AHDB July/August 2013 by Dalia Buffery

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ July/august 2013

Volume 6, Number 6

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

Specialty Pharmaceuticals Update David B. Nash, MD, MBA COMMENTARY

Implications of the Employer Mandate Delay on the Healthcare Marketplace Kip Piper, MA, FACHE; F. Randy Vogenberg, PhD, RPh ™

BUSINESS

Perspectives of Quality Care in Cancer Treatment: A Review of the Literature Lisa M. Hess, PhD; Gerhardt Pohl, PhD Stakeholder Perspective by Craig Deligdish, MD

Burden of Disease: The Psychosocial Impact of Rosacea on a Patient’s Quality of Life Tu T. Huynh, PhD Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

EST. 2008

YEAR ANNIVERSARY

A Critical Connection Between B-Cell Signaling and the Tumor Microenvironment* Until recently, research of B-cell malignancies has been focused primarily on the B cell itself.1 However, new insights have revealed that there are important interactions between the B cell and the extracellular microenvironment that are dependent on intracellular signaling pathways mediated by various kinases including Bruton’s tyrosine kinase (BTK).2,3 These interactions suggest an important role in B-cell homing, adhesion, and migration.4,5 Further elucidation of these processes could change how we view and approach B-cell malignancies.

BTK signaling pathways and the microenvironment*† FDC BCR TLR T cell MyD88

BTK

Lyn

CXCR4/5 PI3K

MSC

PIP3

Syk

BTK

G G

Nucleus

PLCγ2

B cell

BTK

DAG NF-κB

IP3

PKC Ca2+

Based on in vitro data. Illustrations not to scale.

†

Pharmacyclics, Inc., and Janssen Biotech, Inc., are currently investigating BTK in search of insights that could improve the lives of patients with B-cell malignancies. Visit us at www.BCellSignals.com.

BCR

CD79A CD79B

Prosurvival Signals Lyn

Syk

BTK PLCγ2

Nucleus

Normal and malignant B cells rely on multiple prosurvival pathways to avoid apoptosis.6-9 In B-cell malignancies, microenvironmental cues may inappropriately initiate signaling cascades through several kinases, including BTK, driving uncontrolled growth and survival of malignant B cells.5,10-13

NF-κB

B-Cell Homing Cells in the microenvironment secrete chemoattractant factors to promote the homing of B cells to lymphoid tissue.14 These factors act via signaling pathways involving BTK and other kinases.4,15

VCAM-1

Adhesion and Migration

VLA-4

The upregulation and increased migration of B cells may lead to retention of malignant cells in proliferative environments and the promotion of chemoresistance.16-18 BTK is an essential mediator of multiple adhesion and migration processes.4

References: 1. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:96-103. 2. Kil LP, de Bruijn MJW, van Hulst JA, Langerak AW, Yuvaraj S, Hendriks RW. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3:71-83. 3. Pighi C, Gu T-L, Dalai I, et al. Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling. Cell Oncol (Dordr). 2011;34:141-153. 4. de Gorter DJJ, Beuling EA, Kersseboom R, et al. Bruton’s tyrosine kinase and phospholipase C 2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26:93-104. 5. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114:3367-3375. 6. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120:1175-1184. 7. Rauch M, Tussiwand R, Bosco N, Rolink AG. Crucial role for BAFF-BAFF-R signaling in the survival and maintenance of mature B cells. PLoS One. 2009;4:e5456. 8. Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals. Immunol Cell Biol. 2007;85:471-475. 9. Grumont RJ, Rourke IJ, O’Reilly LA, et al. B lymphocytes differentially use the Rel and nuclear factor B1 (NF- B1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med. 1998;187:663-674. 10. Nishio M, Endo T, Tsukada N, et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1 . Blood. 2005;106:1012-1020. 11. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120:4684-4691. 12. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF- B activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117:563-574. 13. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88-92. 14. Okada T, Ngo VN, Ekland EH, et al. Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J Exp Med. 2002;196:65-75. 15. Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood. 1999;94:3658-3667. 16. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009;113:4604-4613. 17. Binsky I, Lantner F, Grabovsky V, et al. TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner. J Immunol. 2010;184:4761-4769. 18. Kurtova AV, Balakrishnan K, Chen R, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood. 2009;114:4441-4450.

July/august 2013

Volume 6, number 6

The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

™

Table of Contents

Publishing Staff

EDITORIAL

298 Specialty Pharmaceuticals Update David B. Nash, MD, MBA commentary

303 Implications of the Employer Mandate Delay on the Healthcare Marketplace Kip Piper, MA, FACHE; F. Randy Vogenberg, PhD, RPh

307 Real-World Corticosteroid Utilization Patterns in Patients with Metastatic Castration-Resistant Prostate Cancer in 2 Large US Administrative Claims Databases Marie-Hélène Lafeuille, MA; Jonathan Gravel, MSc; Amanda Grittner, MA; Patrick Lefebvre, MA; Lorie Ellis, PhD; R. Scott McKenzie, MD 315 Stakeholder Perspective: “Roid Rage” Atheer A. Kaddis, PharmD Continued on page 295

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For subscription information and editorial queries, please contact: editorial@engagehc.com; tel: 732-992-1892; fax: 732-992-1881.

Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Director, Client Services Joseph Beck Ron Gordon Projects Manager John Welz Senior Production Manager Lynn Hamilton The Lynx Group

business

292

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

American Health & Drug Benefits

www.AHDBonline.com

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonato Anthony Trevean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications 1249 South River Road, Suite 202A Cranbury, NJ 08512 Phone: 732-992-1880

July/August 2013

Vol 6, No 6

NEW

For the treatment of elevated IOP

UNLOCK NEW TREATMENT POSSIBILITIES

SIMBRINZA™ Suspension provided additional 1-3 mm Hg IOP lowering compared to the individual components1 ■ IOP measured at 8 AM, 10 AM, 3 PM, and 5 PM was reduced by 21-35% at Month 32-4 ■ Efficacy proven in two pivotal Phase 3 randomized, multicenter, double-masked, parallel-group, 3-month, 3-arm, contribution-of-elements studies2,3 ■ The most frequently reported adverse reactions (3-5%) were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy1 ■ Only available beta-blocker-free fixed combination2,3 INDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination indicated in the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Dosage and Administration The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use. SIMBRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. IMPORTANT SAFETY INFORMATION Contraindications SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product and neonates and infants under the age of 2 years. Warnings and Precautions Sulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide, and although administered topically, is absorbed systemically. Sulfonamide attributable adverse reactions may occur. Fatalities have occurred due to severe reactions to sulfonamides. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation. Corneal Endothelium—There is an increased potential for developing corneal edema in patients with low endothelial cell counts. References: 1. SIMBRINZA™ Suspension Package Insert. 2. Katz G, DuBiner H, Samples J, et al. Three-month randomized trial of fixed-combination brinzolamide, 1%, and brimonidine, 0.2% [published online ahead of print April 11, 2013]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2013.188. 3. Nguyen QH, McMenemy MG, Realini T, et al. Phase 3 randomized 3-month trial with an ongoing 3-month safety extension of fixedcombination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther. 2013;29(3): 290-297. 4. Data on file, 2013.

MG13003JAD

Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA™ Suspension has not been speciﬁcally studied in these patients and is not recommended. Adverse Reactions In two clinical trials of 3 months’ duration with SIMBRINZA™ Suspension, the most frequent reactions associated with its use occurring in approximately 3-5% of patients in descending order of incidence included: blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Adverse reaction rates with SIMBRINZA™ Suspension were comparable to those of the individual components. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients. Drug Interactions—Consider the following when prescribing SIMBRINZA™ Suspension: Concomitant administration with oral carbonic anhydrase inhibitors is not recommended due to the potential additive effect. Use with high-dose salicylate may result in acid-base and electrolyte alterations. Use with CNS depressants may result in an additive or potentiating effect. Use with antihypertensives/cardiac glycosides may result in additive or potentiating effect on lowering blood pressure. Use with tricyclic antidepressants may blunt the hypotensive effect of systemic clonidine and it is unknown if use with this class of drugs interferes with IOP lowering. Use with monoamine oxidase inhibitors may result in increased hypotension. For additional information about SIMBRINZA™ Suspension, please see Brief Summary of full Prescribing Information on adjacent page.

B:6.875” T:6.875” S:6.875” BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. DOSAGE AND ADMINISTRATION The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use. SIMBRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. DOSAGE FORMS AND STRENGTHS Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate. CONTRAINDICATIONS Hypersensitivity - SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product. Neonates and Infants (under the age of 2 years) - SIMBRINZA™ Suspension is contraindicated in neonates and infants (under the age of 2 years) see Use in Specific Populations WARNINGS AND PRECAUTIONS Sulfonamide Hypersensitivity Reactions - SIMBRINZA™ Suspension contains brinzolamide, a sulfonamide, and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of SIMBRINZA™ Suspension. Fatalities have occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation [see Patient Counseling Information] Corneal Endothelium - Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing SIMBRINZA™ Suspension to this group of patients.

Severe Cardiovascular Disease - Brimonidine tartrate, a component of SIMBRINZATM Suspension, has a less than 5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease. Severe Hepatic Impairment - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, has not been studied in patients with hepatic impairment, caution should be exercised in such patients. Potentiation of Vascular Insufficiency - Brimonidine tartrate, a component of SIMBRINZATM Suspension, may potentiate syndromes associated with vascular insufficiency. SIMBRINZA™ Suspension should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangitis obliterans. Contamination of Topical Ophthalmic Products After Use - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information]. ADVERSE REACTIONS 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 the rates in the clinical studies of another drug and may not reflect the rates observed in practice. SIMBRINZA™ Suspension - In two clinical trials of 3 months duration 435 patients were treated with SIMBRINZA™ Suspension, and 915 were treated with the two individual components. The most frequently reported adverse reactions in patients treated with SIMBRINZA™ Suspension occurring in approximately 3 to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual components were comparable. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients. Other adverse reactions that have been reported with the individual components during clinical trials are listed below.

