Sequential therapy 0.250

0.277 Dose: 2066 mcg Not improved, increase dose

Improved 0.630 Sequential therapy 0.370

0.723 Dose: 899 mcg Improved, decrease dose Dose: 1179 mcg Improved, continue dose 0.277

0.750 Dose: 2066 mcg Not improved, increase dose

Improved 0.616 Sequential therapy 0.384

a

Dose: 590 mcg Not improved, continue dose

0.250

0.284

Dose: 2066 mcg Improved, continue dose Dose: 2066 mcg Not improved, increase dose 0.723

0.224

Dose: 151 units Not improved, switch 0.776

Improved 0.861 Sequential therapy 0.139

Improved 0.800 Sequential therapy 0.200 Improved 0.609 Sequential therapy 0.391

P = 0.503 P = 0.000

P = 0.023 P = 0.059

P = 0.027 P = 0.009

P = 0.060 P = 0.035

P = 0.051 P = 0.008

P = 0.012 P = 0.008

P = 0.037 P = 0.009

P = 0.097 P = 0.062

NOTE: The first 2 nodes represent 12-hour intervals. The subsequent nodes represent 24-hour intervals. The probability of improving/not improving is provided for each chance node, and overall probabilities for each path are provided at the terminal nodes. a Indicates that consensus was not reached on probability of improving or on dosage amount, as indicated by placement. rFVIIa indicates recombinant activated factor VII.

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Table Outcomes and Costs, by Adherence to Treatment Algorithm Impact of the algorithma

Adherence

Nonadherence

Patients improving at 72 hr

74.4%

56.7%

Patients requiring sequential therapy

25.6%

43.3%

$87,436

$92,604

Overall average cost

NOTE: Sequential therapy was estimated at $92,604 for 3 days, based on the regimen described in this article and the cost of aPCC and rFVIIa used in the model. If adherence to the model could help reduce sequential therapy by 17%, the savings would be $92,604 ⳯ 0.176 = $16,305 per patient. a Excludes patients who demonstrate consistent improvement from the initiation of bypassing agent therapy.

Clinical Impact In the evaluation of clinical outcomes, patients who demonstrated consistent improvement from initiation of therapy were excluded from the model, because they would not be expected to require changes deviating from the treatment algorithm. The model showed that regardless of the initial bypassing agent administered, when the treatment algorithm was followed, an average of 74.4% of patients would improve during 72 hours (73.7% for aPCC; 75.1% for rFVIIa) compared with an average of 56.7% (51.7% for aPCC; 61.7% for rFVIIa) when the algorithm was not followed—a 31.2% relative increase in clinical improvement after 72 hours, which was attributed to algorithm adherence (Table).

Similarly, the proportion of patients not improving after 72 hours and requiring combined sequential therapy was lower when the algorithm was followed. If the subset of patients who consistently improved from initiation of therapy is removed, an average of 25.6% (26.3% for aPCC; 24.9% for rFVIIa) of patients would require combined sequential therapy when the algorithm is followed; if it is not followed, an average of 43.3% (48.3% for aPCC; 38.3% for rFVIIa) would require this regimen (Table).

Algorithm nonadherence increased the requirement for combined sequential therapy by 69.1%.

Economic Implications Based on a decision-analysis approach, costs associated with bypassing agent therapy are lower for adhering to the algorithm, regardless of the agent initiated. If 50% of patients used aPCC initially and 50% used rFVIIa, adhering to the treatment algorithm would reduce the overall costs by 5.6%.

Additional cost-savings are noted from algorithm

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adherence as a result of a reduction in the percentage of patients requiring combined sequential therapy (Table).

Using combined sequential therapy for 3 days is estimated to be $92,604 per patient in drug costs alone.

Avoidance of combined sequential therapy in 17.6% of patients, based on an absolute reduction from 43.3% to 25.6% of patients requiring sequential therapy, would generate savings as high as $16,305 per patient.

Sensitivity Analysis Sensitivity analyses indicated that the model is robust to changes in drug prices and clinical efficacy. When modeled prices were increased or decreased by 20% around base-case pricing, treatment algorithm application still resulted in cost-savings from 3.3% to 7.7% for aPCC use and from 2.3% to 9.7% for rFVIIa use.

Cost-savings were also demonstrated when initial efficacy (improving or worsening after the first dose) varied by as much as 20%. The range of savings for patients requiring combined sequential therapy was between 17.4% and 17.6% among those receiving aPCC initially and between 16.6% and 18.4% among those receiving rFVIIa initially.

Discussion The model’s purpose was to quantify the clinical impact of adherence to a treatment algorithm in addressing problem bleedings and to assign a monetary value associated with adjusting therapy in a timely manner, based on a systematic approach to therapy. The efficacy of bypassing agents in controlling bleeding episodes in patients with hemophilia who develop inhibitors has been documented, and the reported success rates range from 80% to 93%.6-9 Variability in response to therapy does occur11 and is attributed by some investigators to the different mechanisms of action of aPCC and rFVIIa.10,20,21 Responsiveness to treatment has also been documented to change during the course of a single bleeding episode.13 A clinical trial comparing aPCC and rFVIIa determined that both agents exhibit a similar effect on joint bleedings, but that the efficacy of the 2 agents is rated differently by a substantial proportion of patients with clotting inhibitors.10 Further complicating matters is the lack of agreement on dosing.22 Some protocols suggest the use of high daily doses, whereas others propose lower doses, and the success rates with both approaches are similar.23 These factors underscore the need to assess the adequacy of the response at regular intervals and make appropriate therapy adjustments in suboptimal situations.14,15 If patients who are not improving received treatment according to the algorithm, the dose or frequency of administration would be increased at 12 hours; therapy

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would be switched to the alternate bypassing agent at 24 hours for those still not improving; followed by an increase in dose or in frequency of administration at 48 hours for those whose bleeding remains refractory. As a final step, patients would be given combined sequential therapy if they demonstrated no improvement at 72 hours.

If the treatment algorithm was not followed, the model assumed that no treatment evaluation would be made at 12 hours, and all subsequent decisions would be delayed. Based on the model simulation, adhering to the algorithm could result in a relative improvement of more than 30% at 72 hours. This increase in improvement demonstrates the effect of timely therapy adjustments in this population.

Regardless of the bypassing agent used at the initiation of therapy, algorithm adherence also results in fewer patients requiring combined sequential therapy. Based on the present model results, reducing the percentage of patients requiring sequential therapy by 17.5% has the potential for average cost-savings of $16,035 per patient.

Combined sequential therapy has been used for severe refractory bleedings,24 but its use is controversial.12 Although there may be situations when this approach is justifiable, minimizing the number of patients who require this regimen clearly has economic advantages and averts theoretical patient safety concerns. However, the agents examined in this analysis are not approved for sequential therapy, and adverse events, such as an increased risk of thrombosis, are a concern for some physicians.12 The costs of managing problem bleedings in patients with inhibitors can vary tremendously, depending on the bleeding episode itself and on the medication used.12 As a result, payers, providers, and patients face a significant challenge in trying to contain costs while achieving the best possible patient care. In view of the complexity of the condition, and the lack of consensus on optimal treatment, models such as the one described in this article can help providers with the decision-making process.

Because this model is based on expert opinion, the information and recommendations set forth may assist with the construction of clinical guidelines to guide future therapies. Utilizing the assumption that the inputs derived from the consensus panel reflect real-world costs and outcomes, the information contained in this model may provide insight to clinicians when assessing patients with problem bleeding. In addition, guideline implementation may assist with payment and reimbursement strategies for the use of these agents.

Limitations No evidence-based treatment guidelines are currently available for this patient population, and the results of this study are based on a simulated model and must

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be interpreted as such. As with any model, there are limitations associated with interpreting the results. The model considers only limited direct costs associated with bypassing agent therapy (ie, drug costs).

Additional direct costs, including those for hospitalization, physician visits, and rehabilitation care, as well as indirect costs associated with decreased productivity, were not considered.

In addition, costs were assessed according to Medicare Part B limits, which may not be reflecting an individual institutionâ&#x20AC;&#x2122;s costs. The model aimed to apply the consensus algorithm to a real-world setting by using a panel of experts to characterize treatment patterns and effectiveness in an assessment of the clinical and economic benefits and consequences of algorithm adherence.

For several of the questions posed to the panel, no consensus was reached. In both of the consensus algorithm adherence and nonadherence scenarios presented here, the panel did not reach a consensus on multiple occasions regarding the dosing of rFVIIa. The panel was mostly in agreement with the likelihood of clinical improvement, with the noted exception regarding bleeding worsening at 12 hours and again at 24 hours.

Conclusion The data presented in this article are based solely on expert opinions, recommendations, and assumptions; therefore, generalizing this information to real-world settings should be done cautiously. However, in the absence of studies directly assessing the impact of guideline adherence on clinical and economic outcomes associated with the use of bypassing agents to control spontaneous bleeding episodes in patients with hemophilia who develop inhibitors, these data provide the best available estimate for those outcomes.

Future studies that assess treatment algorithms such as this one may be warranted to obtain further evidence for the outcomes of bypassing agent therapy in patients with hemophilia. Being able to incorporate real-world data may further help to clarify areas of hemophilia treatment where currently no consensus exists.

Adherence to an algorithm in which treatment is altered at regular intervals based on clinical response has the potential to result in an increase in clinical improvement and reduction in the number of nonresponsive patients requiring sequential therapy. Moreover, algorithm adherence would result in a modest cost-savings in patients with hemophilia who develop clotting factor inhibitors and are experiencing problem bleedings. â&#x2013; Funding Source This study was supported by funding from Baxter Healthcare.

Continued

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Author Disclosure Statement Dr Gringeri has received research grants from Baxter Healthcare, Biotest, CSL Behring, and Grifols; he is a Consultant to Baxter Healthcare and Wyeth and is on the Speakers’ Bureau of Baxter Healthcare, Biotest, CSL Behring, Grifols, Kedrion, Novo Nordisk, Octapharma, and Wyeth. Dr Gomperts is a Consultant to Baxter Healthcare.

Dr Leissinger has received research support from and is on the Speakers’ Bureau of Baxter Healthcare and Novo Nordisk.

Dr d’Oiron is a Consultant to and on the Speakers’ Bureau of Baxter Healthcare, and Novo Nordisk. Dr Teitel is a Consultant to Baxter Healthcare and Pfizer and has received grant support from CSL Behring. Dr Young is a Consultant to Baxter Healthcare and Novo Nordisk. Dr Berntorp has received honoraria and research support from Baxter Healthcare. Dr Bonnet, Dr Ewenstein, and Dr Franklin have nothing to disclose.

References 1. Ehrenforth S, Kreutz W, Scharrer I, et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet. 1992;339:504-598.

2. Ljung R, Petrini P, Tengborn L, Sjorin E. Haemophilia B mutations in Sweden: a population-based study of mutational heterogeneity. Br J Haematol. 2001;113:81-86.

3. DiMichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas.

Haemophilia. 2002;8:280-287.

4. FEIBA VH. Anti-Inhibitor Coagulant Complex (vapor heated) [package insert].

Westlake Village, CA: Baxter Healthcare Corporation; 2005.

5. NovoSeven [package insert]. Princeton, NJ: Novo Nordisk; 2006.

6. Negrier C, Goudemand J, Sultan Y, et al. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors.

Thromb Haemost. 1997;77:1113-1119.

7. Parameswaran R, Shapiro AD, Gill JC, Kessler CM. Dose effect and efficacy of rFVIIa in the treatment of hemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry. Haemophilia. 2005;11:100-106.

8. Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost. 1998;80:912-918.

9. Hilgartner MW, Knatterud GL. The use of factor eight inhibitor bypassing activity (FEIBA Immuno) product for treatment of bleeding episodes in hemophiliacs with inhibitors. Blood. 1983;61:36-40.

10. Astermark J, Donfield SM, DiMichele D, et al; for the FENOC Study Group. A randomization comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood. 2007;109: 546-551.

11. Quintana-Molina M, Martínez-Bahamonde F, González-García E, et al. Surgery in haemophilic patients with inhibitor: 20 years of experience. Haemophilia. 2004;10 (suppl 2):30-40.

12. Allen G, Aledort L. Therapeutic decision-making in inhibitor patients. Am J Hematol. 2006;81:71-72.

13. Hayashi T, Tanaka I, Shima M, et al. Unresponsiveness to factor VIII inhibitor bypassing agents during haemostatic treatment for life-threatening massive bleeding in a patient with haemophilia A and a high responding inhibitor. Haemophilia.

2004;10:397-400.

14. Teitel J, Berntorp E, Collins P, et al. A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors.

Haemophilia. 2007;13:256-263.

15. Gomperts ED, Astermark J, Gringeri A, Teitel J. From theory to practice: applying current clinical knowledge and treatment strategies to the care of hemophilia A patients with inhibitors. Blood Rev. 2008;22(suppl 1):S1-S11.

16. Linstone HA, Turoff M, eds. The Delphi Method: Techniques and Applications.

Reading, MA: Addison-Wesley Publishing Company; 1975.

17. Rowe G, Wright G. The Delphi technique as a forecasting tool: issues and analysis. Int J Forecast. 1999;15:353-375.

18. Kaliner M, Amin A, Gehling R, et al. Impact of inhaled corticosteroid–induced oropharyngeal adverse effects on treatment patterns and costs in asthmatic patients: results from a Delphi panel. P&T. 2005;30:573-601.

19. St Louis EK, Gidal BE, Henry TR, et al. Conversions between monotherapy in epilepsy: expert consensus. Epilepsy Behav. 2007;11:222-234.

20. Turecek PL, Varadi K, Gritsch H, Schwarz HP. FEIBA: mode of action.

Haemophilia. 2004;10(suppl 2):3-9.

21. Hoffman M, Monroe DM III. The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis. Dis Mon. 2003;49:14-21.

22. Lloyd Jones M, Wight J, Paisley S, Knight C. Control of bleeding in patients with haemophilia A with inhibitors: a systematic review. Haemophilia. 2003;9:464-520.

23. Ingerslev J. Hemophilia. Strategies for the treatment of inhibitor patients.

Haematologica. 2000;85(10 suppl):15-20.

24. Schneiderman J, Nugent DJ, Young G. Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe hemophilia and inhibitors. Haemophilia. 2004;10:347-351.