Reactions occurring in approximately 3 to 9% of the subjects, in descending order included corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain. The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope. Postmarketing Experience - The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications]. DRUG INTERACTIONS Oral Carbonic Anhydrase Inhibitors - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of SIMBRINZA™ Suspension. The concomitant administration of SIMBRINZA™ Suspension and oral carbonic anhydrase inhibitors is not recommended. High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA™ Suspension. CNS Depressants - Although specific drug interaction studies have not been conducted with SIMBRINZA™, the possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered. Antihypertensives/Cardiac Glycosides - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA™ Suspension is advised. Tricyclic Antidepressants - Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA™ Suspension in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines. Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/ kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral adminis-

AMCM3M0054_SIMBRINZA_JournalAd_PI_ASize_r5.indd 1

There are no adequate and well-controlled studies in pregnant women. SIMBRINZA™ Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers - In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/ kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No other effects were observed. However, following oral administration of 14C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted in breast milk. It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, 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 individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5 years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA™ Suspension is contraindicated in children under the age of 2 years [see Contraindications]. Geriatric Use - No overall differences in safety or effectiveness have been observed between elderly and adult patients. OVERDOSAGE Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following an oral overdose of brinzolamide. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse event reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine as part of medical treatment of congenital glaucoma or by accidental oral ingestion. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. PATIENT COUNSELING INFORMATION Sulfonamide Reactions - Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity occur, they should discontinue the use of the product and consult their physician. Temporary Blurred Vision - Vision may be temporarily blurred following dosing with SIMBRINZA™ Suspension. Care should be exercised in operating machinery or driving a motor vehicle. Effect on Ability to Drive and Use Machinery - As with other drugs in this class, SIMBRINZA™ Suspension may cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for a decrease in mental alertness. Avoiding Contamination of the Product - Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions ]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle. Intercurrent Ocular Conditions - Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container. Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart. Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension, but may be reinserted 15 minutes after instillation. ©2013 Novartis U.S. Patent No: 6,316,441 ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA 1-800-757-9195 alcon.medinfo@alcon.com

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B:9.875”

Contact Lens Wear - The preservative in SIMBRINZA™, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension but may be reinserted 15 minutes after instillation [see Patient Counseling Information].

Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10 to 30% of the subjects, in descending order of incidence, included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus.

Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent.

T:9.875”

Acute Angle-Closure Glaucoma - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA™ Suspension has not been studied in patients with acute angle-closure glaucoma.

The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria.

tration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood.

S:9.875”

Severe Renal Impairment - SIMBRINZA™ Suspension has not been speciﬁcally studied in patients with severe renal impairment (CrCl < 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA™ Suspension is not recommended in such patients.

Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis.

july/August 2013

Volume 6, number 6

The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

(Continued) American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

clinical

321 Perspectives of Quality Care in Cancer Treatment: A Review of the Literature Lisa M. Hess, PhD; Gerhardt Pohl, PhD 329 Q uality of Cancer Care: Emerging Definition and Measurements, but Reimbursement Lagging By Craig Deligdish, MD 348 Burden of Disease: The Psychosocial Impact of Rosacea on a Patient’s Quality of Life Tu T. Huynh, PhD 354 Stakeholder Perspective: The Psychosocial Impact of Skin Disorders: Time for a Closer Look? Matthew Mitchell, PharmD, MBA

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editorial board Editor-in-Chief

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

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

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

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

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

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

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

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

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX J. B. Jones, PhD, MBA Research Investigator, Geisinger Center for Health Research, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes Personalized Health Care Program, University of Utah, Salt Lake City Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

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

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

Jeffrey A. Bourret, RPh, MS, FASHP Medical Lead, Specialty & Payer Strategy Medical Affairs, Pfizer, Inc., PA Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD, FAPhA Professor of Pharmacy Law & Ethics Dept. of Pharmacotherapy, College of Pharmacy Washington State University, Spokane, WA Mike Pucci Sr VP Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC Personalized medicine

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

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, Univ of Cincinnati Medical Center, OH

American Health & Drug Benefits

www.AHDBonline.com

Grant D. Lawless, RPh, MD, FACP Assoc. Prof. and Director, Healthcare Decision Analysis, Dept. of Clinical Pharmacy Univ. of Southern California, Los Angeles PHARMACY BENEFIT DESIGN

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

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

Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

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

July/August 2013

Vol 6, No 6

AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

â&#x201E;˘

The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer CareTM, is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care. Each supplement will explore a specific topic to be considered when developing value-based strategies. IN MULTIPLE MYELOMA

Value-BasedCare FEBRUARY 2013

Â&#x2122;

1st IN A SERIES

Treating Newly Diagnosed Multiple Myeloma: Data on Safety, EfďŹ cacy, and Dosing Regimens

Topics to include: Safety and Efficacy of Front-Line Treatment Assessing the Value of Complete Response Pharmacoeconomic Analysis of Treatment Options Therapeutic Decision Making Based on Cytogenetics Assessing the Value of Progression-Free Survival Data Safety and Efficacy of Therapies in the Relapsed Setting Using Alternate Routes of Drug Administration Cost-Effective Use of Imaging Techniques

Introduction The therapeutic paradigm for multiple myeloma (MM) continues to evolve, due to advances in our understanding of the molecular and genetic basis of the disease.1 Newly diagnosed patients typically undergo multidrug therapy that includes novel, targeted agents, often followed by consolidation with autologous stem cell transplantation (ASCT) and maintenance therapy.1,2 This therapeutic model has altered the value equation in newly diagnosed MM, because survival and life quality have increased along with cost of treatment.1 Enhanced survival, through the use of novel therapies, requires us to balance both short- and long-term outcomes. Over its clinical course, MM has one of the highest direct costs of any cancer.1 For example, in a 2007 analysis, the direct costs associated with a course of treatment with a novel agent plus a steroid (taking into account the drugs themselves, as well as prophylaxis and management of toxicities) ranged from approximately $47,000 to $72,000.1,3 Simple assessment of cost, however, is not sufďŹ cient, because value comprises not only expenses but also outcome over the increasingly prolonged survival time for MM. For example, in the VISTA trial (N=682), newly diagnosed, transplant-ineligible patients who were randomized to either triple therapy with bortezomib/melphalan/prednisone (VMP) or double therapy with melphalan/prednisone (MP) were followed for life quality over nine 6-week cycles.4 The study found that, through cycle 4, health-related quality of life (HRQoL) was lower with VMP than with MP, due to decreased treatment tolerability. However, from cycle 5 through the end of therapy, HRQoL with VMP was not compromised relative to MP, and recovered to the point where HRQoL was comparable for the 2 treatments.4 This investigation also demonstrated the link between antimyeloma efďŹ cacy and HRQoL. Among responders to therapy, HRQoL increased from the time of response to the end of treatment.4 Responders were more common in the VMP group than in the MP group in this trial, in which response rates were 71% and 35%, respectively (P<.001).5 In addition, 5-year overall survival (OS) was prolonged with VMP versus MP,6 another beneďŹ t to consider in the value equation. Pharmacoeconomic analysis of initial treatment with melphalan/prednisone/lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) reported that this regimen, although more expensive than MPR or MP without maintenance, yielded greater cost-effectiveness.7 Although MPR-R increased progression-free survival (PFS) compared with regimens without maintenance, no This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

beneďŹ t in OS has yet been reported with MPR-R, so the observation of cost-effectiveness remains provisional.7 In todayâ&#x20AC;&#x2122;s healthcare environment, when evidence changes the value equation, it changes practice. Therefore, it is critical to be aware of current and emerging data on the tolerability and efďŹ cacy of novel agents, which will inďŹ&#x201A;uence therapeutic strategies. Tolerability: The Role of Optimized Dosing and Novel Drugs For newly diagnosed MM, current recommendations for care typically include the use of bortezomib, lenalidomide, or thalidomide in multidrug regimens, either for pre-ASCT induction or, in transplant-ineligible patients, as an initial course of therapy.2 All

OVERVIEW The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care , is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-ef topic to be considered when developing value-based newly diagnosed MM.

STAKEHOLDERSâ&#x20AC;&#x2122; PERSPECTIVES Assessing the Value of Novel Therapies for Multiple Myeloma ............................................. 5 By William J. Cardarelli, PharmD Atrius Health, Harvard Vanguard Medical Associates

Clinical and Economic Challenges in the Treatment of Multiple Myeloma........................ 6 By Kevin B. Knopf MD, MPH California PaciďŹ c Medical Center

An ofďŹ cial publication of

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Editorial

Specialty Pharmaceuticals Update David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Jefferson School of Population Health, Philadelphia, PA

udos to our colleagues at EMD Serono for the publication of the 9th edition of the EMD Serono Specialty Digest.1 If you are not familiar with this annual survey, you ought to be, as it highlights managed care strategies for specialty pharmaceuticals and is an outstanding source of data. Let me highlight some of the recent findings from the 2013 edition of the report. First of all, EMD Serono does it right. Their team has assembled a diverse external advisory board that comprises pharmacists, physicians, and other specialty pharmacy experts, and they use a well-known external survey company for the data collection. Drawing on results from more than 100 health plans across the country representing more than 100 million covered lives, I am confident that the results are not only valid but also broadly applicable. What do we actually mean by a “specialty pharmaceutical”? Once again, EMD Serono embraces the Academy of Managed Care Pharmacy format for formulary submissions, Version 3.1, whereby a product can be classified as a specialty pharmaceutical “if it includes either of these two requirements: difficult or unusual process or delivery or requires patient management.”1 Although specialty drugs have become the standard of care for many complex diseases, they may be administered by various routes, including oral, injection, and infusion. Sometimes, the administration of the medication requires the expertise of a healthcare provider. Unlike traditional oral agents, however, these specialty drugs may be covered under the pharmacy benefit or under the medical benefit, and they may be distributed or administered to the patient from various sites, including a retail pharmacy, a specialty pharmacy, a physician’s office, an outpatient hospital facility, or a home infusion company. One take-home message from this 2013 survey is that more than 50% of the commercial plans participating in this survey now have unique cost-sharing tiers for specialty drugs, unlike non–specialty drugs. Among plans that utilize a unique specialty drug cost-sharing, 67% use a single tier, which represents 55% of all covered lives in the United States. Multitier cost-sharing is used by 33% of health plans, representing 45% of the covered lives.1

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Not surprisingly, more than 90% of the plans surveyed require prior authorization for specialty pharmaceuticals. Nearly 15% of the plans, for example, provide oncologists with an electronic prior authorization system through a specially designed secure web portal.1 I have also learned by reading this report that provider reimbursement for specialty pharmaceuticals continues to evolve. Because specialty drugs are distributed through a number of different care providers, depending on the specific drug, there are multiple programs, almost on a specialty-specific basis. For example, the actual reimbursement rate to each provider is determined by the health plan itself and can be based on the average wholesale price (AWP) plus or minus a discount, the average sales price plus a percentage, or the wholesale acquisition cost plus or minus a percentage. The reimbursement methodology is also influenced by the type of provider and the site of care. This is especially true when comparing oncologists with other clinical care providers. According to the report, specialty pharmacies receive the lowest AWP-based reimbursement, and oncologists receive the highest AWP-based reimbursement.1 More than 60% of the plans noted that they, currently or in the near future, intend to implement a preferred infusion network. What is evolving here is the further stratification among provider groups that can confer high value to this system. If your infusion center does a good job, makes very few errors, and has high patient satisfaction scores, you will no doubt get a bonus payment from these manufacturers. Under health reform, we will likely see an explosion in these types of targeted and customized reimbursement schemes. I was fascinated to learn that half of all surveyed health plans restrict the use of drugs based on certain companion diagnostic test results. “Recently, several oncology drugs have been approved with a label stating that an FDA-approved test must be used to detect the related genetic mutation. Survey results indicate that 40% of plans currently allow use of the CLIA [Clinical Laboratory Improvement Amendments] lab developed test, while 26% of plans require a use of the specific test as indicated in the FDA label for a drug.”1

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July/August 2013

Vol 6, No 6

Editorial

One aspect of this survey that continues to perplex me is the creation of specialty pharmacy provider networks. Apparently it works this way: “For specialty drugs covered under the medical benefit, health plans may allow medical benefit providers to maintain their own drug inventory and bill the health plan at their contracted rate (commonly referred to as ‘buy and bill’) or, they may require the providers to order the drug from a specialty pharmacy and bill the health plan for their administration and procedural related costs only. In this case the specialty pharmacy bills the health plan and collects any applicable cost share from the patient.”1 This suggests further complexity, opportunity for error, and, of course, an increase in overall costs. Can’t we make this process any simpler? Because these drugs are uniformly expensive, getting patients to adhere to their drug regimens is more important than ever. “Patients may be faced with a higher financial burden and challenged with the complexity of the disease, alternate weeks of delivery and administration and treatment side effects. Payers cite improving adherence to specialty drugs as a top priority.”1 Yet,

according to this recent survey, 70% of health plans say they rely on their specialty pharmacy providers to improve medication adherence. I am confident that this is going to be a battleground for the future. Given how expensive these specialty pharmaceuticals are, how can we better engage with patients across the spectrum of diseases and specialists to improve overall medication adherence? I hope our readers will carefully study this illuminating survey-based document. It is safe to assume that specialty pharmaceuticals will play an increasingly important role as new discoveries make their way from the bench to the bedside. You can download a copy of this year’s report from www.specialtydigest.emdserono.com (registration required). As always, I would be interested in your views about this new and important survey. You can reach me at david.nash@jefferson.edu. n Reference

1. EMD Serono. EMD Serono Specialty Digest, 9th Edition: Managed care strategies for specialty pharmaceuticals. January 2013. www.specialtydigest.emdserono.com. Accessed June 6, 2013.

Lupus Conference Reports from ACR OCTOBER 26-30, 2013

an e-newsletter brought to you by the publishers of THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TOPICS INCLUDE: • • •

Information for payers and healthcare providers treating patients with lupus On-site coverage from ACR/ARHP 2013 Annual Meeting Review of currently approved and future therapies for lupus

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July/August 2013

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FOR ADULT PATIENTS WITH TYPE 2 DIABETES TRADJENTAÂŽ (LINAGLIPTIN) TABLETS: THE ONLY SINGLE-STRENGTH DPP-4 INHIBITOR

Focusing on what matters Improving glycemic control for adult patients with type 2 diabetes Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

Important Safety Information

ADVERSE REACTIONS

CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo

Adverse reactions reported in â&#x2030;Ľ5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. In patients receiving

TRADJENTA delivers proven glycemic control Placebo-adjusted difference in A1C with oral monoand dual therapy at 24 weeks (%) TRADJENTA monotherapy1,2* Baseline A1C 8.0%

*A randomized, multicenter, double-blind, placebo-controlled study of

adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336; mean baseline A1C=8.0%) or placebo (n=167; mean baseline A1C=8.0%) for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 20.9% of patients in the placebo group required rescue therapy vs 10.2% of patients in the TRADJENTA group. Full analysis population using last observation on study.

TRADJENTA add-on to metformin2,3† Baseline A1C 8.1%

–0.7%‡ (n=333) P<0.0001

†

A randomized, double-blind, placebo-controlled, parallel-group study of adult patients with type 2 diabetes (aged 18-80) with insufficient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524; mean baseline A1C=8.1%) or placebo (n=177; mean baseline A1C=8.0%) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. 18.9% of patients in the placebo group required rescue therapy vs 7.8% of patients in the TRADJENTA group. Full analysis population using last observation on study.

‡

0.3% adjusted mean increase from baseline A1C 8.0% with placebo (n=163).2

0.15% adjusted mean increase from baseline A1C 8.0% with placebo plus metformin (n=175).2

–0.6%§ (n=513) P<0.0001

TRADJENTA: A single-strength DPP-4 inhibitor No dose adjustment required regardless of declining renal function or hepatic impairment TRADJENTA is primarily nonrenally excreted with 80% eliminated via the bile and gut and 5% eliminated via the kidney within 4 days of dosing

T:10.5”

TRADJENTA has a demonstrated safety profile evaluated in more than 6000 patients

TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS

should be exercised when TRADJENTA is administered to a nursing woman. The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established. TJ PROF ISI Sept 28 2012

References: 1. Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267. 2. Data on ﬁle. Boehringer Ingelheim Pharmaceuticals, Inc. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efﬁcacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74.

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

There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution

ENTA TRADJ 30 5 MG # O QD Sig: i P ILLS x2 REF

(11/12) TJ527600PROFA

Tradjenta® (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. INDICATIONS AND USAGE Monotherapy and Combination Therapy: TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity. WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. The use of TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets 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 evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes is based on 14 placebo-controlled trials, 1 activecontrolled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated with TRADJENTA 5 mg daily and 2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks. TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks’ duration and in five additional placebocontrolled studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); one with pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks). In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving TRADJENTA (n = 3625) and more commonly than in patients given placebo (n = 2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar to placebo. Table 1 Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy

Nasopharyngitis Diarrhea Cough

Number (%) of Patients TRADJENTA 5 mg Placebo n = 3625 n = 2176 254 (7.0) 132 (6.1) 119 (3.3) 65 (3.0) 76 (2.1) 30 (1.4)

Rates for other adverse reactions for TRADJENTA 5 mg versus placebo when TRADJENTA was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. Following 104 weeks’ treatment in a controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%). Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Hypoglycemia: In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to 56 patients (3.6%) of 1546 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when TRADJENTA was administered as monotherapy or in combination with metformin, or with pioglitazone. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. In the study of patients receiving TRADJENTA as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no significant difference in

the incidence of investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood glucose ≤70 mg/dL, was noted between the TRADJENTA (31.4%) and placebo (32.9%) treated groups. During the same time period, severe hypoglycemic events, defined as requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 11 (1.7%) of TRADJENTA treated patients and 7 (1.1%) of placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 3 (0.5%) patients on TRADJENTA and 1 (0.2%) on placebo. Use in Renal Impairment: TRADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials. The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRADJENTA treated patients and 3 (4.6%) placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on TRADJENTA and 1 (1.5%) on placebo. Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks treatment compared to placebo. Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA. DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of TRADJENTA; 1085 (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in 12 doubleblind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment. OVERDOSAGE In the event of an overdose with TRADJENTA, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. Copyright © 2012 Boehringer Ingelheim International GmbH Revised: September 2012

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Commentary

Implications of the Employer Mandate Delay on the Healthcare Marketplace By Kip Piper, MA, FACHE, and F. Randy Vogenberg, PhD, RPh Mr Piper is Senior Consultant, Sellers Dorsey, Philadelphia, PA, and President, Health Results Group, Washington, DC; Dr Vogenberg is Principal, Institute for Integrated Healthcare, Greenville, SC

he Patient Protection and Affordable Care Act (ACA) imposes an array of new regulations on employers, as well as requiring them to report to government agencies about meeting those requirements.1 Among these new rules is a mandate that most employers must provide all full-time employees with a minimum coverage of healthcare insurance starting in 2014 or pay a penalty to the Internal Revenue Service (IRS). The ACA also requires employers to report to the IRS details of each employee’s coverage.

The Rationale for Delaying the Employer Mandate Until 2015 On July 2, 2013, the Obama Administration announced that it would not enforce the ACA employer coverage mandate or reporting requirements in 2014. Although the ACA and its associated regulations concerning employers remain in effect, the IRS will not enforce them until 2015.2,3 Ostensibly done in response to employer requests for more time to comply, the 1-year delay—officially termed “transition relief ”—is being done for a more complex mix of practical, political, and economic reasons.2 First, as employers wrestled with making the necessary changes to the employee benefits and the systems, employer groups heavily lobbied the White House to delay the coverage mandate and the reporting requirement. Employers were particularly frustrated with the long delays in federal rule-making and with the technical guidance. Second, the ACA employer mandate is already having a negative effect on employment, as discussed below, with every sign of being a drag on employment as the nation headed into the 2014 election year. Although the ACA employer mandate is designed to help expand or at least to stabilize employer-sponsored coverage, the mandate and its associated penalty increase the cost of every full-time equivalent employee in any organization with more than 50 employees. That is, the law taxes full-time employment relative to part-time positions. The tax ef-

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fect varies, depending on whether an employer already covers full-time employees. This, coupled with the ACA’s 1-year look-back provision—where employer coverage practices in 2013 serve as a basis for demonstrating compliance for early 2014—has motivated many employers to change their staffing mix in 2013 by cutting back hours, converting full-time positions to part-time positions, and by delaying hiring decisions. Whether we call this an unintended consequence or a predictable surprise, employers are economic actors, and they respond to costs and to incentives.

The mandate and its associated penalty increase the cost of every full-time equivalent employee in any organization with more than 50 employees. That is, the law taxes full-time employment relative to part-time positions. Third, the government systems were not going to be ready in time. Policy and politics aside, the information system challenges of the ACA are extraordinary. The law requires an unprecedented range of new systems and information technology changes at federal and state agencies, including the IRS, the Centers for Medicare & Medicaid Services, state Medicaid agencies, and the new health insurance exchanges. Furthermore, these complex and varied systems— often built on antiquated structures that were never intended for ACA-like functions—must “talk” to each other, exchanging data that are essential to carrying out the health reform law’s key features. At a practical level, it means rapid interchange of information to support health insurance exchange operations, prescreening for Medicaid eligibility, federal premium subsidy applications, and enforcement of the ACA’s individual and parental coverage mandates and new regulatory framework for health insurance products.