STAKEHOLDER PERSPECTIVE Potential Cost-Savings Using a Treatment Algorithm for Problem Bleeding Episodes in Patients with Hemophilia and Inhibitors MEDICAL/PHARMACY DIRECTORS: Approximately 30% of people with hemophilia will develop a neutralizing alloantibody, called an inhibitor, to the clotting factor used to treat or prevent their bleeding episodes.1,2 The mechanism and reason for developing inhibitors are unknown; however, the following risk factors for developing an inhibitor have been identified1: • Age • Race/ethnicity • Type of hemophilia gene defect

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• Frequency and amount of treatment (inhibitors typically occur within the first 50 exposures to clotting factor) • Family history of inhibitors • Type of factor treatment product • Presence of other immune disorders.

Developing an inhibitor is one of the most serious and costly complications of hemophilia, and direct medical costs are significantly higher for hemophilia patients with inhibitors than those without. The presence of inhibitors has significant clinical implications

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STAKEHOLDER PERSPECTIVE (Continued) and an increased morbidity for those with hemophilia.

In addition, the healthcare costs associated with inhibitors are significant, because of the cost and amount of product required to stop bleeding.1 Moreover, patients with hemophilia with inhibitors are twice as likely to be hospitalized for a bleeding complication.1 Having been involved with the specialty pharmacy provision of clotting factor to individuals with hemophilia and von Willebrand disease for more than 20 years, hemophilia patients with inhibitors represent the greatest clinical challenge to medical staff and to specialty pharmacies that provide clotting factor to them.

Patients with inhibitors consume a disproportionate amount of the specialty “drugs spending” for payers and for managed care organizations. In fact, patients with inhibitors use the most costly clotting factors commercially available, such as activated prothrombin complex concentrate (aPCC; factor VIII inhibitor bypassing activity [FEIBA]) and recombinant activated factor VII (rFVIIa; NovoSeven RT).

PATIENTS: As a parent of 2 sons with bleeding disorders, when your child experiences a major bleed or a life- or limb-threatening bleed, it does not matter what a treatment algorithm suggests you do as a first step. Your immediate priority is to stop the bleeding, even if it means using doses that are higher or have more frequent dosing intervals than what is listed in the product’s package insert or in published treatment algorithms.

PROVIDERS: The information presented in the study is useful and does demonstrate a theoretical costsavings for treating patients with inhibitors. The algorithm serves as a useful road map in treating individuals with inhibitors. For patients with hemophilia, particularly those with inhibitors, bleeding episodes can be severe if not immediately treated.

Patients with hemophilia, particularly those with inhibitors, vary in their responses to treatment.

Recommended doses for one patient may not work or may be unsuitable for another patient. For that reason, treatment guidelines for hemophilia are only that, guidelines, and physicians must still have the flexibility to manage the patient based on their knowledge and

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the clinical background of the patient, as well as the type of hemorrhagic episode.

Additional Clinical Considerations Viral safety. An important consideration in using the aPCC bypassing agent is viral safety. To date, there have been no confirmed reports of transmission of viruses definitely associated with the use of aPCC. However, because this product is derived from human plasma, as is the case with all plasma-derived products, the risk of transmission of infective agents (eg, viruses and the Creutzfeldt-Jakob disease agent) cannot be totally eliminated.3 By contrast, rFVIIa is a recombinant product, entirely free of human plasma.

Thromboembolic events. Serious thrombotic side effects are associated with the use of rFVIIa outside of approved US Food and Drug Administration indications. It should also be noted that people taking aPCCs/PCCs concomitantly with rFVIIa may be at increased risk for thrombotic side effects. When used according to package insert guidelines, rFVIIa has a 1% risk of adverse thrombotic events in patients with inhibitors.4 Thrombotic adverse events with aPCC therapy are <0.009%.3 Payers must not assume that following these published guidelines closely will automatically result in significant cost-savings. An interesting follow-up study would involve patients with inhibitors and the resolution of their bleeding episode as a result of using these treatment algorithms compared with any differences between inhibitor patients who did not follow the algorithm and associated cost differentials between the 2 groups.

1. Centers for Disease Control and Prevention. Inhibitors. www.cdc.gov/ncbddd/ hemophilia/inhibitors.html. Accessed August 3, 2011.

2. Pérez Bianco R, Ozelo MC, Villaça PR, et al. Diagnosis and treatment of congenital hemophilia with inhibitors: a Latin American perspective. Medicina (Buenos Aires). 2008;68:227-242.

3. Baxter Healthcare. About FEIBA. http://feiba.com/hcp/about-feiba/safety.html.

Accessed August 7, 2011.

4. Novo Nordisk. NovoSeven RT. www.novosevenrt.com/. Accessed August 4, 2011.

Hetty A. Lima, RPh, FASHP Vice President, Specialty Infusion Services Diplomat Specialty Pharmacy Flint, MI

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in su 3 pr rvi yea M ev va r ul io l a ov tip us d er le ly van all M un ta ye tre ge lo a m te a d

If You Define Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT 3-YEAR UPDATE- SUSTAINED BENEFIT UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

90

% Patients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

3

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12

15

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21

24

27

30

33

36

39

42

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51

Months Kaplan-Meier estimate.

Patients treated with VELCADE + MP as initial therapy sustained an overall survival benefit over patients randomized to MP alone The overall survival benefit was sustained despite subsequent treatments Median duration of VcMP treatment was 46 weeks/54 planned1 At the initial analysis (median 16.3-month follow-up), median TTP was 20.7 months with VELADE in combination with MP vs 15 months for MP alone (P=0.000002) * VISTA was a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespecified interim analysis (median follow-up 16.3 months) VcMP resulted in significantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. † VcMP=VELCADE + melphalan/prednisone (MP).

If You Define Value as Medication Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1398.00 per 3.5mg vial as of January 1, 2011.

Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen.

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication.

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, option 2 (1-866-835-2233).

www.VELCADE.com 1. San Miguel, Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. New England Journal of Medicine 2008.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone.

The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.

Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, 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: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.

Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright ©2009, Millennium Pharmaceuticals, Inc. All rights reserved.

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Managing Utilization by Exception Matthew Zubiller, MBA Vice President for Decision Management, McKesson Health Solutions, San Francisco, CA

B

ecause of new reform-driven medical loss ratio requirements, now more than ever health plans’ primary lever on profitability is to reduce administrative costs. Rethinking utilization management (UM) processes, especially those that require payer–provider collaboration, could provide excellent targets for health plans to reduce their administrative costs and inappropriate medical costs.

Preauthorization and other aspects of UM have been effective in reducing inappropriate services and managing medical costs. But the traditional preauthorization process is simply too high-touch and “low-tech.”

Whereas claims are reviewed manually only in cases where there is an exception, nearly all UM requests include manual processing. We must begin to manage utilization by exception rather than by manual intervention and put systems in place that approve the vast majority of requests without touching them. This ensures sufficient focus on the 20% to 40% of cases that truly require review depending on the provider practice pattern and procedure specialty.

This next generation of UM uses a prospective, exception-based model that engages providers in a new way, greatly improving the impact of UM on costs while helping to ensure that the most appropriate care is consistently provided. This model facilitates real-time transparency with providers by leveraging automation and evidence-based medicine at the point of care, reducing the hassle that typically accompanies UM. It enables the consistent application of clinical and coverage rules before inappropriate services are performed and ensures timely, optimal care without the administrative costs or burden of traditional programs. This article details the challenges faced today using traditional authorization and discusses the advantages of this new prospective, exception-based approach to UM.

The Current State of Utilization Management According to McKesson research1: • More than 90% of authorizations require a phone call or faxed request • Routine authorizations can take 2 days to 2 weeks to resolve • The average cost of an authorization is $50 to $75 for providers and $75 to $100 for plans • The average cost per appeal is $300.

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Traditional authorization processes are unable to provide the rich data on utilization and network use that are required in today’s era of cost pressure and reform. This lack of insight hinders the development of policy and of effective, highly targeted provider interventions. Also, traditional approaches lack the coverage and complex reimbursement information for a provider to understand if a care procedure or service is covered.

Further complicating this is the antagonistic impact that UM has on payer–provider relationships. Although the traditional authorization process has been of value to health plans, physicians have typically viewed it as intrusive and burdensome. This perception is exacerbated when plans delegate authorization and other UM services to a third party, positioning that party as the “face” of the plan to its network physicians.

Although physicians lack the data and tools they need at the point of care to make efficient UM decisions, they are open to new approaches. According to a study from the American Medical Association,2 approximately 64% of physicians surveyed have difficulty determining which tests, procedures, and drugs require authorizations.

Approximately 63% wait several days for authorization responses on tests and procedures, and 13% wait more than a week.2 In the same study, nearly all the physicians surveyed reported that eliminating traditional authorization hassles is very important (78%) or important (17%).

Seventy-five percent of the surveyed physicians believed automated authorizations would help them manage their patients’ care more efficiently.2 When we look at the current state of UM, many physicians would agree that progress has been slow and payers and providers are not on the same page. UM remains much as it was more than 20 years ago, a process that health plans need and physicians still loathe.

Traditional UM is perceived as pitting health plans against physicians as they seek permission to practice medicine as they see fit. How can plans take action to improve this dynamic and foster the type of effective, collaborative relationship demanded by the changing healthcare environment to significantly reduce administrative costs and enable better decision-making?

Next-Generation Utilization Management Based on our experience, health plan executives are

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looking to drive clinical and financial decision support to the provider at all points of care. They want to enhance clinical decision-making with consistent, up-to-date evidence and comparative analysis rather than simply ensure that physicians get authorizations for a care event. This more collaborative approach aligns plans and physicians to work together to provide efficient, optimal care and help members avoid clinically inappropriate, out-of-network or noncovered services that can delay or prevent the best care and increase costs.

A prospective, exception-based approach is welcomed by providers, reduces overall costs, and ultimately improves members’ health.1 This next generation of UM involves deploying real-time, fully automated decision support tools to the point of care, including widely accepted evidence-based clinical guidelines, combined with health plan coverage rules, before services are performed and expenses are incurred.

This approach ensures that members receive the right service at the right time in the right setting. It saves health plans from paying for unnecessary expenses and recovering them retrospectively or not at all.

This approach ensures that members receive the right service at the right time in the right setting. It saves health plans from paying for unnecessary expenses and recovering them retrospectively or not at all. Because prospective, exception-based UM automates most of the authorization process, the plan’s clinical staff can focus on only the more complex “exceptions” that truly require their time and expertise.

A prospective UM approach frees up the health plan resources to: • Engage their providers in a new, transparent, collaborative way • Reduce the turnaround time for complex reviews • Insource currently outsourced tasks, leading to better control and consistency with providers • Expand UM programs to address rapidly growing areas, such as specialty pharmacy and molecular diagnostics • Increase touch where needed—in care management services to members with complex health conditions • Scale as membership increases without increasing staff.

Reasons for the Model’s Success The prospective, exception-based model succeeds because it allows plans to reap the following benefits.

Identify outliers early on. Research, such as the

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2009 national survey on medical expenses by Atul Gawande, MD, MPH, a general and endocrine surgeon at Brigham and Women’s Hospital and the DanaFarber Cancer Institute in Boston, showed that certain providers drive a larger percentage of improper utilization than others.3 With fully automated authorizations, plans can identify provider-specific practice patterns and utilization trends early in the process and establish unique, automated interventions to address each provider or procedure individually.

Reward quality providers. Automate new, alternative quality contracts based on performance, and/or “gold card privileges” for providers whose practices are consistent with evidence-based medicine, coverage policy, and other rules of medical appropriateness.

Provide flexible options. Alternative approaches to in-depth authorization can streamline plan–provider collaboration, while educating providers on evidencebased clinical appropriateness. As a result, health plans can enable behavior change without the intrusiveness of a permission-based process. One alternative is electronic notifications, which are one-way transactions from the provider to the health plan, indicating intent to perform or to order a medical service. These transactions enable plans to gather data to refine or target ongoing UM efforts with reduced effort and time.

Notifications are less costly and invasive than authorizations and provide powerful data to address an increase in utilization for a specific service before it impacts the plan’s bottom line.

Drive more in-network activity. With physicians directing patients to the most appropriate facilities, point-of-care decision support tools can help providers ensure that procedures, care episodes, diagnostics, and other services are performed in-network.

Drive alignment with providers while accommodating variation. By using widely accepted evidence-based clinical guidelines across care management, payers and providers become aligned in their decision-making and the performance is transparent. At the same time, it is important to quickly see plan-specific rules without manual lookups and telephone calls.

New Tools Enable Health Plans to Revise Their UM Approach With the capabilities of new, innovative evidencebased decision support tools, health plans can reconsider traditional UM administration. These new decision management solutions provide the infrastructure needed to deploy prospective, exception-based UM, with a light footprint, including: • Real-time, fully automated provider UM processes (eg, preauthorization)

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• Evidence-based clinical criteria that provide a common language to drive payer–provider collaboration • Condition-specific criteria that focus on the whole patient, including comorbidities and severity, requiring fewer case managers to intervene, and expediting the transition from retrospective to prospective care management.

In addition, the same UM tools used to support alignment and expense reduction can be leveraged as part of a bundled payment strategy. Specifically, real-time, point-of-care decision support provides the means to identify scenarios that would initiate a care episode and potentially provide integration to back-end bundled payment management. Thus, health plans will be able to address payment reform and leverage their investment in payer–provider UM collaboration tools to support bundled payment initiatives.

By implementing a prospective, exception-based UM decision support platform, health plans can identify: • Whether a service is covered based on plan benefits • Whether a service is covered based on medical appropriateness • What alternative services are medically appropriate if the request is not recommended by clinical evidence • Which in-network providers are optimal to perform the service • What level of benefits apply • Whether to use UM to trigger a care episode and corresponding bundled payment.

A Critical Solution for the Age of Healthcare Reform Health plans have worked hard to help improve their members’ health and manage medical and administrative costs. However, with increasing utilization, the continuous introduction of new technology, higher medical costs, and the enormous impact of healthcare reforms, the pressure on health plans is unprecedented and daunting. Plan executives need to look at innovative approaches, such as prospective, exception-based utilization management, to dramatically reduce their administrative costs.