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Implications for Health Insurance Exchanges and Medicaid The 1-year delay in enforcing the employer mandate has interesting implications for the new health insurance exchanges and for state Medicaid programs. The ACA creates a new framework for eligibility and for enrollment for federally subsidized health coverage that is available only through the new publicly run exchanges and for Medicaid in those states that opt to expand eligibility. From 2014 through 2023, the federal government is expected to spend approximately $1.8 trillion on the cost of this coverage expansion.4 Therefore, considerable importance rests on the speed, accuracy, and integrity of the process that individuals will use to apply for taxpayer-subsidized coverage.

The delay does take away a financial disincentive, albeit for only 1 year, for employers who are dropping coverage. The employer mandate penalty is intended to discourage employers from dropping coverage and to add a new cost for employers who do not already cover full-time workers. That is one of the ways where employer reporting comes in. Via the IRS system, exchanges were to use information on the availability of employer-sponsored coverage to verify eligibility for government-sponsored coverage. Now, absent this information, exchanges and state Medicaid programs will need to rely on personal attestations—that is, they will need to take the applicant’s word for it. Although most applicants are honest, this does increase the opportunities for fraud and abuse. It also increases the risks for applicants, because once the information is available, the IRS can retroactively recover premium subsidies made on behalf of an individual or family, as well as impose a $25,000 fine.1 The delay does take away a financial disincentive, albeit for only 1 year, for employers who are dropping coverage. The employer mandate penalty—$2000 or $3000 per full-time employee, depending on whether the employee applied for the federal premium subsidy—is intended to discourage employers from dropping coverage and to add a new cost for employers who do not already cover full-time workers.1 In many ways, the ACA creates an incentive for employers to drop coverage and to shift responsibility to taxpayers and to individuals. Unlike before the ACA, under the ACA there will be the guaranteed issue, por-

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tability, no preexisting condition exclusions or annual or lifetime limits, adjusted community rating, a defined benefit package, a new individual market in the exchanges, Medicaid expansion in some states, and subsidized coverage for individuals and families who are between 100% and 400% of the federal poverty level (400% of poverty is approximately $94,200 for a family of 4).5 In other words, there will be a coverage option for employees other than their employers. Most large employers are unlikely to drop coverage, especially in the near-term. However, small businesses with fewer than 500 employees and organizations without pricing power are far more likely to drop coverage or to reduce hours for their existing workforce. We knew that this was going to happen to some degree—before the delay, the Congressional Budget Office (CBO) projected that the ACA would translate to approximately 7 million workers losing employer-sponsored coverage6; but absent the penalty in 2014, changes by small employers and by organizations such as school districts will likely be accelerated. The CBO now projects that the delay in enforcement of the employer mandate will cause another 1 million workers to lose employer health coverage, with half of these workers gaining taxpayer-supported coverage and the other half joining the ranks of the uninsured.7 The bottom line is more, or at least a faster rate of, “crowd out” of private coverage by ACA dollars; in other words, more employees are moving from coverage paid with private funds to Medicaid or to exchange-based coverage financed by public money. Again, this was going to happen to some degree in any case under the ACA. Crowd out is an economic certainty whenever there is a new or an expanded government benefit in a marketplace in which businesses or individuals already spend their own private money. The new public funding “crowds out” private spending. But the combination of “trust me” eligibility verification and temporary removal of a key disincentive to drop employer-sponsored coverage could be expected to increase enrollment in Medicaid and in the new federally subsidized exchange coverage.

What This Means for Employers, Health Plans, and Exchanges Rapid advances in medical technology, including drugs, along with globalization are 2 “mega” trends driving a renewed interest in healthcare value determination by employer plan sponsors (employers) at the same time that they face the implementation of ACA, known as healthcare reform. The coincidence of these issues is not lost on employers, regardless of their size; however, size does make a difference in the way that healthcare reform was framed by Congress. First, this delay does not directly affect small employ-

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ers with fewer than 50 employees. However, small employers have to deal with less insurance market clout, and with being more susceptible to local market changes, which impacts their ability to find choice in buying health insurance. Small employers also have to be aware of what is happening with their state insurance exchange regarding health insurance options, because that is driving some variations in insurance market access change for 2014 across the United States.8 Large employers are directly affected by this delay. For large employers with more than 50 full-time employees, there are 2 main approaches to purchasing employee coverage—buy fully funded health insurance from a commercial health plan, or self-insure and hire an administrative service organization to manage the employer plan. In the market, these 2 categories have very different implications and choices to consider under the new healthcare reform landscape, so a delay of the employer mandate penalties for large employers that do not provide health insurance coverage becomes an impor tant insurance strategy and tactical shift held out by the Obama Administration to employers. At the same time, those commercial health plans or administrative services entities are closely following regulatory signals from the implementation of the healthcare reform and are making changes in response to their own business operations. Such changes can be subtle in some markets, but they can also leave other markets with little-to-no competition among plans. Such unintended implications of this delay or other healthcare reform implementation mandates will have an impact on the future of employer-sponsored insurance through the end of this decade. It is important to note that these mandates are still law and will be enforced starting in 2015 (ie, employers still have to get ready to implement and make decisions about the mandate). Regardless of a delay, the framework remains, and large employers must make plans over the long run as to how best to offer coverage, or not offer coverage, as it relates to their business strategy, including the need for retaining or recruiting a workforce. More likely, this will be an easier exercise for private employers than for publicly traded companies. In addition, because there are implications for commercial insurers both in and outside a public insurance exchange, it is important to cross-track both markets. To date, although each state will have an exchange, states differ in market rules and the roles of the federal and state governments. Most exchanges will be entirely federally operated, with the rest either run by the state or

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run through a federal–state partnership.7 Such wide variation in public exchange models, along with anticipated delays in operationalizing them, has caused many employers, large and small, to seek out a growing number of private exchanges.8

Because there are implications for commercial insurers both in and outside a public insurance exchange, it is important to cross-track both markets. To date, although each state will have an exchange, states differ in market rules and the roles of the federal and state governments. Conclusion The implications of the employer mandate delay for private exchanges have yet to be fully determined, but despite the large delay, there is interest as well as continued growth in the number of lives covered through these group purchasing styles of entities.8 Healthcare reform is neither for the faint of heart nor for those who do not embrace change. With so many moving parts in trying to make changes in healthcare, it will be even more important to take our time to get this right, because actual lives hang in the balance. n Author Disclosure Statement Mr Piper and Dr Vogenberg reported no conflicts of interest.

References

1. US Congress. The Patient Protection and Affordable Care Act. Public Law 111148. 2010. http://housedocs.house.gov/energycommerce/ppacacon.pdf. Accessed July 29, 2013. 2. Mazur MJ. Continuing to implement the ACA in a careful, thoughtful manner. Treasury Notes. July 2, 2013. www.treasury.gov/connect/blog/Pages/Continuing-toImplement-the-ACA-in-a-Careful-Thoughtful-Manner-.aspx. Accessed July 29, 2013. 3. Radnofsky L. Health law penalties delayed: larger employers get one-year reprieve on fines for leaving workers uncovered. Wall Street Journal. Updated July 3, 2013. http://online.wsj.com/article/SB10001424127887324436104578582082787214660. html. Accessed July 29, 2013. 4. US Congressional Budget Office. Effects on health insurance and the federal budget for the insurance coverage provisions in the Affordable Care Act—May 2013 Baseline. May 14, 2013. www.cbo.gov/sites/default/files/cbofiles/attachments/44190_ EffectsAffordableCareActHealthInsuranceCoverage_2.pdf. Accessed July 29, 2013. 5. US Department of Health and Human Services. 2013 Poverty guidelines. http:// aspe.hhs.gov/poverty/13poverty.cfm. Accessed July 29, 2013. 6. Banthin J, Masi S; for the US Congressional Budget Office. CBO’s estimate of the net budgetary impact of the Affordable Care Act’s health insurance coverage provisions has not changed much over time. May 14, 2013. www.cbo.gov/publication/44176. Accessed July 29, 2013. 7. US Congressional Budget Office. Analysis of the administration’s announced delay of certain requirements under the Affordable Care Act. July 30, 2013. www.cbo.gov/ sites/default/files/cbofiles/attachments/44465-ACA.pdf. Accessed July 30, 2013. 8. Pearson CF. The race to open enrollment: critical success factors for exchanges. Am Health Drug Benefits. 2013;6(5):168-170.

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Original Article

Real-World Corticosteroid Utilization Patterns in Patients with Metastatic Castration-Resistant Prostate Cancer in 2 Large US Administrative Claims Databases Marie-Hélène Lafeuille, MA; Jonathan Gravel, MSc; Amanda Grittner, MA; Patrick Lefebvre, MA; Lorie Ellis, PhD; R. Scott McKenzie, MD Background: Prostate cancer is the most common noncutaneous malignancy in men in the United States. Patients with metastatic castration-resistant prostate cancer (mCRPC) may be treated with secondary hormonal therapy or with chemotherapy, and potentially with concomitant corticosteroids. Corticosteroids can help manage the side effects of chemotherapy and secondary hormonal therapy and ameliorate prostate cancer–related symptoms, although corticosteroids are also associated with adverse effects. With an increasing number of available treatment options for mCRPC, evaluating the real-world concomitant use of corticosteroids in this patient population is important. Objective: To evaluate the utilization patterns of corticosteroids for the treatment of patients with mCRPC based on real-world data from 2 large claim databases. Methods: This retrospective analysis included medical and pharmacy claims from 2 large publicly available healthcare claims databases covering more than 31 million individuals to identify treatment patterns in adult patients with mCRPC. A total of 2593 patients with mCRPC were identified in data set 1 and 626 patients in data set 2 between 2005 and 2011. The appropriate treatment for castration-resistant prostate cancer (CRPC) was defined as chemotherapy, an antiandrogen, an adrenal androgen blocker, or estrogen. The index date was the date of the first CRPC treatment or the first metastasis diagnosis, whichever occurred later. The observation period spanned from the index date to the end of health insurance eligibility. Study end points included population characteristics, the distribution of mCRPC therapies, and corticosteroid utilization patterns. Results: The study population came from the 2 data sets and included 3219 men who were treated for mCRPC. Bone and lymph nodes were the predominant metastatic sites. Bicalutamide was the most common secondary hormonal therapy, and docetaxel was the most common chemotherapy used for these patients. Overall, 73.4% of the patients in data set 1 received concomitant corticosteroids, as did 71.6% of patients in population 2 during the entire period from the index date to the end of eligibility date. In addition, 62.8% and 60.4% of patients, respectively, received concomitant corticosteroids during the secondary hormonal therapy period, and 93.8% and 95.1% of patients, respectively, received concomitant corticosteroids during the chemotherapy period. Similar patterns of corticosteroid use were observed across geographic areas of the United States. Conclusion: This study shows consistently similar utilization patterns of corticosteroids in patients with mCRPC in 2 large national databases. Using real-world data to inform concomitant corticosteroid use in the treatment of patients with mCRPC may assist healthcare providers with treatment selection and with sequencing decision. Future research is warranted to investigate evolving treatment options for patients with mCRPC.

Stakeholder Perspective, page 315

Am Health Drug Benefits. 2013;6(6):307-316 www.AHDBonline.com Disclosures are at end of text

Ms Lafeuille is Senior Economist, Mr Gravel is Economist, Ms Grittner is Economist, and Mr Lefebvre is Vice President, Groupe d’Analyse, Ltée, Montreal, Quebec, Canada; Dr Ellis is Associate Director and Dr McKenzie is Senior Director, Janssen Scientific Affairs, Titusville, NJ.

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Key Points Corticosteroids can help manage the side effects of chemotherapy or secondary hormonal therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) and ameliorate prostate cancer–related symptoms. ➤ Real-world data on corticosteroid use and treatment patterns are infrequently reported in patients with mCRPC. ➤ Using real-world evidence from medical and pharmacy claims in 2 large claims databases covering >31 million lives, this study identified corticosteroid utilization patterns in patients with mCRPC. ➤ Results show that, in actual practice, the use of concomitant corticosteroid therapy in patients with mCRPC is consistent with the drug’s labeling information across US regions. ➤ In this study, patients with mCRPC were exposed to corticosteroid therapy approximately 33% of the time between 2005 and 2011. ➤ Such real-world data may offer providers positive feedback regarding their treatment selection and sequencing decisions for this patient population. ➤

rostate cancer is the most frequently diagnosed noncutaneous malignancy in males and is a leading cause of cancer-related morbidity and mortality among men in the United States.1,2 The American Cancer Society has estimated that approximately 238,600 new cases of prostate cancer will be diagnosed in 2013, and that approximately 29,700 men will die of the disease.3 Many patients will be cured with a primary therapy of surgery, radiation therapy, and potential adjuvant hormonal therapy, but a subset of patients will experience disease progression with metastases spreading to other organs or to tissues in the body, such as to the bladder or bone. For such patients, androgen-deprivation therapy (ADT) is a widely accepted treatment option. Disease progression despite ADT and castrate levels of testosterone is considered castration-resistant prostate cancer (CRPC).4,5 Up to 85% of patients with CRPC are estimated to have metastatic CRPC (mCRPC) and may be considered for secondary hormonal therapy or for chemotherapy.6,7 Historically, treatment for mCRPC was predominantly palliative; however, recent pharmacologic advances have led to increased treatment options showing survival benefits in addition to pain reduction and improvements in quality of life.7,8 An early trial showed that mono

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therapy with prednisone may contribute to pain relief and a reduced need for analgesics in a subset of patients.9 In addition, several treatment regimens approved by the US Food and Drug Administration (FDA) for mCRPC involve corticosteroids. Prednisone in combination with mitoxantrone has been associated with pain reduction and with improvement in quality of life in men with advanced, hormone-refractory prostate cancer, but not with improved survival.10 Treatment with docetaxel in combination with prednisone was the first chemotherapy regimen shown to increase survival among patients with mCRPC.10 Men receiving treatment every 3 weeks with docetaxel plus a daily dose of prednisone had a 24% lower probability of death (hazard ratio, 0.76) compared with men treated with mitoxantrone plus prednisone.10 More recent FDA-approved treatment regimens administered with concomitant corticosteroids include abir aterone acetate in combination with prednisone, an oral androgen biosynthesis inhibitor for the treatment of patients with mCRPC, and cabazitaxel in combination with prednisone, a cytotoxic regimen for patients with metastatic hormone-refractory prostate cancer whose disease progresses and who have previously received docetaxel.11,12 Other recently approved treatment regimens without specific corticosteroid requirements include sipuleucel-T, an autologous cellular immunotherapy for asymptomatic or minimally symptomatic patients with mCRPC, and enzalutamide, an androgen receptor inhibitor for patients with progressed mCRPC who have previously received treatment with docetaxel.13,14 Corticosteroids can help manage the side effects of chemotherapy and secondary hormonal therapy and can ameliorate prostate cancer–related symptoms, although they are also associated with adverse effects. An increasing number of treatment options for mCRPC included in the National Comprehensive Cancer Network guidelines involve corticosteroids, but real-world data on corticosteroid use and treatment patterns have been reported infrequently in this patient population.15 The goal of the present study was to address this gap by evaluating the real-world corticosteroid treatment patterns for patients with mCRPC in the United States. A retrospective study design was used to describe the treatment patterns of patients with mCRPC.

Methods Data Source This retrospective study used data from the Truven Health Analytics MarketScan Research Databases (quarter 1 of 2005 through quarter 1 of 2011) and from the Optum Insight Clinformatics Data Mart database (quarter 1 of 2005 through quarter 2 of 2012). The Truven data-

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Figure 1 Study Design

Start of data availability: Q1 of 2005

Start of eligibility

ADT therapy

Index date Initiation of first CRPC therapy or first diagnosis of metastases, whichever was later

Baseline period: 6 mos before index date

End of eligibility

End of data availability: Q1 of 2011a/ Q2 of 2012b

Observation period

Data availability for data set 1 (Truven Health Analytics MarketScan) ended in Q1 of 2011. Data availability for data set 2 (Optum Insight Clinformatics Data Mart) ended in Q2 of 2012. ADT indicates androgen-deprivation therapy; CRPC, castration-resistant prostate cancer; Q, quarter.

base (data set 1) includes data from 45 large employers, health plans, and government and public organizations covering more than 18 million lives through a commercial insurer or through Medicare. Enrollees in the database include employees, dependents, and retirees in the United States with primary or Medicare supplemental coverage through privately insured fee-for-service, point of service, or capitated health plans. All census regions are represented, although most enrollees are from the South and North Central (ie, Midwest) regions. The Optum database (data set 2) contains claims from more than 13 million privately insured individuals covered by 69 self-insured Fortune 500 companies with locations in all census areas of the United States. Data are available for all company beneficiaries, including employees, spouses, dependents, and retirees. Both databases contain information from integrated, individual-level claims of commercial health insurances, including medical claims for outpatient and inpatient services, pharmacy claims for prescription drugs, and eligibility information on demographics and health plan characteristics. The data were deidentified in compliance with the Health Insurance Portability and Accountability Act of 1996 to preserve patient confidentialÂ ity. Institutional Review Board approval and informed consent were not required for this study.

Study Design and Population Selection Adult patients who were treated for mCRPC after ADT, defined as either having at least 1 dispensing of luteinizing hormone-releasing hormone (LHRH) or an orchiectomy, who had at least 1 diagnosis of a malignant neoplasm of the prostate (International Classification of Diseases, Ninth Revision [ICD-9], 185.xx) and at least 1 additional diagnosis of any history of prostate cancer

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(ICD-9, 185.xx or V10.46) within 1 year of at least 1 metastatic diagnosis (ICD-9, 196-199) were included in the study population. Eligible treatments for CRPC included chemotherapy (eg, docetaxel, doxorubicin, estramustine phosphate, etoposide, mitoxantrone, cabazitaxel, paclitaxel, vinÂ blastine, carboplatin, and vinorelbine); antiandrogens (eg, bicalutamide, flutamide, and nilutamide) unless initiated within 90 days of LHRH initiation; adrenal androgen blockers (eg, ketoconazole and aminoglutethimide); and estrogens (eg, diethylstilbestrol, conjugated estrogens, and other estrogens). To ensure that metastases stemmed from prostate cancer, men with another cancer diagnosis (ICD-9, 140.xx-184.xx, 186.xx-209.xx) within 1 year of the first metastatic diagnosis were excluded from the sample. Continuous eligibility for health insurance was required for at least 1 year before the first metastatic diagnosis and at least 6 months before the first CRPC treatment. To obtain a sufficiently long observation period, patients who had an index date less than 3 months before the end of the availability of the data (ie, cutoff date) were excluded from the analysis. Figure 1 illustrates the study design. The index date was defined as either the initiation of the first CRPC therapy or the date of the first diagnosis of metastases, whichever occurred later. The 6 months preceding the index date constituted the baseline period. The observation period spanned from the index date until the end of the individual patientâ&#x20AC;&#x2122;s health insurance eligibility or until the end of data availability.

Study End Points Population baseline characteristics The demographic and clinical characteristics of the

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study population were evaluated during the baseline period. These characteristics included age, payer type, region, year of index date, clinical history (including score on the Quan-Charlson comorbidity index [CCI]16,17), sites of metastases at the first metastatic diagnosis, and length of observation period.

Evaluation of mCRPC therapies The distribution of mCRPC therapies was evaluated to assess the treatment patterns of patients with mCRPC. The therapies were stratified into secondary hormonal therapies and chemotherapies. Secondary hormonal therapies included antiandrogens, excluding any antiandrogens initiated within 90 days of the initiation of LHRH therapy; adrenal androgen blockers; and estrogen. Relative frequencies for the first treatment of mCRPC and for all treatments during the observation period were calculated. Evaluation of corticosteroid use Because corticosteroid utilization may be different when accompanying chemotherapy or secondary hormonal therapy, the use of corticosteroids was evaluated over 3 study periods: the “overall mCRPC period,” the “secondary hormonal therapy period,” and the “chemotherapy period.” The overall mCRPC period was defined as the entire observation period that spans from index date to the end of eligibility or data availability. The secondary hormonal therapy period was from the first date of treatment with secondary hormonal therapy to the initiation of chemotherapy or the end of eligibility or data availability, whichever occurred first. The chemotherapy period started with the first date of chemotherapy and ended with the start of a secondary hormonal therapy treatment or the end of eligibility or data availability, whichever occurred earlier. If there were more than 1 secondary hormonal therapy or chemotherapy periods for a single patient, the periods were summed to obtain the total secondary hormonal therapy and chemotherapy periods. To describe corticosteroid utilization patterns, the number of patients using corticosteroids (overall and stratified by region), the number of prescriptions per patient, the proportion of days covered, and the length of treatment exposure were reported for each of the periods. The proportion of days covered was calculated as the sum of nonoverlapping days of drug supply in a given period divided by the number of days in that given period. The number of patients receiving prednisone and dexamethasone (stratified by oral and injection administration forms) and the daily prednisone dose were also reported. The daily dose of pharmacy dispensings was obtained by multiplying the medication strength with

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the prescribed quantity and then dividing the result by the days of supply.