The next generation of UM is indeed a prospective, exception-based approach that combines innovative automation with payer-specific clinical and financial decision support. It addresses cornerstones of reform by promoting optimal care at the right cost through a collaborative plan–provider model. This model enables

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Successful Case of Utilization Management Implementation Organization: A state Medicaid plan in the Midwest Challenge: Rapidly rising radiology utilization, impacting costs to the state and exposing members to unnecessary radiation Approach: Deployed prospective, exception-based UM approach to decrease administrative costs Solution: McKesson decision management (including InterQual and Clear Coverage) Results: Within 10 months of implementation, of the nearly 50,000 preauthorization requests that were processed: • >40% received instant, fully automated approval • 8% were cancelled by requesting providers • 4% were denied as medically inappropriate • An estimated $2.4 million in annual costs were avoided. plans’ clinical staff to focus on only the complex exceptions that truly require their skills and expertise.

This new approach to UM is a powerful strategy in this age of healthcare reform for reducing administrative costs and inappropriate medical costs, while engaging providers in a new, collaborative, transparent way that focuses on cost-effective care performance. It helps to ensure consistent, evidence-based care by educating providers in real-time as they order treatments and diagnostics before services are performed and expenses are incurred. This approach also helps to ensure that patients consistently get the right treatments in the first place, eliminating waste in the system and ultimately improving overall healthcare and outcomes. ■ Author Disclosure Statement Mr Zubiller reported no conflicts of interest.

References 1. Zubiller M. Prospective, exception-based utilization management. 2011. www.mckesson.com/static_files/McKesson.com/MHS/Documents/Exceptionbased%20Utilization%20Management.pdf. Accessed July 21, 2011.

2. New AMA survey finds insurer preauthorization policies impact patient care [press release]. Chicago, IL: American Medical Association; November 22, 2010. www.ama-assn.org/ama/pub/news/news/survey-insurer-preauthorization.page.

Accessed July 21, 2011.

3. Gawande A. The cost conundrum: what a Texas town can teach us about health care. The New Yorker. June 1, 2009. www.newyorker.com/reporting/2009/06/01/ 090601fa_fact_gawande?currentPage=all. Accessed July 21, 2011.

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INDICATION %8!,'/ÂŽ TABLETS ARE AN EXTENDED RELEASE ORAL FORMULATION OF THE OPIOID AGONIST HYDROMORPHONE HYDROCHLORIDE THAT IS INDICATED FOR ONCE DAILY ADMINISTRATION FOR THE MANAGEMENT OF MODERATE TO SEVERE PAIN IN OPIOID TOLERANT PATIENTS REQUIRING CONTINUOUS AROUND THE CLOCK OPIOID ANALGESIA FOR AN EXTENDED PERIOD OF TIME IMPORTANT RISK INFORMATION WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time.

Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/ hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer.

EXALGO is for use in opioid tolerant patients only.

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain.

EXALGO is not intended for use as an as-needed analgesic.

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone.

s %8!,'/ IS ALSO CONTRAINDICATED IN PATIENTS WHO NEED MANAGEMENT OF MILD PAIN OR PAIN NOT EXPECTED TO PERSIST HAVE SIGNIlCANT IMPAIRED RESPIRATORY FUNCTION INCLUDING THOSE WITH ACUTE OR SEVERE BRONCHIAL ASTHMA OR HYPERCARBIA HAVE OR ARE SUSPECTED TO HAVE PARALYTIC ILEUS HAVE NARROWED OR OBSTRUCTED GASTROINTESTINAL TRACT INCLUDING THOSE FROM PREVIOUS SURGERY OR hBLIND LOOPSv IN THE ') TRACT HAVE KNOWN HYPERSENSITIVITY TO ANY COMPONENTS INCLUDING HYDROMORPHONE HYDROCHLORIDE AND SULlTES s !VOID CONCURRENT USE OF ALCOHOL AND %8!,'/ #ONCURRENT USE OF %8!,'/ WITH #.3 DEPRESSANTS INCLUDING ALCOHOL INCREASES RISK OF RESPIRATORY DEPRESSION HYPOTENSION AND PROFOUND SEDATION

POTENTIALLY RESULTING IN COMA OR DEATH %8!,'/ MAY IMPAIR THE ABILITY TO DRIVE A CAR OR OPERATE MACHINERY s .OT INTENDED IN PATIENTS WHO HAVE RECEIVED -!/ INHIBITORS WITHIN DAYS OF STARTING %8!,'/ s 5SE WITH CAUTION AND IN REDUCED DOSES IN OLDER OR DEBILITATED PATIENTS AS WELL AS PATIENTS WITH RENAL OR HEPATIC INSUFlCIENCY

!DDISON S DISEASE DELIRIUM TREMENS MYXEDEMA OR HYPOTHYROIDISM

PROSTATIC HYPERTROPHY OR URETHRAL STRICTURE TOXIC PSYCHOSIS -AY AGGRAVATE CONVULSIONS IN PATIENTS WITH CONVULSIVE DISORDERS MAY INDUCE OR AGGRAVATE SEIZURES IN SOME CLINICAL SETTINGS #ONSIDER USE OF AN ALTERNATE ANALGESIC IN PATIENTS WITH SEVERE RENAL IMPAIRMENT s 2ESPIRATORY DEPRESSION WHICH OCCURS MORE FREQUENTLY IN ELDERLY OR DEBILITATED PATIENTS IS THE CHIEF HAZARD WITH %8!,'/ s 3ERIOUS ADVERSE EVENTS COULD ALSO INCLUDE HYPOTENSIVE EFFECTS

') EFFECTS CARDIAC ARREST FROM OVERDOSE AND PRECIPITATION OF WITHDRAWAL -OST COMMON ADVERSE EVENTS SEEN IN CLINICAL STUDIES . WERE CONSTIPATION NAUSEA

VOMITING SOMNOLENCE ASTHENIA AND DIZZINESS s 5SE %8!,'/ WITH EXTREME CAUTION IN PATIENTS SUSCEPTIBLE TO INTRACRANIAL EFFECTS OF #/ RETENTION s $O NOT ABRUPTLY DISCONTINUE %8!,'/ Please see brief summary of Full Prescribing Information, including boxed warning, on following pages. #/6)$)%. #/6)$)%. WITH LOGO AND #OVIDIEN LOGO ARE 5 3 AND INTERNATIONALLY REGISTERED TRADEMARKS OF #OVIDIEN !' %8!,'/ IS A REGISTERED TRADEMARK OF -ALLINCKRODT )NC ¥ -ALLINCKRODT )NC A #OVIDIEN COMPANY -+ -AY 0RINTED IN 53!

WHERE IS HER DAY HEADED WITHOUT A 24-HOUR PAIN MEDICATION? EXALGO® puts the power of hydromorphone into a once-daily dose, so your patients can worry less about their medicine wearing off.

To find out more, visit www.EXALGO.com.

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BRIEF SUMMARY - Consult full prescribing information before use.

EXALGOÂŽ (hydromorphone HCl) Extended-Release Tablets WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)].

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg of oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer [see Indications and Usage (1) and Dosage and Administration (2)].

EXALGO is for use in opioid tolerant patients only [see Indications and Usage (1) and Dosage and Administration (2)].

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.1)].

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain [see Indications and Usage (1)].

EXALGO is not intended for use as an as-needed analgesic [see Indications and Usage (1)].

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5)].

CONTRAINDICATIONS Opioid Non-Tolerant Patients EXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.

Impaired Pulmonary Function EXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia.

Paralytic Ileus EXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus.

Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI Tract EXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have â&#x20AC;&#x153;blind loopsâ&#x20AC;? of the gastrointestinal tract or gastrointestinal obstruction.

Allergy or Hypersensitivity EXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)].

WARNINGS AND PRECAUTIONS Information Essential for Safe Administration EXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning].

EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning].

EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Misuse and Abuse EXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit.

This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion.

Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)].

If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration.

Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose.

Interactions with Alcohol and Other CNS Depressants The concurrent use of EXALGO with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. Avoid concurrent use of alcohol and EXALGO [see Clinical Pharmacology (12.3)].

Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of EXALGO and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, EXALGO can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Hypotensive Effect EXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone.

Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal Effects Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, â&#x20AC;&#x153;short gutâ&#x20AC;? syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckelâ&#x20AC;&#x2122;s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.

The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition.

It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

MAO Inhibitors EXALGO is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Special Risk Groups EXALGO should be administered with caution in elderly (â&#x2030;Ľ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)].

EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addisonâ&#x20AC;&#x2122;s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis.

EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Use in Pancreatic/Biliary Tract Disease EXALGO can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should be exercised in the administration of EXALGO to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery.

Driving and Operating Machinery EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. Also warn patients about the potential combined effects of EXALGO with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7)].

Precipitation of Withdrawal Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, including EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Do not abruptly discontinue EXALGO. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with EXALGO and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: K &3A>7@/B=@G 3>@3AA7=< [see Warnings and Precautions (5.3)] K Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)] K G>=B3<A7D3 4431B [see Warnings and Precautions (5.6)] K /AB@=7<B3AB7</: 4431BA [see Warnings and Precautions (5.7)] K /@27/1 @@3AB [see Overdosage (10)] K %@317>7B/B7=< =4 +7B62@/E/: [see Warnings and Precautions (5.13)]

Clinical Studies 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 clinical practice.

EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year.

The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.

A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1.

Table 1.

Number (%) of Patients with Adverse Reactions Reported in â&#x2030;Ľ2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Preferred Term Open-Label Double-Blind Treatment Phase Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) 16 (4) 2 (1) 6 (4) Asthenia a Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) 10 (2) 2 (1) 0 (0) Anorexia b Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) 9 (2) 4 (3) 3 (2) Abdominal Pain c Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) a b c

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 2.

Table 2.

Number (%) of Patients with Adverse Reactions Reported in â&#x2030;Ľ2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia a 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) Anorexia b 139 (6) Dry Mouth 121 (5) Abdominal Pain c 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia d 88 (4) Depression 81 (3) Dyspnea e 76 (3) Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) Chest Discomfort f 51 (2) a b c d e f

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain Reflux esophagitis, gastroesophageal reflux disease and Barrettâ&#x20AC;&#x2122;s esophagus were grouped and reported with dyspepsia Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension DRUG INTERACTIONS CNS Depressants The concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)].

Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment.

Mixed Agonist/Antagonist Opioid Analgesics The concomitant use of EXALGO with morphine agonist/antagonists (buprenorphone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended.

Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Cytochrome P450 Enzymes In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)].

Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day).

Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.

Nonteratogenic Effects In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day).

Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor and Delivery EXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate.

However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression.

Nursing Mothers Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk.

Pediatric Use The safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established.

Geriatric Use Elderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose.

Neonatal Withdrawal Syndrome Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Hepatic Impairment In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0- ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration.

The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0- of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)].

Renal Impairment Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)].

DRUG ABUSE AND DEPENDENCE Controlled Substance EXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse.

Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

“Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts.

In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances.

With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].

OVERDOSAGE Symptoms Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

Deaths due to overdose could occur with abuse and misuse of EXALGO. Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours.

Treatment Give primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose.

Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

OROS is a registered trademark of ALZA Corporation.

EXALGO is a registered trademark of Mallinckrodt Inc. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG. © 2010 Mallinckrodt Inc., a Covidien company Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA Issued 11/2010

Mallinckrodt

CLINICAL

ORIGINAL RESEARCH

Anticoagulation Bridging Therapy Patterns in Patients Undergoing Total Hip or Total Knee Replacement in a US Health Plan: Real-World Observations and Implications Onur Baser, MS, PhD; Dylan Supina, PhD; Nishan Sengupta, PhD; Li Wang, MS, PhD

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2011;4(4):240-248 www.AHDBonline.com Disclosures are at end of text

Background: The necessity for anticoagulant bridging therapy after joint replacement surgery is widely understood, but treatment administration patterns in the prevention of venous thromboembolism (VTE) after total hip replacement (THR) or total knee replacement (TKR) surgery during the hospital stay have yet to be examined.

Objective: To investigate anticoagulation thromboprophylaxis patterns, especially the use of anticoagulant bridging therapy and/or nonbridged treatment strategies, in patients undergoing THR/TKR surgery.

Methods: This retrospective study was based on a large hospital database linked with outpatient claims from 2005 through 2007. The study population included 1770 patients who were admitted for either THR or TKR surgery and were aged â&#x2030;Ľ18 years on the date of the surgery, defined as the index date. Patients were required to have commercial insurance or Medicare coverage and be continuously enrolled in their health plan for at least 180 days before and 90 days after the index date. The data were analyzed retrospectively for riskadjusted postsurgery VTE and major bleeding events among patients receiving anticoagulation thromboprophylaxis. Patterns of anticoagulant bridging therapy use were also assessed.

A risk adjustment was performed using propensity score matching.

Results: Of 1770 eligible patients, 1551 (88%) received anticoagulant VTE prophylaxis; 264 (15%) received combination low-molecular-weight heparin and warfarin. Of these, 105 (40%) patients were switched between the 2 monotherapies, and 159 (60%) received bridged (overlapping) prophylaxis. The overall rates of VTE and bleeding events were significantly lower with bridged therapy than with nonbridged therapy (5.8% vs 18.4%, respectively, for VTE, P <.02; 2.3% vs 4.60% for major bleeding, P = .41; 1.15% vs 8.05% for minor bleeding, P <.03).

Conclusion: Although existing guidelines recommend anticoagulant bridging therapy after THR or TKR surgery, the limited data regarding anticoagulant bridging practice patterns suggest that patients who undergo such surgery do not receive adequate anticoagulant thromboprophylaxis immediately after discharge. Our findings suggest that increased use of bridging therapy after THR or TKR surgery may help improve postsurgery patient outcomes by reducing VTE and bleeding rates.

A

n estimated 350,000 to 600,000 American patients experience venous thromboembolism (VTE) annually, which includes deep-vein

Dr Baser is Adjunct Professor of Internal Medicine, University of Michigan, and President, STATinMED Research, Ann Arbor; Dr Supina was Associate Director, Worldwide Market Access, Johnson & Johnson, Raritan, NJ, at the time of this study; Dr Sengupta is Compound Market Access Leaderâ&#x20AC;&#x201C; Xarelto (Rivaroxaban) Worldwide Market Access, Johnson & Johnson, Raritan, NJ; Dr Wang is Director, Analytic Research, STATinMED Research, Dallas, TX.