Statistical analysis Univariate descriptive statistics included the mean (± standard deviation) and the median values for continuous variables and relative frequencies for categorical variables. All analyses were conducted using SAS Version 9.2 (SAS Institute; Cary, NC) or a newer version. Results Population Baseline Characteristics Table 1 (page 311) shows the demographic and clinical baseline characteristics of the study population. The mean age was 73.3 years in population 1 and 68.4 years in population 2. The populations from the 2 databases differed substantially with respect to payer types; although most (73.2%) patients from data set 1 were enrolled in Medicare, almost all (99.5%) patients from data set 2 were covered by commercial insurance. In contrast, the distribution across regions was similar in both databases, with the Midwest and the South accounting for the majority of patients in both databases (38.1% and 32.7% in data set 1 and 31.6% and 42.3% in data set 2, respectively). The mean CCI score was 0.8 in population 1 and 1.0 in population 2. In terms of comorbidities, 19.9% and 24.0% of patients had diabetes in populations 1 and 2, respectively; 35.0% and 53.7%, had hypertension; and 34.4% and 31.8%, had cardiovascular diseases. In both populations, the most common metastatic sites were bone and bone marrow (62.9% in population 1, 63.9% in population 2). The mean observation period lasted 493.3 days in population 1 and 478.0 days in population 2. Evaluation of mCRPC Therapies Table 2 (page 312) shows the distribution of mCRPC therapies in the study populations. The type of first treatment at or after the index date was similar across the study populations, with 35.7% and 31.6% of patients in population 1 and population 2, respectively, undergoing chemotherapy, and 51.7% and 55.9%, respectively, receiving secondary hormonal therapy. Docetaxel was the most common chemotherapy used, accounting for 25.2% of the first treatment and 41.1% of all treatments in population 1, and for 20.3% of the first treatment and 37.5% of all treatments in population 2. Antiandrogens constituted the largest part of secondary hormonal therapies in both populations, with 40.9% of new therapies in data set 1 and 46.0% in data set 2. Bicalutamide was the predominant antiandrogen used, accounting for 37.1% and 40.7% of first treatment and 41.5% and 45.0% of all treatments in population 1 and

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Table 1 Patient Population Baseline Characteristics in the 2 Data Sets Characteristics Age, mean ± SD [median] Age group, N (%) <55 yrs 55-64 yrs 65-74 yrs ≥75 yrs Payer type, N (%) Medicare enrollees Commercial claims enrollees HMO PPO POS Indemnity EPO Other/unknown Medicaid enrollees Region, N (%) Midwest Northeast South West Unknown Year of index date, N (%) 2005 2006 2007 2008 2009 2010 2011 2012 Clinical history, N (%) Charlson comorbidity index, mean ± SD [median] Diabetes Hypertension Cardiovascular diseases Seizures Metastatic sites at first metastatic diagnosis, N (%) Secondary and unspecified malignant neoplasm of lymph nodes Secondary malignant neoplasm of respiratory and digestive systems Secondary malignant neoplasm of other specified sites Kidney Other urinary organs Skin Brain and spinal cord Other parts of nervous system Bone and bone marrow Adrenal gland Other specified sites Malignant neoplasm without specification of site Observation period, mean days ± SD [median]

Data set 1 (N = 2593)

Data set 2 (N = 626)

73.3 ± 10.4 [75.0]

68.4 ± 10.6 [66.0]

102 (3.9) 557 (21.5) 607 (23.4) 1327 (51.2)

46 (7.3) 238 (38.0) 158 (25.2) 184 (29.4)

1898 (73.2) 695 (26.8) 70 (2.7) 440 (17.0) 84 (3.2) 0 (0.0) 0 (0.0) 101 (3.9) 0 (0.0)

2 (0.3) 623 (99.5) 63 (10.1) 75 (12.0) 310 (49.5) 135 (21.6) 38 (6.1) 2 (0.3) 1 (0.2)

988 (38.1) 263 (10.1) 848 (32.7) 491 (18.9) 3 (0.1)

198 (31.6) 40 (6.4) 265 (42.3) 123 (19.6) 0 (0.0)

369 (14.2) 475 (18.3) 565 (21.8) 547 (21.1) 504 (19.4) 133 (5.1) 0 (0.0) 0 (0.0)

5 (0.8) 93 (14.9) 103 (16.5) 110 (17.6) 100 (16.0) 89 (14.2) 104 (16.6) 22 (3.5)

0.8 ± 1 [0.0] 516 (19.9) 907 (35.0) 892 (34.4) 21 (0.8)

1.0 ± 1.4 [1.0] 150 (24.0) 336 (53.7) 199 (31.8) 10 (1.6)

240 (9.3) 167 (6.4) 1955 (75.4) 1 (0.0) 63 (2.4) 3 (0.1) 45 (1.7) 2 (0.1) 1630 (62.9) 3 (0.1) 208 (8.0) 231 (8.9) 493.3 ± 409.1 [403.0]

68 (10.9) 39 (6.2) 461 (73.6) 0 (0.0) 15 (2.4) 0 (0.0) 5 (0.8) 0 (0.0) 400 (63.9) 1 (0.2) 40 (6.4) 58 (9.3) 478.0 ± 434.3 [347.0]

EPO indicates exclusive provider organization; HMO, health maintenance organization; POS, point of service; PPO, preferred provider organization; SD, standard deviation.

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Table 2 Distribution of Therapies for Metastatic Castration-Resistant Prostate Cancer

Therapy

Data set 1 (N = 2593) First treatment, All treatments, N (%) N (%)

Data set 2 (N = 626) First treatment, All treatments, N (%) N (%)

Chemotherapy

926 (35.7)

1345 (51.9)

198 (31.6)

309 (49.4)

Docetaxel

653 (25.2)

1067 (41.1)

127 (20.3)

235 (37.5)

Carboplatin

52 (2.0)

146 (5.6)

14 (2.2)

41 (6.5)

Estramustine

31 (1.2)

107 (4.1)

9 (1.4)

24 (3.8)

Mitoxantrone

28 (1.1)

262 (10.1)

7 (1.1)

43 (6.9)

Cyclophosphamide

23 (0.9)

96 (3.7)

6 (1.0)

15 (2.4)

Secondary hormonal therapy

1340 (51.7)

1496 (57.7)

350 (55.9)

391 (62.5)

1060 (40.9)

1193 (46.0)

288 (46.0)

319 (51.0)

961 (37.1)

1076 (41.5)

255 (40.7)

282 (45.0)

48 (1.9)

88 (3.4)

17 (2.7)

25 (4.0)

Antiandrogena Bicalutamide Flutamide Nilutamide Adrenal androgen blocker Ketoconazole

51 (2.0)

124 (4.8)

16 (2.6)

32 (5.1)

261 (10.1)

507 (19.6)

60 (9.6)

119 (19.0)

259 (10.0)

506 (19.5)

60 (9.6)

119 (19.0)

Aminoglutethimide

2 (0.1)

3 (0.1)

0 (0.0)

19 (0.7)

53 (2.0)

2 (0.3)

8 (1.3)

Diethylstilbestrol

3 (0.1)

13 (0.5)

0 (0.0)

Conjugated estrogens

5 (0.2)

10 (0.4)

1 (0.2)

4 (0.6)

11 (0.4)

30 (1.2)

1 (0.2)

4 (0.6)

327 (12.6)

78 (12.5)

Estrogens

Other estrogens None of the above

Antiandrogens initiated within 90 days before or after the initiation of luteinizing hormone-releasing hormone were not considered as a castration-resistant prostate cancer therapy.

population 2, respectively. Approximately 13% of the entire study population did not receive any treatment for CRPC after the mCRPC index date.

Evaluation of Corticosteroid Use Table 3 (page 313) outlines the patterns of corticosteroid use. In population 1, 73.4% of patients had at least 1 prescription for corticosteroids during the overall period of mCRPC, 62.8% during secondary hormonal therapy, and 93.8% during chemotherapy. In population 2, 71.6% of patients received corticosteroids during the overall mCRPC period, 60.4% during secondary hormonal therapy, and 95.1% during chemotherapy. During the overall mCRPC period, the proportion of days covered was 35% in data set 1 and 38% in data set 2. The regional stratification of cortico足 steroid use during the overall period of mCRPC in Figure 2 (page 314) shows that the utilization patterns are very similar across all US regions. The use of prednisone also followed similar patterns in both populations, with 43.5% and 45.5% of patients receiving at least 1 prescription during the overall period

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of mCRPC, 33.0% and 37.9% during secondary hormonal therapy, and 58.0% and 59.9% during chemotherapy in populations 1 and 2, respectively. In population 1, the median daily prednisone dose was 10.4 mg during the overall period of mCRPC, 10.1 mg during secondary hormonal therapy, and 10.3 mg during chemotherapy. This corresponds to the numbers in population 2, where the median daily dose was 10.3 mg, 10.1 mg, and 10.2 mg in the mCRPC, the secondary hormonal therapy, and the chemotherapy periods, respectively.

Discussion This observational analysis of data from 2 commercially available administrative claims databases shows that corticosteroid utilization was observed in an overwhelming majority of patients with mCRPC; the analysis of the 2 databases showed that 73.4% of patients with mCRPC in population 1 and 71.6% of patients with mCRPC in population 2 received corticosteroids overall and that 93.8% and 95.1% of patients received corticosteroids after chemotherapy initiation. Similarly, the analysis of the 2 populations showed that pat-

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Corticosteroid Utilization in Patients with mCRPC

Table 3 Corticosteroid Use in Patients with mCRPC Data set 1

Data set 2

Overall mCRPC period (N = 2593)

Secondary hormonal therapy period (N = 1496)

Chemotherapy period (N = 1345)

Secondary Overall hormonal mCRPC period therapy period (N = 626) (N = 391)

1903 (73.4)

939 (62.8)

1262 (93.8)

448 (71.6)

236 (60.4)

294 (95.1)

Drugs dispensed, N

12.5 ± 13.7 [8.0]

5.0 ± 5.9 [3.0]

14.3 ± 14.0 [10.0]

12.0 ± 10.7 [10.0]

6.0 ± 7.0 [3.0]

12.7 ± 10.2 [10.0]

Proportion of days covered,a mean ± SD [median]

35% ± 39 [25]

36% ± 33 [26]

37% ± 32 [29]

38%± 39 [28]

39% ± 33 [32]

41% ± 35 [29]

Exposure period, days,b mean ± SD [median]

540 ± 408 [540]

406 ± 354 [406]

419 ± 353 [419]

536 ± 441 [388]

414 ± 417 [281]

383 ± 370 [285]

1129 (43.5)

493 (33.0)

780 (58.0)

285 (45.5)

148 (37.9)

185 (59.9)

Chemotherapy period (N = 309)

Corticosteroid use Patients, N (%)

Prednisone use Patients, N (%)

14.7 ± 15.4 [10.4] 16.9 ± 20.6 [10.1] 12.8 ± 10.7 [10.3] Daily dose, mg,c mean ± SD [median]

13.8 ± 10.8 [10.3] 15.0 ± 13.8 [10.1] 12.3 ± 7.4 [10.2]

Dexamethasone use Patients, N (%)

1409 (54.3)

412 (27.5)

1180 (87.7)

347 (55.4)

110 (28.1)

283 (91.6)

Dexamethasone oral, N (%)

878 (33.9)

347 (23.2)

651 (48.4)

214 (34.2)

97 (24.8)

149 (48.2)

Dexamethasone injection, N (%)

1092 (42.1)

97 (6.5)

1039 (77.2)

274 (43.8)

25 (6.4)

262 (84.8)

The proportion of days covered was calculated as the sum of nonoverlapping days of supply in a given period divided by the number of days in that given period. b For the subset of patients with corticosteroid use, the exposure period was defined as the number of days of observation for each period. c The daily dose was obtained by multiplying the medication strength with the prescribed quantity and then dividing the result by days of supply. mCRPC indicates metastatic castration-resistant prostate cancer. a

terns of corticosteroid use were consistent across US geographic population subsets. To our knowledge, this study is the first to investigate corticosteroid treatment patterns in a population of patients with mCRPC using real-world data. The findings of this study are consistent with the indications of FDA-approved therapies for patients with mCRPC: many of these regimens involve corticosteroids, including mitoxantrone plus prednisone, docetaxel plus prednisone, abiraterone plus prednisone, and cabaz itaxel plus prednisone. Two agents recently approved by the FDA for mCRPC—enzalutamide and sipuleucel-T— do not include corticosteroids as part of the treatment regimen. However, a recent post-hoc analysis of the enzalutamide randomized controlled trial reported that 48% of patients had received corticosteroids during

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treatment with enzalutamide.18 To our knowledge, the concurrent use of immunosuppressive agents (including corticosteroids) with sipuleucel-T has not been evaluated. Because sipuleucel-T aims at stimulating the immune system, the concurrent use of immunosuppressive agents may alter its efficacy and safety profile.13 Reviews of clinical trial designs of investigational treatments for mCRPC have also reported the widespread use of corticosteroids in this patient population. MacVicar and Hussain reviewed investigational treatments and found that a majority of phase 3 randomized controlled trials of patients with mCRPC included corticosteroids in the interventional arm, the control arm, or both arms.19 The inclusion of corticosteroids in clinical trials of immunotherapy for patients with mCRPC differs across trials. Clinical trials of some investigational im-

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orticosteroid Use in Patients with mCRPC, Figure 2 C by Geographic Region Data set 1 Data set 2 80

Patients with mCRPC using corticosteroids, %

72.3%

70.7%

71.5%

75.0%

76.4% 70.9%

71.3%

73.2%

60 50 40 30 20 10 0

Midwest

Northeast

South

West

US region

mCRPC indicates metastatic castration-resistant prostate cancer.

munologic agents, such as intetumumab, have included corticosteroids in their design,20 whereas trials of other agents, such as ipilimumab, have not.21 Corticosteroids are prescribed concomitantly with chemotherapies and secondary hormonal therapies to manage the adverse effects of these therapies and to

Corticosteroids are prescribed concomitantly with chemotherapies and secondary hormonal therapies to manage the adverse effects of these therapies and to ameliorate the symptoms of the underlying malignancy. However, corticosteroids are themselves associated with potential adverse effects that may require monitoring. ameliorate the symptoms of the underlying malignancy. However, corticosteroids are themselves associated with potential adverse effects that may require monitoring. Our study shows that, in the real world, corticoste-

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roids have been widely used in this patient population, at a median daily dose of approximately 10 mg for prednisone, which is the FDA-approved dose for several treatment regimens involving prednisone. This supports the fact that real-world corticosteroid utilization is consistent with the labeling information for mCRPC treatment regimens. We also found that patients with mCRPC were exposed to corticosteroids for approximately 33% of the entire observation period (proportion of days covered, 35%-38%), which may potentially attenuate the adverse events associated with long-term corticosteroid treatment. In the context of emerging treatment options that are indicated with or without concomitant use of corticosteroids, this information may assist healthcare providers and patients in their treatment selection and treatment-sequencing decisions.

Limitations As with all analyses, some limitations must be taken into consideration. First, analyses based on claims data have inherent limitations, such as potential miscoding or incomplete coding of diagnoses. Second, the study presented here was limited to treatment patterns of men with mCRPC in the United States. Additional findings may be reported for other global geographic regions. Furthermore, because of data availability at the time the analyses were conducted, the study time period was limited to the period from quarter 1 of 2005 to quarter 1 of 2011 in the first database and from quarter 1 of 2005 to quarter 2 of 2012 in the second database. Therefore, it is possible that more recent corticosteroid treatment patterns will differ from those described in this article. Conclusion The findings in this study show that there is widespread use of corticosteroids in patients with mCRPC across 2 large national databases and provide new insight into the treatment patterns of this class of medications in patients with prostate cancer. The consistency of utilization patterns across US geographic areas shows that these results are not limited to a specific regional pattern. The finding about the real-world prevalence and treatment patterns of concomitant corticosteroid use in the treatment of patients with mCRPC confirms that, overall, corticosteroids are used in accordance with the FDA labeling indications. Future observational research on treatment patterns is warranted as emerging treatments become available for this patient population. Study Funding This study was funded by Janssen Scientific Affairs.

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Author Disclosure Statement Ms Lafeuille, Mr Gravel, Ms Grittner, and Mr Lefebvre are employees of Groupe d’Analyse Ltée; Dr Ellis and Dr McKenzie are employees of Janssen Scientific Affairs and stockholders of Johnson & Johnson.

References

1. Kohli M, Tindall DJ. New developments in the medical management of prostate cancer. Mayo Clin Proc. 2010;85:77-86. 2. Sartor O, Michels RM, Massard C, de Bono JS. Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting. Oncologist. 2011;16:1487-1497. 3. American Cancer Society. What are the key statistics about prostate cancer? Revised May 15, 2013. www.cancer.org/cancer/prostatecancer/detailedguide/prostatecancer-key-statistics. Accessed March 3, 2013. 4. Scher HI, Halabi S, Tannock I, et al; for the Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148-1159. 5. Saad F, Hotte SJ; for the Canadian Urologic Oncology Group, and the Canadian Urological Association. Guidelines for the management of castrate-resistant prostate cancer. Can Urol Assoc J. 2010;4:380-384. 6. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-1192. 7. Toren PJ, Gleave ME. Evolving landscape and novel treatments in metastatic castrate-resistant prostate cancer. Asian J Androl. 2013;15:342-349. 8. Seruga B, Tannock IF. Chemotherapy-based treatment for castration-resistant prostate cancer. J Clin Oncol. 2011;29:3686-3694. 9. Tannock I, Gospodarowicz M, Meakin W, et al. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic

indices of response. J Clin Oncol. 1989;7:590-597. 10. Tannock IF, de Wit R, Berry WR, et al; for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 11. Zytiga (abiraterone acetate) tablets [prescribing information]. Horsham, PA: Janssen Biotech, Inc; December 2012. 12. Jevtana (cabazitaxel) injection [prescribing information]. Bridgewater, NJ: sanofi-aventis US LLC; 2013. 13. Provenge (sipuleucel-T) suspension [prescribing information]. Seattle, WA: Dendreon Corporation; June 2011. 14. Xtandi (enzalutamide) capsules [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; August 2012. 15. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guideline®): prostate cancer. Version 2.2013. March 11, 2013. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed May 21, 2013. 16. Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43:1130-1139. 17. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373-383. 18. Scher HI, Fizazi K, Saad F, et al. Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor. J Clin Oncol. 2013;31(6 suppl 6):Abstract 6. 19. MacVicar GR, Hussain MH. Emerging therapies in metastatic castration-sensitive and castration-resistant prostate cancer. Curr Opin Oncol. 2013;25:252-260. 20. Heidenreich A, Rawal SK, Szkarlat K, et al. A randomized, double-blind, multicenter, phase 2 study of a human monoclonal antibody to human αν integrins (intetumumab) in combination with docetaxel and prednisone for the first-line treatment of patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2013;24: 329-336. 21. Higano CS, Crawford ED. New and emerging agents for the treatment of castration-resistant prostate cancer. Urol Oncol. 2011;29(6 suppl):S1-S8.

Stakeholder Perspective

“Roid Rage” By Atheer A. Kaddis, PharmD Senior Vice President, Sales and Business Development, Diplomat Specialty Pharmacy, Flint, MI

o not let the title of this perspective confuse you. The article by Lafeuille and colleagues in the current issue of American Health & Drug Benefits has nothing to do with anabolic steroids or the “rage” that occurs in some individuals who utilize them.1 Rather, the article by Lafeuille and colleagues focuses on the real- world use of corticosteroids in patients being treated for metastatic castration-resistant prostate cancer (mCRPC). PAYERS: The issue of corticosteroid use in patients with mCRPC has received attention recently because of the new therapies that have been approved by the US Food and Drug Administration (FDA) for this condition that do not require the use of concomitant corticosteroid therapy. This is a significant advance in the treatment of patients with mCRPC, because corticosteroids, although effective at reducing side effects of chemotherapy and hormonal treatments as well as ameliorating some of the symptoms of the disease, also contribute some potentially troubling side effects. These side effects can include, among

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others, fungal infections, down regulation of the immune system, diabetes, weakening of bones, and stomach ulcer.2 The article by Lafeuille and colleagues shows that corticosteroids are used by more than 70% of patients over their entire course of mCRPC treatment. Furthermore, more than 90% of the patients who receive docetaxel (Taxotere), the most frequently used chemotherapy agent for mCRPC, also receive corticosteroids. And approximately 50% of patients receiving hormonal treatment for mCRPC also receive corticosteroids. There is some good news to report here. The fact that patients are receiving corticosteroids concomitantly with chemotherapy and hormonal therapies shows that guidelines for the treatment of mCRPC and FDA-approved labeling for the specific medications were being followed during the period when the data were culled for the present article by Lafeuille and colleagues. The important question now is whether we can offer

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Stakeholder Perspective Continued patients with mCRPC the opportunity to achieve positive outcomes using a corticosteroid-free regimen for the management of their cancer. The most common firstline chemotherapy treatment today for mCRPC is docetaxel, and the standard regimen requires the concomitant use of corticosteroids. Docetaxel may be replaced by abiraterone (Zytiga) in the near future, because abiraterone has also been approved by the FDA as first-line therapy for mCRPC.3 Abiraterone is an oral medication and also has to be administered with concomitant corticosteroids. Other agents that are growing in popularity are enzalutamide (Xtandi), cabazitaxel (Jevtana), and sipuleucel-T (Provenge). Of these additional therapies, enzalutamide has the greatest opportunity to offer a corticosteroid-free regimen for mCRPC. Enzalutamide therapy does not require concomitant corticosteroid administration.4 The challenge today is that enzalutamide is FDA approved as a second-line therapy for mCRPC. This means that patients might have already received corticosteroids during first-line treatment.