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thrombosis and pulmonary embolism.1-5 Patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery are at high risk for VTE, because the large veins in the legs carrying blood back to the heart are significantly injured during these procedures.6,7 As a result of the aging and increasingly obese US population, an estimated 500,000 THR operations and 3.5 million TKR operations are expected to be performed by 2030.8 Much is known about how to prevent and minimize the consequences of VTE. A number of established guidelines emphasize the need to provide appropriate

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thromboprophylaxis to patients at risk for VTE.9-12 However, the approach to the management and prevention of VTE varies, as is evident by the different clinical practice guidelines for VTE that have been developed by several organizations—most notably the American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons—according to their medical specialty and specific concerns and needs.9,13 At the heart of this diversity are differing interpretations of evidence supporting anticoagulant therapy in a number of clinical settings, the contrasting opinions regarding the potential risk of bleeding that all anticoagulants carry, and the historical precedents that may unduly influence management decisions.13,14 As a result, many clinicians often find it difficult to know which VTE guidelines to follow and how to adhere to them in everyday practice.

The ACCP’s evidence-based guidelines recommend that anticoagulation be used for at least 10 days and extended for up to 35 days after THR or TKR surgery.9 Bridging therapy is central to the recommendations for perioperative management for patients receiving longterm anticoagulant therapy. In general, bridging therapy may be defined as postoperative anticoagulant overlapping of at least 2 therapies that are administered together during the period of switching from an injectable anticoagulation agent (most often intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin [LMWH]) to oral anticoagulation (most often a vitamin K antagonist, such as warfarin).

Because warfarin requires a minimum of 3 to 4 days to reach therapeutic concentration,15 it is necessary to continue the use of injectable anticoagulants during the transitional (switching) period. When determining whether to use bridging therapy, the risk of bleeding should be balanced against the risk of thromboembolism.

Although a consensus exists among the various guidelines on the need for bridging therapy, treatment patterns in clinical practice have yet to be examined.

The aim of this retrospective study was to examine thromboprophylaxis patterns—particularly involving the use of anticoagulant bridging and/or nonbridged strategies—for patients undergoing either THR or TKR surgery. Because a main goal was to make the results of this analysis relevant to practicing clinicians, inpatient data from a large hospital database were linked to outpatient claims for accurate tracking of anticoagulant use.

Methods Data Sources and Study Population The data used in this study were derived from a subset of data from the MarketScan Hospital Drug Database and its linked outpatient files from the MarketScan

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Patients undergoing total hip or knee replacement are at high risk for venous thromboembolism (VTE), which has serious implications to patients, providers, and payers; in 2008, the US Surgeon General issued a call to action emphasizing the importance of preventing VTE and pulmonary embolism.

Prophylactic anticoagulation therapy should be used for 10 to 35 days after total knee or hip replacement surgery to prevent VTE. Various clinical guidelines emphasize the need for bridging anticoagulant therapy in this patient population, but real-world treatment patterns have yet to be examined.

This retrospective study investigated the patterns of bridging and nonbridging anticoagulation therapy in patients undergoing total knee or total hip replacement surgery.

Patients who received bridged therapy had a 50% to 80% lower rate of VTE than those not receiving such therapy; only a small minority of patients received bridging therapy after hospital discharge.

Furthermore, patients who developed VTE during the hospital stay rarely were discharged with appropriate bridging anticoagulation therapy.

These results indicate that proper postoperative prophylactic anticoagulation therapy can reduce the incidence of thrombosis and improve outcomes.

Commercial and Medicare Supplemental database from Thomson Reuters covering the period from January 1, 2005, to December 31, 2007. The hospital data consisted of claims linked to detailed service-level hospital bills for the same admissions. The linkage was conducted for 172 hospitals identifiable in hospital and in claims databases.

Data for nearly 22,189 patient-level hospital records were successfully linked to longitudinal claims histories.

For each contributing hospital, the hospital database contained the full census annual admissions. Claims data were fully validated and were from covered medical and pharmacy services and geographically dispersed private and public health plans.

The study population included patients admitted for either THR surgery (defined by International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9CM] codes 81.42-81.47, 81.54-81.55) or TKR surgery (ICD-9-CM codes 81.40, 81.51-81.53), who were aged ≥18 years on the date of surgery (defined as the index date). Patients were required to have commercial or Medicare insurance and be continuously enrolled in their health plan for at least 180 days before and 90 days after the index date.

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Claims and inpatient databases were matched according to each patient’s date of admission, date of discharge, age, sex, and principal diagnosis. For the analysis, patients were categorized to 1 of 2 groups according to their prescribed anticoagulant therapy: 1. Bridged anticoagulant therapy (ie, overlapping use of 2 anticoagulants for at least 2 days in the hospital just before discharge or an overlap of at least 2 days in the outpatient setting) or 2. Switched anticoagulant therapy (ie, less than 2 days treatment of overlapping anticoagulants in the inpatient or outpatient setting).

The study investigators made an empirical decision to use a minimum of 2 days of overlap as the criterion for bridged therapy, because, based on warfarin’s requirement for 3 to 4 days to reach therapeutic concentration,15 none of the practice guidelines recommend overlapping anticoagulation therapy for less than that period, whether in the inpatient or the outpatient setting.

Patient and Provider Characteristics Demographic characteristics (age, gender, geographic location) were available in the enrollment data of the claims database. Using the Deyo adaptation of the Charlson Comorbidity Index,16-18 we assessed each patient’s comorbidities at baseline and used ICD-9-CM codes to identify hypertension, renal disease, and selected cancers—the common diagnoses that affect the outcomes in this patient population. Hospital characteristics (ie, number of beds and teaching status) were available in the hospital drug database.

Cost data were available for patients with fee-for-service health plans. However, cost data were unavailable for partially or fully capitated plans. Therefore, the value of patients’ service utilization under the capitated plans was priced and imputed using the average payments from the MarketScan fee-for-service inpatient and outpatient services, by region, year, and procedure. These were also adjusted for inflation using the medical component of the Consumer Price Index, as defined by the US Bureau of Labor Statistics.19 Outcome Measures Diagnostic codes. VTE and major bleeding events were assessed for up to 90 days from the hospitalization index date. VTE events were identified when a patient claim had an ICD-9-CM code for deep-vein thrombosis (code 451.1x-451.81, 451.83-451.9x, 452.xx, or 453.2-453.9x) or pulmonary embolism (code 415.1x).

Major bleeding events were identified by ICD-9-CM codes (see Appendix, page 247).

Minor bleeding was identified if a patient claim had any of the following ICD-9-CM codes: 784.7, 532.8,

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599.7, 791.2, 531.00-531.31, 531.9, 532.00-532.31, 532.9, 533.00-533.31, 533.9, 534.00-534.31, 534.9, 535.01, 535.4, 578.9, 530.82, 569.3, 786.3, 729.92, 432.1.

Tests. Baseline characteristics were compared between the cohorts, and descriptive statistics were calculated as means (±SD) and percentages. Differences between the cohorts were analyzed using the t-test, Mann-Whitney U-test, and the chi-square test.

Propensity score. A key problem that often plagues retrospective cohort studies is the lack of randomization in assigning participants to either a bridged or nonbridged therapy group. Differences in patient and provider characteristics that influence the choice of treatment can confound the outcome measures. One method used to adjust for differences in patient profiles is propensity score analysis.

The propensity score is the conditional probability of a patient receiving treatment, given the patient’s covariates, such as demographic and clinical factors.

Previous research has shown that if patients are matched according to their propensity score, a large percentage of the bias resulting from unequal distributions in patient characteristics can be removed.20 For example, if there are 2 patients, 1 in the treatment (ie, bridged therapy) group and 1 in the control (ie, switched therapy) group, with the same or similar propensity scores, then these patients can be considered randomly assigned to each group, and therefore, as equivalently treated or untreated.

Propensity score analysis can be implemented in a variety of ways. For the bridged and nonbridged therapy groups in this present study, we used a logistic regression model to predict the probability that patients belonged in each group on the basis of their observed characteristics. After several matching techniques (1:1, kernel, radius, and Mahalanobis distance) were applied, we used the one that provided the best balance between patients receiving bridged therapy and those receiving switched therapy, according to the guidelines provided by Baser.21 The 1:1 matching technique that was used yielded a total of 174 patients (87 in each group) of 264 patients who were matched.

Outcome measures for the matched group are presented in the article (see Results section), because these values are not confounded by the baseline differences and are therefore risk-adjusted.

Statistical terms. Interaction terms were used, but these were all nonsignificant. The C-statistic of the logistic regression used to create propensity scores was 0.87, justifying the value of propensity score matching.22 Statistical analyses were performed using SAS v9.2 (SAS Institute, Cary, NC) and Stata v10 (StataCorp, College Station, TX). Bootstrapping techniques were

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used to estimate the standard errors, because the sample size was small.23 Standard difference, which represents the percentage difference between the means after adjusting for differences in the standard deviation between the groups, was used. Values >10% represent significant practical differences.

gery and received combination anticoagulation therapy, 48 (64%) received overlapping therapy (46 inpatients, 2 outpatients) and 27 (36%) received switched therapy, all in the hospital. For the 2 outpatients, the overlapping therapy lasted 5 days and 14 days, respectively (Table 1).

Compared with patients who underwent THR surgery, a slightly smaller percentage of those who underwent TKR surgery received bridged therapy. Among patients receiving combination therapy after TKR surgery, 114 (60%) received overlapping therapy, only 1 of whom received it as an outpatient (2 days of overlap; Table 1).

Switched therapy was used in 74 patients (39%) who underwent TKR surgery, all before hospital discharge.

Results Of the 1770 patients who were eligible for the analysis, 219 (12%) did not receive anticoagulants. Of the remaining 1551 (88%) patients who received anticoagulants, 264 received combination therapy with intravenous or subcutaneous LMWH and oral warfarin, 75 (28%) of whom underwent THR surgery and 189 (72%), TKR surgery (Table 1).

Of these 264 patients, 163 (62%) received overlapping (â&#x2030;Ľ2 days) anticoagulant therapy; however, this was not considered bridged therapy unless both days of therapy were administered either in the hospital just before discharge or in the outpatient setting.

Of these 163 patients, 160 (98%) received overlapping therapy in the hospital and 3 (2%) received it in the outpatient setting. One of the 3 outpatients received only 2 days of overlapping therapy, the second received 5 days, and the third, 14 days. Only 105 (approximately 40%) patients using combination therapy received bridged prophylaxis as defined in this study (ie, overlapping therapy for â&#x2030;Ľ2 days in either the hospital, just before discharge, or the outpatient setting); 101 patients (38%) were switched to anticoagulant therapy (ie, <2 days of overlapping treatment).

Among the 75 patients who underwent THR sur-

Demographic and Baseline Characteristics Table 2 outlines baseline characteristics stratified by use of bridging therapy. Overall, patients who received bridged therapy were younger and more likely to have commercial insurance than patients who received nonbridged therapy (ie, switched therapy or overlapping therapy for <2 days in either the hospital, just before discharge, or the outpatient setting), although these differences were not significant.

The frequency of certain baseline comorbidities, such as renal disease, was lower among patients who received bridged therapy than in patients who received nonbridged therapy, but the frequency of selected cancers was higher (not a significant difference) in those receiving bridging therapy.

Although there were no differences between the 2 groups in demographic characteristics such as age, sex, and region, patients who received bridging therapy were

Table 1 Distribution of Combination Therapies, by Number of Days of Overlap Overall (N = 264) Days of overlap, N

THR (N = 75)

TKR (N = 189)

Inpatients, N

Outpatients, N

Inpatients, N

Outpatients, N

Inpatients, N

Outpatients, N

0

57

0

14

0

43

0

1

44

0

13

0

31

0

2

66

1

18

0

48

1

3

58

0

20

0

38

0

4

22

0

4

0

18

0

5

4

1

1

1

3

0

6

5

0

0

0

5

0

7

3

0

3

0

0

0

8

2

0

0

0

2

0

14

0

1

0

1

0

0

THR indicates total hip replacement; TKR, total knee replacement.

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3

South

West

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0.98

57.23%

0.64

91

33

9

Renal disease

Cancer, excluding MDS

5.66%

10

8

62

0.81

52

53

2

68

33

2

48

55

50

0

64.34

Mean, N

9.52%

7.62%

59.05%

1.68

49.52%

50.48%

1.90%

64.76%

31.43%

1.90%

45.71%

52.38%

47.62%

0.00%

9.86

Stdb

45.28%

25.16%

27

72

40

32

200-299 beds

300-499 beds

500+ beds

Teaching hospital

July/August 2011 19

28

25

37

15

18.10%

26.67%

23.81%

35.24%

14.29%

.6825

.7837

.0004

.0007

.6889

.6521

.2345

.0039

.7700

.3566

.2186

.2186

.9916

.7493

.5858

.9916

.8951

.2798

.2369

.4155

.1172

5.00%

30.00%

57.50%

1.18

57.50%

42.50%

2.50%

62.50%

30.00%

2.50%

50.00%

52.50%

47.50%

0.00%

10.40

Stdb

4

3

19

1.06

16

19

1

20

14

0

18

18

17

0

64.74

Mean, N

11.43%

8.57%

54.29%

2.17

45.71%

54.29%

2.86%

57.14%

40.00%

0.00%

51.43%

51.43%

48.57%

0.00%

10.88

Stdb

Bridged (N = 35)

6

7

19

8

6

15.00%

17.50%

47.50%

20.00%

15.00%

6

9

8

14

4

17.14%

25.71%

22.86%

40.00%

11.43%

6768.56 5939.76 5180.68 5602.39

2

12

23

0.70

23

17

1

25

12

1

20

21

19

0

63.93

P value Mean, N

Nonbridged (N = 40)

THR (N = 75)

.8006

.3863

.0265

.0577

.6499

.2377

.3059

.0206

.7797

.3894

.3081

.3081

.9237

.6366

.3640

.3463

.9017

.9262

.9262

.7412

5.88%

17.65%

57.14%

0.91

57.14%

42.86%

1.68%

68.07%

27.73%

1.68%

45.38%

61.34%

37.82%

0.84%

8.60

Stdb

6

5

43

0.69

36

34

1

48

19

2

30

37

33

0

64.14

Mean, N

8.57%

7.14%

61.43%

1.38

51.43%

48.57%

1.43%

68.57%

27.14%

2.86%

42.86%

52.86%

47.14%

0.00%

9.39

Stdb

26

33

53

19

14

21.85%

27.73%

44.54%

15.97%

11.76%

13

19

17

23

11

18.57%

27.14%

24.29%

32.86%

15.71%

6188.12 7402.53 7564.35 8969.54

7

21

68

0.62

68

51

2

81

33

2

54

73

45

1

67.02

P value Mean, N

TKR (N = 189) Bridged Nonbridged (N = 70) (N = 119)

.5908

.9303

.0054

.0070

.4390

.2802

.4806

.0429

.5633

.7302

.4457

.4457

.8935

.9427

.9303

.5874

.7363

.2533

.2085

.4419

.0380

P value

NOTE: The standard difference represents the percentage difference between the means after adjusting for differences in the standard deviation between the groups.

Values >10% represent significant practical differences in the comparisons shown (see Methods section). a Baseline is 180 days before admission date of first TKR surgery. b Values for age, Charlson Comorbidity Index, and cost are expressed as SD. c Reported in 2007 dollars.

MDS indicates myelodysplastic syndrome; SD, standard deviation; Std, standard difference; THR, total hip replacement; TKR, total knee replacement.

20.13%

16.98%

20

<200 beds

12.58%

6334.14 7049.62 6769.80 8056.87

Hospital characteristic

Cost,c $

57.23%

91

Medicare

Comorbidity Charlson Comorbidity Index Hypertension

20.75%

42.77%

1.89%

66.67%

28.30%

1.89%

46.54%

59.12%

40.25%

0.63%

9.15

Stdb

68

Commercial

Insurance

45

North central

Northeast

3

94

65+

Region

1

64

18-40

66.24

Mean, N

41-65

Age category

Age

Baseline characteristica

Overall (N = 264) Nonbridged Bridged (N = 159) (N = 105)

Table 2 Demographic and Clinical Characteristics of Patients Receiving Bridged or Nonbridged Therapy after THR/TKR Surgery

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more likely to be admitted to low-capacity hospitals with 200 to 299 beds and less likely to be admitted to highcapacity hospitals with 300 to 499 beds than patients who received nonbridged therapy (Table 2).

Among patients who underwent THR surgery, the frequency of comorbidities was similar to that in the overall sample. Patients who received bridged therapy tended to live in the north central United States and were less likely to be admitted to high-capacity (300-499 bed) hospitals. Patients who received bridged therapy after TKR surgery were younger, less likely to have renal disease at baseline, and less likely to be admitted to highcapacity hospitals than those who received nonbridged therapy. There were no differences in hospital characteristics (Table 2).

Because cost data will be analyzed separately, we did not consider them to be within the scope of this paper, which focuses on clinical outcomes. It should be noted, however, that cost data presented in Table 2 are in 2007 dollars.

Table 3 provides a comparison of the overall (THR and TKR combined), as well as THR- and TKR-specific,

rates of VTE, major bleeding, and minor bleeding in the propensity scoreâ&#x20AC;&#x201C;matched subset of patients receiving bridged or nonbridged therapy. Event rates were low in all treatment groups, but the incidence of VTE and minor bleeding events was lower in patients receiving anticoagulant bridging therapy than in those receiving nonbridged therapy; the event rate was significantly lower in the overall analysis (Table 3).

In particular, patients receiving bridged therapy overall were >3 times less likely to experience a VTE event (5.75% vs 18.39%, respectively), 50% less likely to have major bleeding (4.6% vs 2.3%, respectively), and >7 times less likely to experience minor bleeding events (8.05% vs 1.15%, respectively).

In this study population, none of the matched 13 patients who underwent THR and received bridged therapy experienced VTE or any bleeding events. The rates of VTE and of all bleeding were 50% to 80% lower in patients who received bridged therapy after undergoing TKR surgery compared with those who received nonbridged therapy.

Because the number of events was small, standard dif-

Table 3 Risk-Adjusted Rates of VTE and Any Bleeding 90 Days after Discharge in Patients Receiving Bridged or Nonbridged Anticoagulation Therapy after THR/TKR Surgery Eventa

Nonbridged (N = 87)

Overall (N = 174)

Mean, N

Std, %

Mean, N

Std, %

P value

Std, %

VTE

16

18.39

5

5.75

.0164

39.34

Major bleeding

4

4.60

2

2.30

.4142

12.55

Minor bleeding

7

8.05

1

1.15

.0339

33.19

VTE

1

7.69

0

0.00

39.22

Major bleeding

1

7.69

0

0.00

39.22

Minor bleeding

1

7.69

0

0.00

39.22

VTE

12

20.34

5

8.47

.0707

33.99

Major bleeding

2

3.39

1

1.69

.5637

10.69

Minor bleeding

5

8.47

1

1.69

.1025

30.97

Bridged (N = 87)

THR (N = 26; 13 in each group)

TKR (N = 118; 59 in each group)

NOTE: The standard difference represents the percentage difference between the means after adjusting for differences in the standard deviation between the groups. Values >10% represent significant practical differences in the comparisons shown (see Methods section). a

From surgery date until 90 days after discharge.

Std indicates standard difference; THR, total hip replacement; TKR, total knee replacement; VTE, venous thromboembolism.

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ferences are reported in the rightmost column (Table 3) for all patient comparisons. These values ranged from approximately 10 to 39, indicating significant differences in the comparisons reported.

Discussion One of the provisions in the Patient Protection and Affordable Care Act passed in May 2010 is the need to reduce the frequency of preventable complications in healthcare, thereby increasing the quality of care while lowering costs.24 Results from this study showed that after risk adjustment, patients receiving bridged therapy were >3 times less likely to experience VTE events, 50% less likely to have minor bleeding, and >7 times less likely to experience major bleeding.

Because VTE is increasingly understood to have a farreaching impact on patients, payers, and providers, the US Surgeon General issued a call to action in 2008, emphasizing the importance of preventing VTE and pulmonary embolism.5 Similarly, the Centers for Medicare & Medicaid Servicesâ&#x20AC;&#x2122; never event list underscores the urgency to adopt stringent guidelines to prevent VTE in patients who undergo THR/TKR surgery.25 Therefore, stringent guidelines must be adapted for bridged therapy, which is an option that could be adapted for accountable care organizations, organizations aimed at reducing the cost and improving the quality and overall care of Medicare beneficiaries enrolled in the traditional fee-forservice program.

Although postoperative thromboprophylaxis can reduce the incidence of thrombosis dramatically, postdischarge anticoagulation therapy of appropriate duration is essential in the setting of THR/TKR surgery.9 Properly implemented, anticoagulant bridging can be a critical component of such thromboprophylaxis strategies.26,27 Our results, however, show that patients who developed VTE after either THR or TKR while still in the hospital were rarely discharged with appropriate anticoagulant bridge therapy.

Using our criterion of including patients in the bridged therapy group who underwent overlapping therapy for as few as 2 days, we found that among 1770 patients who underwent THR/TKR surgery, only 3 (approximately 0.2%) received bridged anticoagulation therapy as outpatients; all these were in the combination therapy group (Table 1). One of these patients had only 2 days of overlap, the second 5 days, and the third 14 days. Had we adhered to the guideline recommendation of 3 days,9 an even smaller percentage of patients would have received appropriate treatment.

Using linked in-hospital and outpatient claims data, this studyâ&#x20AC;&#x2122;s findings confirmed the observation that anticoagulation use does not conform to established guide-

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lines.28 Only 264 of 1170 patients received combination anticoagulation therapy. Moreover, as shown in Table 1, only 96 patients (8%) who received it had at least 3 days of overlapping therapy, as recommended in published guidelines.9 Lack of adherence to guidelines may be an effect of the inherent complexities of currently available agents that make proper prophylaxis difficult to achieve for physicians and for patients. Potential barriers to good compliance may include confusion arising out of differences in practice guidelines from different specialists; real or perceived fear of increased risk of bleeding; and problems resulting from the complex issues related to the administration and monitoring that characterize often used available therapies.

Limitations This study has several limitations, which is typical of any retrospective claims database.29 Although claims data are extremely valuable for treatment patterns, healthcare resource utilization, and costs, these data are collected for the purpose of payment rather than research. The presence of diagnoses codes on medical claims is not necessarily proof of actual disease, as such codes may have been assigned incorrectly or included as rule-out criteria rather than as documentation of actual disease.

To mitigate such problems, we applied detailed quality checks for the data set before starting the analysis presented here. Medications purchased over the counter (eg, aspirin) or provided as samples by physicians were not measurable in the claims data. Nevertheless, because our analysis is descriptive and based on comparing combination therapy with monotherapy, we do not believe that this lack of information significantly affected our results.

Additional study limitations include the small sample size and the low event rates.

Conclusion Existing data on anticoagulant bridging practice patterns are limited. Our study shows that few patients undergoing THR or TKR surgery receive appropriate anticoagulant prophylactic therapy. Based on our findings, we suggest that increased use of bridging therapy after THR and TKR surgery can help to improve adherence to guidelines, and ultimately, patient outcomes.

Newer anticoagulants may eventually prove useful in this setting, especially if they do not require routine anticoagulation monitoring. The results of the present study may help to clarify the problem of appropriate thromboprophylaxis after THR or TKR surgery, but further research is warranted. â&#x2013;

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Acknowledgment Ruth Sussman, PhD, provided editorial support with funding from Ortho-McNeil Janssen Scientific Affairs, LLC. Funding Source This research was funded by Ortho-McNeil Janssen Scientific Affairs, LLC. Author Disclosure Statement STATinMED Research is a consultant to Johnson & Johnson; Dr Baser is an employee of STATinMED Research; Dr Supina was an employee of Johnson & Johnson at the time of this study; Dr Sengupta is an employee of Johnson & Johnson; and Dr Wang is an employee of STATinMED Research.

References 1. Bulger CM, Jacobs C, Patel NH. Epidemiology of acute deep vein thrombosis. Tech Vasc Interv Radiol. 2004;7:50-54.

2. Fowkes FJ, Price JF, Fowkes FG. Incidence of diagnosed deep vein thrombosis in the general population: systematic review. Eur J Vasc Endovasc Surg. 2003;25:1-5.

3. Michota F. Venous thromboembolism: epidemiology, characteristics, and consequences. Clin Cornerstone. 2005;7:8-15.

4. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158:585-593.

5. US Department of Health and Human Services. The Surgeon Generalâ&#x20AC;&#x2122;s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism 2008. Washington, DC: US Department of Health and Human Services. www.surgeongeneral.gov/topics/ deepvein/calltoaction/call-to-action-on-dvt-2008.pdf. Accessed January 18, 2011.

6. Warwick D, Dahl OE, Fisher WD. Orthopaedic thromboprophylaxis: limitations of current guidelines. J Bone Joint Surg Br. 2008;90:127-132.

7. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359: 938-949.

8. Kurtz S, Ong K, Lau E, Mowat F, et al. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007;89:780-785.

9. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th Edition. Chest. 2008;133:381S-453S. 10. Johanson NA, Lachiewicz PF, Lieberman JR, et al. American Academy of Orthopaedic Surgeons clinical practice guideline on prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty. J Bone Joint Surg Am. 2009;91:1756-1757.

11. National Institute for Health and Clinical Excellence. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. NICE clinical guideline No. 92; www.nice.org.uk/guidance/ index.jsp?action=byID&o=12695. Accessed July 4, 2010.

12. Parvizi J, Azzam K, Rothman RH. Deep venous thrombosis prophylaxis for total joint arthroplasty: American Academy of Orthopaedic Surgeons guidelines.

J Arthroplasty. 2008;23:2-5.

13. American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty. Adopted by the American Academy of Orthopedic Surgeons Board of Directors May 2007. www.aaos.org/research/guidelines/PE_guideline.pdf. Accessed January 18, 2011.

14. Caprini JA, Tapson VF, Hyers TM, et al. Treatment of venous thromboembolism: adherence to guidelines and impact of physician knowledge, attitudes, and beliefs.

J Vasc Surg. 2005;42:726-733.

15. Hirsh J. Oral anticoagulant drugs. N Engl J Med. 1991;324:1865-1875.

16. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47:1245-1251.

17. Dâ&#x20AC;&#x2122;Hoore W, Bouckaert A, Tilquin C. Practical considerations on the use of the Charlson comorbidity index with administrative data bases. J Clin Epidemiol. 1996; 49:1429-1433.

18. Baser O, Palmer L, Stephenson J. The estimation power of alternative comorbidity indices. Value Health. 2008;11:946-955.

19. US Department of Labor. Bureau of Labor Statistics. Consumer price index.

Measuring price change for medical care in the CPI. http://data.bls.gov/cpi/cpi fact4.htm. Accessed January 18, 2011.

20. Heckman JJ. Econometric causality. Int Stat Rev. 2008;76:1-27.

21. Baser O. Choosing propensity score matching over regression adjustment for causal inference: when, why and how it makes sense. J Med Econ. 2007;10:379-391.

22. Baser O. Too much ado about propensity score models? Comparing methods of propensity score matching. Value Health. 2006;9:377-385.

23. Baser O, Crown WH, Pollicino C. Guidelines for selecting among different types of bootstraps. Curr Med Res Opin. 2006;22:799-808.

24. Office of the Legislative Counsel for the US House of Representatives.

Compilation of Patient Protection and Affordable Care Act. May 2010. http://docs. house.gov/energycommerce/ppacacon.pdf. Accessed January 18, 2011.

25. Centers for Medicare & Medicaid Services, US Department of Health and Human Services. CMS improves patient safety for Medicare and Medicaid by addressing never events. www.cms.gov/apps/media/press/factsheet.asp?Counter=3224 &intNumPerPage=10&checkDate=&checkKey=&srchType=1&numDays=0&srch Opt=0&srchData=&keywordType=All&chkNewsType=6&intPage=&showAll=1& pYear=1&year=2008&desc=false&cboOrder=date. Accessed January 18, 2011.

26. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119(1 suppl):176S-193S. 27. Kearon C. Duration of venous thromboembolism prophylaxis after surgery. Chest.

2003;124:386S-392S. 28. Caprini JA, Hyers TM. Compliance with antithrombotic guidelines. Manag Care. 2006;15:49-50,53-60,66.

29. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med. 2000;342:1878-1886.

Appendix ICD-9-CM Codes for Major Bleeding Events Type of major event

ICD-9-CM code

Intracranial hemorrhage

430, 431, 432.0, 432.1, 432.9, 852.0x, 852.2x, 852.4x, and 853.0 (primary or secondary)a

Gastrointestinal

455.2, 455.5, 455.8, 456.0, 456.20, 459.0, 530.7, 530.82, 531.00-.01, 531.20-.21, 531.40.41, 531.60-.61, 532.00-.01, 532.20-.21, 532.40-.41 , 532.60-.61, 533.00-.01, 533.20-.21, 533.40-.41, 533.60-.61, 534.00-.01, 534.20-.21, 534.40-.41, 534.60-.61, 535.01, 535.11, 535.21, 535.31, 535.41, 535.51, 535.61, 537.83, 562.02, 562.03, 562.12, 562.13, 568.81, 569.3, 569.85, 578.0, 578.1, 578.9

(primary only)b Intraocular

360.43 (primary or secondary)

Spinal

336.1 (primary or secondary)

Other

599.7, 719.1x, 786.3, 423.0, 593.81, 784.7, and 784.8 (primary only)c

a

Intracranial hemorrhage not counted if accompanied by trauma (ICD-9-CM 852.1, 852.3, 852.5, or 853.1) during hospitalization. b Defined as gastrointestinal and intra-abdominal hemorrhage. c Defined as hematuria, upper and lower extremity hemarthrosis, hemoptysis, and other bleeding events.

ICD-9-CM indicates International Classification of Diseases, 9th Revision, Clinical Modification.

Stakeholder perspective on page 248

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STAKEHOLDER PERSPECTIVE Anticoagulation Bridging Therapy after Total Hip or Knee Replacement: A Missed Opportunity?

MEDICAL DIRECTORS: In an era of comparative effectiveness and evidence-based medicine, can we really afford to ignore the established treatment guidelines that have been vetted through various esteemed medical associations? These highly acclaimed boards, with input from some of the country’s most prestigious key opinion leaders in their area of expertise, have placed their imprimatur on rigorously researched guidelines for ultimately improved patient care and outcomes.

This brings us to the question of the use of anticoagulation bridging therapy after total hip replacement (THR) or total knee replacement (TKR) surgery. As stated in this retrospective study, there is a consensus on the need for bridging therapy, according to the various published guidelines. Yet the results show the use of anticoagulation bridging therapy to be extremely infrequent in actual practice.

This statement should not be a surprise, because only 264 of the eligible 1770 patients (14.9%) in the study actually received combination anticoagulation therapy. Such a low percentage alone would suggest that the use of anticoagulation after THR or TKR often does not follow any set guidelines. This begs a larger question: Why have established, well-accepted guidelines if the general medical community, at least when it comes to THR or TKR, chooses not to implement the treatment algorithm?

For argument’s sake, let’s review the results of this retrospective study on anticoagulation bridging therapy after THR or TKR. Those patients who received bridged therapy were more than 3 times less likely to experience a venous thromboembolism (VTE) event, 50% less likely to have minor bleeding, and more than 7 times less likely to experience

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major bleeding than patients who did not receive the bridged therapy.

The costs associated with the treatment of VTE and of major bleeding with a THR or TKR are well documented in the medical literature. In addition, the patient complications associated with both VTE and major bleeding are quite frequent and costly.

PROVIDERS: Those involved in patient care recognize that there are inherent risks involving a THR or TKR, and more often than not, managing a patient postsurgery with anticoagulation therapy can be more art than science, given the patient’s history and presenting comorbidities.

After reviewing the risk-benefit ratio from the results presented in this study, however, it appears that more credence should be given to the use of anticoagulation bridging therapy after THR or TKR. If the opportunity exists to decrease the risk of patients experiencing a VTE and minor and/or major bleeding, and any associated complications, then why not take advantage of anticoagulation bridging therapy after THR or TKR? Adding this beneficial bridging therapy appears to improve patient outcomes, while avoiding the healthcare costs associated with treating the potential complications after THR or TKR. Perhaps the accountable care organizations (ACOs) that are forming across the country will take the use of anticoagulation bridging therapy after THR or TKR more seriously, because those involved in ACOs are interested in reducing costs and unnecessary patient complications while improving patient care and, ultimately, outcomes.

Charles E. Collins, Jr., MS, MBA Vice President, Client Strategy Fusion Medical Communications

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AMERICAN DIABETES ASSOCIATION HIGHLIGHTS

Emerging Therapies for Type 1 and Type 2 Diabetes

M

any new drugs are in various stages of development for the treatment of type 1 and type 2 diabetes. This article highlights some of the novel therapies that were featured at the 2011 annual meeting of the American Diabetes Association and were recently approved by the US Food and Drug Administration (FDA) or are furthest along in clinical trials.

New Drugs for Type 2 Diabetes Dipeptidyl Peptidase-4 Inhibitors Linagliptin (Tradjenta) belongs to the dipeptidyl peptidase (DPP)-4 inhibitor class that was recently approved by the FDA for type 2 diabetes and has the potential to replace sulfonylureas in the future, according to Baptist Gallwitz, MD, Outpatient Clinics for Endocrinology, Diabetes, and Metabolism, Eberhard Karls Universität, Tübingen, Germany. Linagliptin is not excreted renally and therefore no dose adjustments are needed in patients with renal impairment. With sulfonylureas, patients need to be taught to self-measure blood glucose, which involves substantial costs in terms of healthcare personnel time and purchasing testing strips and meters; this is not necessary with linagliptin, which could potentially result in cost-savings, according to Dr Gallwitz.

Alogliptin (Nesina) is another DPP-4 agent in latestage development. It is already approved in Japan.

Alogliptin had been submitted for approval to the FDA, but in 2008 the FDA requested additional information regarding cardiovascular safety. A clinical trial examining the cardiovascular safety profile of the drug is ongoing.

On July 26, 2011, alogliptin was resubmitted to the FDA, based on interim results from the ongoing trial showing cardiovascular safety for this drug.

Glucagon-Like Peptide-1 Receptor Agonists Exenatide is being investigated as 2 new formulations—once weekly (Bydureon) and once monthly.

The twice-daily formulation of this drug (Byetta) was approved by the FDA in 2005. Exenatide works by reducing the level of blood glucose, mimicking the effect of incretins, such as glucagon-like peptide (GLP)-1 receptor agonists. The GLP-1 agonists increase the secretion of insulin from the pancreas, slow the absorption of glucose from the gut, and reduce the action of glucagon.

In addition, GLP-1 agents reduce appetite, an important quality in a disease that is often associated with being

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overweight. Studies have shown that the original formulation of exenatide sustains glycemic control and weight loss for up to 2 years.

At the meeting, 3-year data from Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) and 84-week data from Once-Weekly Exenatide Injection Improves Blood Sugar Control More Than Daily Oral Sitagliptin or Pioglitazone and Induces More Weight Loss (DURATION-2) were presented. Long-term extensions of the DURATION-1 and 3 additional studies demonstrated that after 3 years, the once-weekly formulation achieved a significant 1.6% reduction from baseline in hemoglobin (Hb) A1c and weight (5.1 lb).

Cardiometabolic risk markers also improved, including systolic blood pressure (–2.1 mm Hg), total cholesterol (–9.9 mg/dL), low-density lipoprotein cholesterol (–7.0 mg/dL), and triglyceride levels (–12%). Bydureon was approved in the European Union in June 2011.

A phase 2 clinical trial showed that the oncemonthly investigational formulation of injectable exenatide achieved substantial improvements in glycemic control, including reductions in HbA1c and fasting plasma glucose and modest weight loss. The study included 121 patients given 3 different doses of once-monthly exenatide. More than 90% of the patients completed the study.

Lixisenatide (Lyxumia) achieved positive results in patients not achieving glycemic goal with oral therapies or basal insulin. In the GetGoal-X trial, once-daily lixisenatide achieved noninferiority results in HbA1c reduction versus twice-daily exenatide; both drugs were used as add-on to metformin in patients inadequately controlled with metformin.

A second study, GetGoal-L Asia, presented at the meeting showed that Asian patients with type 2 diabetes who were inadequately controlled with basal insulin with and without a sulfonylurea were significantly improved with lixisenatide once daily versus placebo at week 24, as reflected by the improvement in HbA1c level, with a target of <6.5% or <7.0%.

Sodium-Glucose Cotransporter-2 Inhibitors Sodium-glucose cotransporter (SGLT)-2 inhibitors represent a promising new class of drugs for treatment of type 2 diabetes. These drugs work by inhibiting reabsorp-

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tion of endogenously produced glucose in the proximal tubules of the kidney.

Results from a phase 3 trial showed that the investigational SGLT-2 inhibitor dapagliflozin added to metformin sustained reductions in HbA1c from 52 weeks to 104 weeks in adults with type 2 diabetes compared with glipizide (a frequently used sulfonylurea) added to metformin. Adverse events were similar in frequency between the 2 treatment arms. These results are from an extension phase of the original 52-week trial.

Weight reduction was sustained at 104 weeks, and hypoglycemic episodes were reported 10 times more frequently in patients treated with glipizide plus metformin (45.8% with glipizide plus metformin vs 4.2% for dapagliflozin plus metformin). Genital and urinary tract infections were more frequent with dapagliflozin than with glipizide.

A randomized, double-blind, placebo-controlled, parallel-group, multidose study showed that canagliflozin is safe and generally well-tolerated at doses up to 300 mg twice daily when added to stable doses of insulin in subjects with type 2 diabetes. The drug reduced the renal threshold for glucose excretion, improved glycemic control, and was associated with weight loss. A trend toward blood pressure reduction was observed, with no orthostatic symptoms.

Ultra–Long-Acting Insulin Degludec Studies show promise for the investigational ultra– long-acting basal insulin, degludec. This drug’s activity lasts for up to 40 hours and may be able to reduce the frequency of insulin dosing. At the meeting, two phase 3, 52-week trials (one in type 1 diabetes and one in type 2 diabetes) showed that ultra–long-acting insulin degludec reduced the rates of hypoglycemia compared with insulin glargine.

A second late-breaking 26-week study showed that insulin degludec could be dosed at different times from day to day.

Drugs in Development for Type 1 Diabetes In a phase 3, double-blind, multinational study, the anti-CD3 drug teplizumab (which modulates T-cells) failed to show a significant improvement over placebo on the combined goal of reducing the HbA1c level to <6.5% for patients newly diagnosed with type 1 diabetes and reducing the amount of insulin needed to <0.5 U/kg of body weight per day.

Although the study did not achieve this combined goal, 5% of the patients who received treatment with

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teplizumab no longer needed insulin at the end of 1 year compared with none of those who received placebo, noted lead researcher Nicole Sherry, MD, Director of the Diabetes Center at the Massachusetts General Hospital for Children in Boston.

In a post-hoc analysis, 40% of those who received a 14-day regimen of teplizumab experienced a preservation of or increase in C-peptide levels compared with 28% of those in the placebo group.

A phase 2 study looked at whether giving a second course of teplizumab intravenously a year after it was first administered could prolong its effects. Those who were given teplizumab continued to show improved beta-cell function even 2 years after diagnosis over an untreated group.

Teplizumab recipients experienced a 45% decrease in beta-cell function over 2 years compared with a 77% decrease for those in the untreated group. In addition, at 24 months, the untreated group used 57% more insulin, on average, than the group that received teplizumab.

DiaPep277 is a potential vaccine for type 1 diabetes, with the goal of preventing beta-cell destruction. During the development of type 1 diabetes, an increase in a protein in the beta-cell, called “heat shock” protein, is thought to cause beta-cell destruction through activation of destructive T-cells.

In a phase 2 study, the altered heat shock protein, given subcutaneously to 100 patients newly diagnosed with type 1 diabetes, succeeded in protecting the betacells, replicating in humans the findings in laboratory mice. Administering this vaccine also allowed beta-cells to continue to secrete insulin for up to 2 years after a type 1 diagnosis. The drug is currently in phase 3 trials in which beta-cell function, insulin use, and glucose control are being monitored.

Abatacept is being studied in a phase 2, randomized study that is comparing the effects of abatacept with those of placebo in patients newly diagnosed with type 1 diabetes. Abatacept recipients experienced a 59% increased level of C-peptide at the end of 2 years compared with the placebo group. On average, abatacept preserved beta-cell function for an additional 9.6 months.

“The problem is, despite giving the drug for 2 years, we only had a 9.6-month delay,” said Jay Skyler, MD, Chairman of the National Institutes of Health–funded Type 1 Diabetes TrialNet study group, which conducted the study. “That means that the effect over time may have been lost. It may have had an effect early on that created the delay and then may have lost further effect as time went on.” ■

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Vol 4, No 4

WELCHOL KNOCKS DOWN ®

TWO WITH ONE

FDA-approved, in addition to diet and exercise, for use in adults with T2DM* and primary hyperlipidemia1 Lowers both A1C & LDL-C, without systemic absorption Flexible dosing options: Oral Suspension and Tablet formulations Once-daily dosing

*Type 2 diabetes mellitus.

Welchol for Oral Suspension can now be mixed with fruit juices and diet soft drinks, in addition to water

IMPORTANT INFORMATION ABOUT WELCHOL (colesevelam HCI) Indications Welchol is indicated as an adjunct to diet and exercise to: – reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethylglutaryl-coenzyme (HMG CoA) reductase inhibitor (statin) – improve glycemic control in adults with type 2 diabetes mellitus Important Limitations of Use – Welchol should not be used for glycemic control in type 1 diabetes or for the treatment of diabetic ketoacidosis – Welchol has not been studied in type 2 diabetes as monotherapy or in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones – Welchol has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias Contraindications Welchol is contraindicated in individuals with a history of bowel obstruction, those with serum triglyceride (TG) concentrations of >500 mg/dL, or with a history of hypertriglyceridemia-induced pancreatitis.

Warnings and Precautions The effect of Welchol on cardiovascular morbidity and mortality has not been determined.

Welchol can increase serum TG concentrations particularly when used in combination with sulfonylureas or insulin.

Caution should be exercised when treating patients with TG levels >300 mg/dL.

Welchol may decrease the absorption of fat-soluble vitamins A, D, E, and K. Patients on vitamin supplements should take their vitamins at least 4 hours prior to Welchol. Caution should be exercised when treating patients with a susceptibility to vitamin K or fat-soluble vitamin deficiencies.

Caution should also be exercised when treating patients with gastroparesis, gastrointestinal motility disorders, a history of major gastrointestinal tract surgery, and when treating patients with dysphagia and swallowing disorders.

Welchol reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam (cyclosporine, glyburide, levothyroxine, and oral contraceptives [ethinyl estradiol, norethindrone]) should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol.

Alternatively, the physician should monitor drug levels of the co-administered drug.

To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form.

Due to tablet size, Welchol for Oral Suspension is recommended for, but not limited to, any patient who has difficulty swallowing tablets.

Phenylketonurics: Welchol for Oral Suspension contains 48 mg phenylalanine per 3.75 gram dose.

Adverse Reactions In clinical trials, the adverse reactions observed in ≥2% of patients, and more commonly with Welchol than placebo, regardless of investigator assessment of causality seen in:

– Adults with Primary Hyperlipidemia were: constipation (11.0% vs 7.0%), dyspepsia (8.3% vs 3.5%), nausea (4.2% vs 3.9%), accidental injury (3.7% vs 2.7%), asthenia (3.6% vs 1.9%), pharyngitis (3.2% vs 1.9%), flu syndrome (3.2% vs 3.1%), rhinitis (3.2% vs 3.1%), and myalgia (2.1% vs 0.4%) – Adult patients with Type 2 Diabetes were: constipation (8.7% vs 2.0%), nasopharyngitis (4.1% vs 3.6%), dyspepsia (3.9% vs 1.4%), hypoglycemia (3.0% vs 2.3%), nausea (3.0% vs 1.4%), and hypertension (2.8% vs 1.6%) Post-marketing experience: Due to the voluntary nature of these reports it is not possible to reliably estimate frequency or establish a causal relationship: – Increased seizure activity or decreased phenytoin levels have been reported in patients receiving phenytoin concomitantly with Welchol – Reduced International Normalized Ratio (INR) has been reported in patients receiving warfarin concomitantly with Welchol – Elevated thyroid-stimulating hormone (TSH) has been reported in patients receiving thyroid hormone replacement therapy Pregnancy Welchol is Pregnancy Category B.

Please see brief summary of the full Prescribing Information about Welchol on next page.

Reference: 1. Welchol (colesevelam HCI). Prescribing Information. Daiichi Sankyo, Inc., Parsippany, NJ, 2011. ©2011 Daiichi Sankyo, Inc.

Printed in USA

07/11

DSWC11001413

www.welchol.com

WELCHOL (colesevelam hydrochloride) Initial U.S. Approval: 2000 BRIEF SUMMARY: See package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.1 Primary Hyperlipidemia WELCHOL is indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin).

WELCHOL is indicated as monotherapy or in combination with a statin to reduce LDL-C levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: a.LDL-C remains ≥ 190 mg/dL or b.LDL-C remains ≥ 160 mg/dL and • There is a positive family history of premature cardiovascular disease or • Two or more other CVD risk factors are present in the pediatric patient.

Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate [See Clinical Studies (14.1) in the full prescribing information].

In patients with coronary heart disease (CHD) or CHD risk equivalents such as diabetes mellitus, LDL-C treatment goals are <100 mg/dL. An LDL-C goal of <70 mg/dL is a therapeutic option on the basis of recent trial evidence. If LDL-C is at goal but the serum triglyceride (TG) value is >200 mg/dL, then non-HDL cholesterol (non-HDL-C) (total cholesterol [TC] minus high density lipoprotein cholesterol [HDL-C]) becomes a secondary target of therapy. The goal for non-HDL-C in persons with high serum TG is set at 30 mg/dL higher than that for LDL-C. 1.2 Type 2 Diabetes Mellitus WELCHOL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [See Clinical Studies (14.2) in the full prescribing information].

Diabetes mellitus is considered a CHD risk equivalent. In addition to glycemic control, intensive lipid control is warranted [See Indications and Usage (1.1) and Warnings and Precautions (5.2)].

1.3 Important Limitations of Use • WELCHOL should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis.

• WELCHOL has not been studied in type 2 diabetes as monotherapy or in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones.

• WELCHOL has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias.

• WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls.

4 CONTRAINDICATIONS WELCHOL is contraindicated in patients with • A history of bowel obstruction [See Warnings and Precautions (5.4)] • Serum TG concentrations >500 mg/dL [See Warnings and Precautions (5.2)]

• A history of hypertriglyceridemia-induced pancreatitis [See Warnings and Precautions (5.2)] 5WARNINGS AND PRECAUTIONS 5.1 General The effect of WELCHOL on cardiovascular morbidity and mortality has not been determined.

5.2 Serum Triglycerides WELCHOL, like other bile acid sequestrants, can increase serum TG concentrations.

WELCHOL had small effects on serum TG (median increase 5% compared to placebo) in trials of patients with primary hyperlipidemia [See Adverse Reactions (6.1) and Clinical Studies (14.1) in the full prescribing information].

In clinical trials in patients with type 2 diabetes, greater increases in TG levels occurred when WELCHOL was used in combination with sulfonylureas (median increase 18% compared to placebo in combination with sulfonylureas) and when WELCHOL was used in combination with insulin (median increase 22% compared to placebo in combination with insulin) [See Adverse Reactions (6.1) and Clinical Studies (14.2) in the full prescribing information]. Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of hypertriglyceridemia on the risk of coronary artery disease is uncertain. In patients with type 2 diabetes, the effect of WELCHOL on LDL-C levels may be attenuated by WELCHOL’s effects on TG levels and a smaller reduction in non-HDL-C compared to the reduction in LDL-C. Caution should be exercised when treating patients with TG levels greater than 300 mg/dL. Because most patients in the WELCHOL clinical trials had baseline TG <300 mg/dL, it is unknown whether patients with more uncontrolled baseline hypertriglyceridemia would have greater increases in serum TG levels with WELCHOL. In addition, the use of WELCHOL is contraindicated in patients with TG levels >500 mg/dL [See Contraindications (4)]. Lipid parameters, including TG levels and non-HDL-C, should be obtained before starting WELCHOL and periodically thereafter.

WELCHOL should be discontinued if TG levels exceed 500 mg/dL or if the patient develops hypertriglyceridemiainduced pancreatitis [See Adverse Reactions (6.1)].

5.3 Vitamin K or Fat-Soluble Vitamin Deficiencies Precautions Bile acid sequestrants may decrease the absorption of fat-soluble vitamins A, D, E, and K. No specific clinical studies have been conducted to evaluate the effects of WELCHOL on the absorption of co-administered dietary or supplemental vitamin therapy. In non-clinical safety studies, rats administered colesevelam hydrochloride at doses greater than 30-fold the projected human clinical dose experienced hemorrhage from vitamin K deficiency. Patients on oral vitamin supplementation should take their vitamins at least 4 hours prior to WELCHOL. Caution should be exercised when treating patients with a susceptibility to deficiencies of vitamin K (e.g., patients on warfarin, patients with malabsorption syndromes) or other fat-soluble vitamins.

5.4 Gastrointestinal Disorders Because of its constipating effects, WELCHOL is not recommended in patients with gastroparesis, other gastrointestinal motility disorders, and in those who have had major gastrointestinal

tract surgery and who may be at risk for bowel obstruction. Because of the tablet size, WELCHOL Tablets can cause dysphagia or esophageal obstruction and should be used with caution in patients with dysphagia or swallowing disorders.

To avoid esophageal distress, WELCHOL for Oral Suspension should not be taken in its dry form. Always mix WELCHOL for Oral Suspension with water, fruit juice, or diet soft drinks before ingesting.

5.5 Drug Interactions WELCHOL reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam should be administered at least 4 hours prior to WELCHOL. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to WELCHOL. Alternatively, the physician should monitor drug levels of the coadministered drug [See Drug Interactions (7) and Clinical Pharmacology (12.3) in the full prescribing information].

5.6 Phenylketonurics WELCHOL for Oral Suspension contains 24 mg phenylalanine per 1.875 gram packet and 48 mg phenylalanine per 3.75 gram packet [See Description (11) in the full prescribing information].

6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice.

In the lipid-lowering trials, 807 adult patients received at least one dose of WELCHOL (total exposure 199 patientyears). In the type 2 diabetes trials, 566 patients received at least one dose of WELCHOL (total exposure 209 patient-years).

In clinical trials for the reduction of LDL-C, 68% of patients receiving WELCHOL vs. 64% of patients receiving placebo reported an adverse reaction.

In clinical trials of type 2 diabetes, 60% of patients receiving WELCHOL vs. 56% of patients receiving placebo reported an adverse reaction.

Primary Hyperlipidemia: In 7 doubleblind, placebo-controlled, clinical trials, 807 patients with primary hyperlipidemia (age range 18-86 years, 50% women, 90% Caucasians, 7% Blacks, 2% Hispanics, 1% Asians) and elevated LDL-C were treated with WELCHOL 1.5 g/day to 4.5 g/day from 4 to 24 weeks.

Table 1 Placebo-Controlled Clinical Studies of WELCHOL for Primary Hyperlipidemia: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) WELCHOL Placebo N = 807 N = 258 Constipation 89 (11.0) 18 (7.0) Dyspepsia 67 (8.3) 9 (3.5) Nausea 34 (4.2) 10 (3.9) Accidental injury 30 (3.7) 7 (2.7) Asthenia 29 (3.6) 5 (1.9) Pharyngitis 26 (3.2) 5 (1.9) Flu syndrome 26 (3.2) 8 (3.1) Rhinitis 26 (3.2) 8 (3.1) Myalgia 17 (2.1) 1 (0.4)

Pediatric Patients 10 to 17 Years of Age: In an 8-week double-blind, placebo-controlled study boys and post-menarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia (heFH) (n=192), were treated with WELCHOL Tablets (1.9-3.8 g, daily) or placebo tablets [See Clinical Studies (14.1) in the full prescribing information].

Table 2 Placebo-Controlled Clinical Study of WELCHOL for Primary Hyperlipidemia in heFH Pediatric Patients: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) WELCHOL Placebo N = 129 N = 65 Nasopharyngitis 8 (6.2) 3 (4.6) Headache 5 (3.9) 2 (3.1) Fatigue 5 (3.9) 1 (1.5) Creatine Phosphokinase Increase 3 (2.3) 0 (0.0) Rhinitis 3 (2.3) 0 (0.0) Vomiting 3 (2.3) 1 (1.5) The reported adverse reactions during the additional 18-week open-label treatment period with WELCHOL 3.8 g per day were similar to those during the double-blind period and included headache (7.6%), nasopharyngitis (5.4%), upper respiratory tract infection (4.9%), influenza (3.8%), and nausea (3.8%) [See Clinical Studies (14.1) in the full prescribing information].

Type 2 Diabetes Mellitus: The safety of WELCHOL in patients with type 2 diabetes mellitus was evaluated in 4 double-blind, 12-26 week, placebo-controlled clinical trials. These trials involved 1128 patients (566 patients on WELCHOL; 562 patients on placebo) with inadequate glycemic control on metformin, sulfonylurea, or insulin when these agents were used alone or in combination with other anti-diabetic agents. Upon completion of the pivotal trials, 492 patients entered a 52-week open-label uncontrolled extension study during which all patients received WELCHOL 3.8 g/day while continuing background treatment with metformin, sulfonylurea, or insulin alone or in combination with other anti-diabetic agents.

A total of 6.7% of WELCHOL-treated patients and 3.2% of placebo-treated patients were discontinued from the diabetes trials due to adverse reactions.

This difference was driven mostly by gastrointestinal adverse reactions such as abdominal pain and constipation.

One patient in the pivotal trials discontinued due to body rash and mouth blistering that occurred after the first dose of WELCHOL, which may represent a hypersensitivity reaction to WELCHOL. Table 3 Placebo-Controlled Clinical Studies of WELCHOL Add-on Combination Therapy with Metformin, Insulin, Sulfonylureas: Adverse Reactions Reported in ≥2% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality Number of Patients (%) WELCHOL Placebo N = 566 N = 562 Constipation 49 (8.7) 11 (2.0) Nasopharyngitis 23 (4.1) 20 (3.6) Dyspepsia 22 (3.9) 8 (1.4) Hypoglycemia 17 (3.0) 13 (2.3) Nausea 17 (3.0) 8 (1.4) Hypertension 16 (2.8) 9 (1.6)

Hypertriglyceridemia: Patients with fasting serum TG levels above 500 mg/dL were excluded from the diabetes clinical trials.

In the phase 3 diabetes trials, 637 (63%) patients had baseline fasting serum TG levels less than 200 mg/dL, 261 (25%) had baseline fasting serum TG levels between 200 and 300 mg/dL, 111 (11%) had baseline fasting serum TG levels between 300 and 500 mg/dL, and 9 (1%) had fasting serum TG levels greater than or equal to 500 mg/dL. The median baseline fasting TG concentration for the study population was 172 mg/dL; the median post-treatment fasting TG was 195 mg/dL in the WELCHOL group and 177 mg/dL in the placebo group.

WELCHOL therapy resulted in a median placebo-corrected increase in serum TG of 5% (p=0.22), 22% (p<0.001), and 18% (p<0.001) when added to metformin, insulin and sulfonylureas, respectively [See Warnings and Precautions (5.2) and Clinical Studies (14.2) in the full prescribing information]. In comparison, WELCHOL resulted in a median increase in serum TG of 5% compared to placebo (p=0.42) in a 24-week monotherapy lipid-lowering trial [See Clinical Studies (14.1) in the full prescribing information].

Treatment-emergent fasting TG concentrations ≥500 mg/dL occurred in 4.1% of WELCHOL-treated patients compared to 2.0% of placebo-treated patients. Among these patients, the TG concentrations with WELCHOL (median 604 mg/dL; interquartile range 538-712 mg/dL) were similar to that observed with placebo (median 644 mg/dL; interquartile range 574-724 mg/dL). Two (0.4%) patients on WELCHOL and 2 (0.4%) patients on placebo developed TG elevations ≥1000 mg/dL. In all WELCHOL clinical trials, including studies in patients with type 2 diabetes and patients with primary hyperlipidemia, there were no reported cases of acute pancreatitis associated with hypertriglyceridemia.

It is unknown whether patients with more uncontrolled, baseline hypertriglyceridemia would have greater increases in serum TG levels with WELCHOL [See Contraindications (4) and Warnings and Precautions (5.2)].

Cardiovascular adverse events: During the diabetes clinical trials, the incidence of patients with treatment-emergent serious adverse events involving the cardiovascular system was 3% (17/566) in the WELCHOL group and 2% (10/562) in the placebo group. These overall rates included disparate events (e.g., myocardial infarction, aortic stenosis, and bradycardia); therefore, the significance of this imbalance is unknown.

Hypoglycemia: Adverse events of hypoglycemia were reported based on the clinical judgment of the blinded investigators and did not require confirmation with fingerstick glucose testing. The overall reported incidence of hypoglycemia was 3.0% in patients treated with WELCHOL and 2.3% in patients treated with placebo. No WELCHOL treated patients developed severe hypoglycemia.

6.2 Post-marketing Experience The following additional adverse reactions have been identified during post-approval use of WELCHOL. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

c Drug Interactions with concomitant Cyclosporine levels should be monitored Type 2 Diabetes Mellitus: Of the 1128 patients enrolled in the four diabetes WELCHOL administration include: and, based on theoretical grounds, studies, 249 (22%) were ≥65 years old, cyclosporine should be administered at • Increased seizure activity or decreased and 12 (1%) were ≥75 years old. In these least 4 hours prior to WELCHOL. phenytoin levels in patients receiving trials, WELCHOL 3.8 g/day or placebo was phenytoin. Phenytoin should be In an in vivo drug interaction study, added onto background anti-diabetic administered 4 hours prior to WELCHOL. WELCHOL and warfarin coadministration • Reduced International Normalized Ratio had no effect on warfarin drug levels. This therapy. No overall differences in safety or effectiveness were observed between the (INR) in patients receiving warfarin study did not assess the effect of elderly and younger patients, but greater therapy. In warfarin-treated patients, INR WELCHOL and warfarin coadministration sensitivity of some older individuals should be monitored frequently during on INR. In postmarketing reports, cannot be ruled out.

WELCHOL initiation then periodically concomitant use of WELCHOL and thereafter. warfarin has been associated with reduced 8.6 Hepatic Impairment • Elevated thyroid-stimulating hormone INR. Therefore, in patients on warfarin No special considerations or dosage (TSH) in patients receiving thyroid therapy, the INR should be monitored adjustments are recommended when hormone replacement therapy. Thyroid before initiating WELCHOL and frequently WELCHOL is administered to patients hormone replacement should be enough during early WELCHOL therapy to with hepatic impairment. administered 4 hours prior to WELCHOL ensure that no significant alteration in INR [See Drug Interactions (7)]. occurs. Once the INR is stable, continue to 8.7 Renal Impairment Type 2 Diabetes Mellitus: Of the 1128 Gastrointestinal Adverse Reactions monitor the INR at intervals usually patients enrolled in the four diabetes recommended for patients on warfarin.

Bowel obstruction (in patients with a studies, 696 (62%) had mild renal history of bowel obstruction or resection), [See Post-marketing Experience (6.2)] insufficiency (creatinine clearance [CrCl] dysphagia or esophageal obstruction 8 USE IN SPECIFIC POPULATIONS 50-<80 mL/min), 53 (5%) had moderate (occasionally requiring medical 8.1 Pregnancy renal insufficiency (CrCl 30-<50 mL/ min), intervention), fecal impaction, pancreatitis, and none had severe renal insufficiency Pregnancy Category B. There are no abdominal distension, exacerbation of (CrCl <30 mL/min), as estimated from adequate and well-controlled studies of hemorrhoids, and increased baseline serum creatinine using the colesevelam use in pregnant women. transaminases.

Modification of Diet in Renal Disease Animal reproduction studies in rats and Laboratory Abnormalities rabbits revealed no evidence of fetal harm. (MDRD) equation. No overall differences Hypertriglyceridemia in safety or effectiveness were observed Requirements for vitamins and other between patients with CrCl <50 mL/min nutrients are increased in pregnancy.

7 DRUG INTERACTIONS (n=53) and those with a CrCl ≥50 mL/min However, the effect of colesevelam on the Table 4 lists the drugs that have been (n=1075). absorption of fat-soluble vitamins has not tested in in vitro binding or in vivo drug been studied in pregnant women. This interaction studies with colesevelam 10 OVERDOSAGE drug should be used during pregnancy and/or drugs with postmarketing reports Doses of WELCHOL in excess of 4.5 g/day only if clearly needed. consistent with potential drug-drug have not been tested. Because WELCHOL interactions. Orally administered drugs In animal reproduction studies, is not absorbed, the risk of systemic that have not been tested for interaction colesevelam revealed no evidence of toxicity is low. However, excessive doses with colesevelam, especially those with a fetal harm when administered to rats of WELCHOL may cause more severe local narrow therapeutic index, should also be and rabbits at doses 50 and 17 times gastrointestinal effects (e.g., constipation) administered at least 4 hours prior to the maximum human dose, respectively. than recommended doses.

WELCHOL. Alternatively, the physician Because animal reproduction studies are should monitor drug levels of the conot always predictive of human response, administered drug. this drug should be used in pregnancy only if clearly needed.

Table 4 Drugs Tested in In Vitro Binding 8.3 Nursing Mothers or In Vivo Drug Interaction Testing or Colesevelam hydrochloride is not expected With Post-Marketing Reports to be excreted in human milk because colesevelam hydrochloride is not absorbed c systemically from the gastrointestinal tract. cyclosporine , a glyburide , 8.4 Pediatric Use a Drugs with a levothyroxine , and The safety and effectiveness of WELCHOL known interaction oral contraceptives as monotherapy or in combination with a with colesevelama containing ethinyl statin were evaluated in children, 10 to 17 estradiol and years of age with heFH [See Clinical norethindrone Studies (14.1) in the full prescribing information]. The adverse reaction profile Drugs with was similar to that of patients treated with postmarketing placebo. In this limited controlled study, reports consistent there were no significant effects on with potential phenytoina, growth, sexual maturation, fat-soluble drug-drug warfarinb vitamin levels or clotting factors in the interactions when adolescent boys or girls relative to placebo coadministered [See Adverse Reactions (6.1)]. with WELCHOL Due to tablet size, WELCHOL for Oral Suspension is recommended for use in the cephalexin, pediatric population. Dose adjustments are ciprofloxacin, b not required when WELCHOL is administered digoxin, warfarin , to children 10 to 17 years of age. fenofibrate, Drugs that do lovastatin, WELCHOL has not been studied in not interact with metformin, children younger than 10 years of age colesevelam metoprolol, or in pre-menarchal girls. based on in vitro pioglitazone, 8.5 Geriatric Use or in vivo testing quinidine, Primary Hyperlipidemia: Of the 1350 repaglinide, patients enrolled in the hyperlipidemia valproic acid, clinical studies, 349 (26%) were verapamil ≥65 years old, and 58 (4%) were ≥75 years old. No overall differences in safety a Should be administered at least 4 hours or effectiveness were observed between prior to WELCHOL these subjects and younger subjects, b No significant alteration of warfarin drug and other reported clinical experience Daiichi Sankyo, Inc. has not identified differences in responses Marketed by: levels with warfarin and WELCHOL Parsippany, New Jersey coadministration in an in vivo study which between the elderly and younger patients, 07054 did not evaluate warfarin pharmacodynamics but greater sensitivity of some older (INR). [See Post-marketing Experience (6.2)] individuals cannot be ruled out.

P1801115

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Victoza® (liraglutide [rDNA origin] injection) Rx Only BRIEF SUMMARY. Please consult package insert for full prescribing information.

WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications and Warnings and Precautions].

INDICATIONS AND USAGE: Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis.

Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied.

CONTRAINDICATIONS: Victoza® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza® will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies [see Boxed Warning, Contraindications]. In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza®-treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non-liraglutide-treated patient developed elevated calcitonin concentrations while on treatment. Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza® clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza®treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza® 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza® 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza®. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza® 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza® 1.2 mg, placebo and active control, respectively. Otherwise, Victoza® did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. Patients with MTC usually have calcitonin values >50 ng/L. In Victoza® clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza®-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza®-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza®. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza®-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza®. The clinical significance of these findings is unknown. Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza®, if serum calcitonin is measured and found to be elevated, the

patient should be referred to an endocrinologist for further evaluation. Pancreatitis: In clinical trials of Victoza®, there were 7 cases of pancreatitis among Victoza®-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. In one case in a Victoza®-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. One additional case of pancreatitis has subsequently been reported in a Victoza®-treated patient. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis with Victoza® treatment. After initiation of Victoza®, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza® and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza® should not be restarted. Use with caution in patients with a history of pancreatitis. Use with Medications Known to Cause Hypoglycemia: Patients receiving Victoza® in combination with an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin secretagogues [see Adverse Reactions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.

ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Victoza® was evaluated in a 52-week monotherapy trial and in five 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza® 1.2 mg daily, Victoza® 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza® 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza® 1.2 mg, Victoza® 1.8 mg or placebo. Withdrawals: The incidence of withdrawal due to adverse events was 7.8% for Victoza®-treated patients and 3.4% for comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza®-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. Tables 1, 2 and 3 summarize the adverse events reported in *5% of Victoza®-treated patients in the six controlled trials of 26 weeks duration or longer.

Table 1: Adverse events reported in *5% of Victoza®-treated patients or *5% of glimepiride-treated patients: 52-week monotherapy trial All Victoza® N = 497 Glimepiride N = 248 (%) (%) Adverse Event Term Nausea 28.4 8.5 Diarrhea 17.1 8.9 Vomiting 10.9 3.6 Constipation 9.9 4.8 Upper Respiratory Tract Infection 9.5 5.6 Headache 9.1 9.3 Influenza 7.4 3.6 Urinary Tract Infection 6.0 4.0 Dizziness 5.8 5.2 Sinusitis 5.6 6.0 Nasopharyngitis 5.2 5.2 Back Pain 5.0 4.4 Hypertension 3.0 6.0 Table 2: Adverse events reported in *5% of Victoza®-treated patients and occurring more frequently with Victoza® compared to placebo: 26-week combination therapy trials Add-on to Metformin Trial All Victoza® + Placebo + Glimepiride + Metformin N = 724 Metformin N = 121 Metformin N = 242 (%) (%) (%) Adverse Event Term Nausea 15.2 4.1 3.3 Diarrhea 10.9 4.1 3.7 Headache 9.0 6.6 9.5 Vomiting 6.5 0.8 0.4 Add-on to Glimepiride Trial All Victoza® + Placebo + Rosiglitazone + Glimepiride N = 695 Glimepiride N = 114 Glimepiride N = 231 (%) (%) (%) Adverse Event Term Nausea 7.5 1.8 2.6 Diarrhea 7.2 1.8 2.2 Constipation 5.3 0.9 1.7 Dyspepsia 5.2 0.9 2.6

Add-on to Metformin + Glimepiride Placebo + Metformin Glargine + Metformin Victoza® 1.8 + + Glimepiride + Glimepiride Metformin + N = 232 N = 114 Glimepiride N = 230 (%) (%) (%) Adverse Event Term Nausea 13.9 3.5 1.3 10.0 5.3 1.3 Diarrhea Headache 9.6 7.9 5.6 Dyspepsia 6.5 0.9 1.7 Vomiting 6.5 3.5 0.4 Add-on to Metformin + Rosiglitazone ® All Victoza + Metformin + Placebo + Metformin Rosiglitazone N = 355 + Rosiglitazone N = 175 (%) (%) Adverse Event Term Nausea 34.6 8.6 Diarrhea 14.1 6.3 12.4 2.9 Vomiting Decreased Appetite 9.3 1.1 Anorexia 9.0 0.0 Headache 8.2 4.6 Constipation 5.1 1.1 Fatigue 5.1 1.7 Table 3: Treatment-Emergent Adverse Events in 26 Week Open-Label Trial versus Exenatide (Adverse events with frequency *5% and occurring more frequently with Victoza® compared to exenatide are listed) Exenatide 10 mcg twice Victoza® 1.8 mg once daily + metformin and/or daily + metformin and/or sulfonylurea N = 232 sulfonylurea N = 235 (%) (%) Preferred Term Diarrhea 12.3 12.1 Dyspepsia 8.9 4.7 Constipation 5.1 2.6 Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related.

Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In a 26-week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza® and exenatide. In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time.

Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/or sulfonylurea, the proportion of patients with nausea also declined over time. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials.

Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients.

However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies.

Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions.

Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients (2.6 cases per 1000 patient-years) and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 4). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake).

Table 4: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials Victoza® Active Placebo Treatment Comparator Comparator ® Monotherapy Victoza Glimepiride None (N = 497) (N = 248) Patient not able to self−treat 0 0 — Patient able to self−treat 9.7 (0.24) 25.0 (1.66) — Not classified 1.2 (0.03) 2.4 (0.04) — ® Placebo + Glimepiride + Add-on to Victoza + Metformin Metformin Metformin Metformin (N = 121) (N = 242) (N = 724) Patient not able to self−treat 0.1 (0.001) 0 0 Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) ® Add-on to Glimepiride Victoza + Placebo + Rosiglitazone + Glimepiride Glimepiride Glimepiride (N = 114) (N = 231) (N = 695) Patient not able to self−treat 0.1 (0.003) 0 0 Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) Not classified 0.9 (0.05) 0.9 (0.02) 0 Victoza® + Placebo + Add-on to None Metformin + Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 175) (N = 355) Patient not able to self−treat 0 — 0 Patient able to self−treat 7.9 (0.49) — 4.6 (0.15) Not classified 0.6 (0.01) — 1.1 (0.03) Placebo + Victoza® + Add-on to Insulin glargine Metformin + Metformin + + Metformin + Metformin + Glimepiride Glimepiride Glimepiride Glimepiride (N = 114) (N = 232) (N = 230) Patient not able to self−treat 2.2 (0.06) 0 0 Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) Not classified 0 1.7 (0.04) 0 In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparatortreated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown.

OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

More detailed information is available upon request.

For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: December 22, 2010 Version: 2 Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark Victoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending. © 2011 Novo Nordisk 140586-R2 2/2011

For patients who need more than metformin

Help grab type 2 diabetes by the roots.

Once-daily Victoza® provides powerful and sustained* reductions in A1C and:

Impacts beta-cell function to help regulate insulin secretion May reduce weight – Victoza® is not indicated for the management of obesity – Weight change was a secondary end point in clinical trials *Victoza® was evaluated in a 52-week monotherapy trial and in five 26-week, add-on combination trials.

Indications and usage Important safety information Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk.

Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.

In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators.

Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®.

Use with caution in patients with a history of pancreatitis.

Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

The concurrent use of Victoza® and insulin has not been studied.

Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies.

Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries.

It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed.

When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.

There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug.

The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials.

Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients.

Victoza® should be used with caution in patients with renal impairment and in patients with hepatic impairment.

Please see brief summary of Prescribing Information on adjacent page.

To learn how Victoza® can help your patients manage their type 2 diabetes, visit VictozaPro.com/Benefit.

Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S. © 2011 Novo Nordisk 0311-00001944-1

April 2011