PROVIDERS/PATIENTS: The other troubling information contained in the present article by Lafeuille and colleagues is that approximately 48% of patients who received enzalutamide also received concomitant corticosteroid therapy. Here lies the dilemma. Regardless of whether newer therapies require concomitant corticosteroid administration, the likelihood is that these agents will continue to be prescribed for patients with mCRPC, because they also provide support for the management of symptoms associated with prostate cancer. They are not only used to manage the side effects of chemotherapy and hormonal therapy, they are part of the treatment regimen for patients with mCRPC in general, and thus continues the “roid rage.” 1. Beaver KM, Vaughn MG, Delisi M, Wright JP. Anabolic-androgenic steroid use and involvement in violent behavior in a nationally representative sample of young adult males in the United States. Am J Public Health. 2008;98:2185-2187. 2. MedlinePlus. Prednisone. www.nlm.nih.gov/medlineplus/druginfo/meds/a601102. html#side-effects. Accessed July 5, 2013. 3. National Comprehensive Cancer Network. NCCN Guidelines Version 4.2013. Prostate Cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed July 5, 2013. 4. Xtandi (enzalutamide) capsules for oral use [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012.

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In the fight against active, autoantibody-positive systemic lupus erythematosus (SLE) in adult patients receiving standard therapy

Add BENLYSTA to Help Make SLE More Manageable When added to standard therapy, BENLYSTA significantly reduced disease activity vs standard therapy alone at Week 521

•

BENLYSTA 10 mg/kg + standard therapy demonstrated superior efficacy vs placebo + standard therapy in reducing disease activity at Week 52 in 2 Phase III trials (Total N=1684)1-3

•

The primary endpoint was the percentage of patients meeting the SLE Responder Index (SRI) at Week 52. The SRI components measure reduction in disease activity defined as clinical improvement (SELENA-SLEDAI*) with no significant worsening in any organ system (BILAG†) and no worsening in overall patient condition (PGA‡)1

– •

A Phase II trial (Total N=449) did not meet the prespecified co-primary endpoints of percent change in SELENA-SLEDAI at Week 24 and time to first flare over 52 weeks. The Phase II trial led to the selection of a targeted autoantibody-positive population in the Phase III trials (28% of the Phase II trial population was autoantibody negative at baseline) 4

In Phase II and III clinical trials, 1458 patients with SLE have been exposed to BENLYSTA for a total of 1516 patient-years2-5

* SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment Version of the Systemic Lupus Erythematosus Disease Activity Index). † BILAG (British Isles Lupus Assessment Group). ‡ PGA (Physician’s Global Assessment).

Indication BENLYSTA is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy. Limitations of Use: The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations. How supplied: BENLYSTA is available as 120 mg in a 5-mL single-use vial and 400 mg in a 20-mL single-use vial for injection, for intravenous use only.

Important Safety Information for BENLYSTA CONTRAINDICATION BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab.

WARNINGS AND PRECAUTIONS MORTALITY There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred in the following groups: 3/675 in placebo, 5/673 in BENLYSTA 1 mg/kg, 0/111 in BENLYSTA 4 mg/kg, and 6/674 in BENLYSTA 10 mg/kg. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide. SERIOUS INFECTIONS Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Caution should be exercised when considering use in patients with a history of chronic infections. Patients receiving therapy for a chronic infection should not receive BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while receiving BENLYSTA. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.

Please see additional Important Safety Information for BENLYSTA on following page. Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent pages.

www.GSKSource.com

Important Safety Information for BENLYSTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) MALIGNANCY The impact of treatment with BENLYSTA on the development of malignancies is not known. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk of malignancies. HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS) AND INFUSION REACTIONS Hypersensitivity reactions, including anaphylaxis and death, have been reported with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Some patients received premedication; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of these reactions. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Manifestations of hypersensitivity included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. In the event of a serious hypersensitivity reaction, discontinue BENLYSTA immediately and administer appropriate medical therapy. Infusion-associated adverse events were also reported. Serious infusion reactions included bradycardia, myalgia, headache, rash, urticaria, and hypotension. In the event of an infusion reaction, the infusion rate may be slowed or interrupted. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur. DEPRESSION In clinical trials, psychiatric events (primarily depression, insomnia, and anxiety) were reported more frequently with BENLYSTA than with placebo. Serious psychiatric events, serious depression, and two suicides were also reported. It is unknown if BENLYSTA treatment is associated with increased risk for these events. Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes. IMMUNIZATION Live vaccines should not be given for 30 days before or concurrently with BENLYSTA. BENLYSTA may interfere with the response to immunizations. USE WITH BIOLOGIC THERAPIES OR IV CYCLOPHOSPHAMIDE BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or IV cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with these therapies.

ADVERSE REACTIONS The most commonly reported adverse reactions (≥5%) were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

Other Important Information for BENLYSTA USE IN SPECIFIC POPULATIONS Pregnancy: Category C. BENLYSTA should be used during pregnancy only if the potential benefit outweighs the risk. Women of childbearing potential should use adequate contraception during BENLYSTA treatment and for at least 4 months after the last dose. Pregnancy Registry: Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296. Effect in black/African American patients: In exploratory analyses of 2 Phase III trials, response rates were lower for black patients (N=148) in the BENLYSTA group relative to black patients in the placebo group. In the Phase II trial, black patients (N=106) in the BENLYSTA group did not appear to have a different response than the rest of the study population. Although no definitive conclusions can be drawn from these analyses, caution should be used when considering BENLYSTA for black/African American patients. References: 1. BENLYSTA [package insert]. Rockville, MD: Human Genome Sciences, Inc; 2012. 2. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721-731. 3. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918-3930. 4. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 2009;61(9):1168-1178. 5. Data on file, Human Genome Sciences, Inc.

Please see Brief Summary of Prescribing Information for BENLYSTA on adjacent pages.

BRIEF SUMMARY BENLYSTA® (belimumab) for injection, for intravenous use only. The following is a brief summary only; see full Prescribing Information for complete product information. INDICATIONS AND USAGE BENLYSTA® (belimumab) is indicated for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy. Limitations of Use The efficacy of BENLYSTA has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. BENLYSTA has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations. CONTRAINDICATIONS BENLYSTA is contraindicated in patients who have had anaphylaxis with belimumab. WARNINGS AND PRECAUTIONS Mortality There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg groups, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease and suicide. Serious Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting BENLYSTA therapy in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely. In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred in 0.3% (4/1458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo. Malignancy The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. As with other immunomodulating agents, the mechanism of action of BENLYSTA could increase the risk for the development of malignancies. Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. Delay in the onset of acute hypersensitivity reactions has been observed. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions. BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of a hypersensitivity reaction and instructed to seek immediate medical care should a reaction occur. Infusion Reactions In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity

reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (≥ 3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions]. Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [see Adverse Reactions]. BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely. Depression In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if BENLYSTA treatment is associated with increased risk for these events. Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes. Immunization Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations. Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2133 patients in 3 controlled studies. Patients received BENLYSTA at doses of 1 mg/kg (N=673), 4 mg/kg (N=111; Trial 1 only), or 10 mg/kg (N=674) or placebo (N=675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In two of the studies (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other study (Trial 2) treatment was given for 72 weeks [see Clinical Studies]. Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo. The population had a mean age of 39 (range 18-75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with BENLYSTA reported an adverse reaction compared with 92% treated with placebo. The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively) [see Warnings and Precautions]. The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis. The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA and 7.1% for patients receiving placebo. The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1.0% placebo). Brief summary of Prescribing Information continued on reverse.

Table 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.

Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to BENLYSTA, a pregnancy registry has been established. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-681-6296.

Table 1. Incidence of Adverse Reactions Occurring in at Least 3% of Patients Treated With BENLYSTA 10 mg/kg Plus Standard of Care and at Least 1% More Frequently Than in Patients Receiving Placebo plus Standard of Care in 3 Controlled SLE Studies

Nursing Mothers It is not known whether BENLYSTA is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys. Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.

Preferred Term Nausea Diarrhea Pyrexia Nasopharyngitis Bronchitis Insomnia Pain in extremity Depression Migraine Pharyngitis Cystitis Leukopenia Gastroenteritis viral

BENLYSTA 10 mg/kg + Standard of Care (n = 674) %

Placebo + Standard of Care (n = 675) %

15 12 10 9 9 7 6 5 5 5 4 4 3

12 9 8 7 5 5 4 4 4 3 3 2 1

Immunogenicity In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known. The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS Formal drug interaction studies have not been performed with BENLYSTA. In clinical trials of patients with SLE, BENLYSTA was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated [see Pharmacokinetics]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well-controlled clinical studies using BENLYSTA in pregnant women. Immunoglobulin G (IgG) antibodies, including BENLYSTA, can cross the placenta. Because animal reproduction studies are not always predictive of human response, BENLYSTA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with BENLYSTA and for at least 4 months after the final treatment. Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5 and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24% and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8% and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of IgM in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.

Pediatric Use Safety and effectiveness of BENLYSTA have not been established in children. Geriatric Use Clinical studies of BENLYSTA did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients. Race In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects in the BENLYSTA group relative to black subjects in the placebo group [see Clinical Studies]. Use with caution in black/AfricanAmerican patients. OVERDOSAGE There is no clinical experience with overdosage of BENLYSTA. Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg. PATIENT COUNSELING INFORMATION See Medication Guide. Advice for the Patient Patients should be given the Medication Guide for BENLYSTA and provided an opportunity to read it prior to each treatment session. It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed. Mortality: Patients should be advised that more patients receiving BENLYSTA in the main clinical trials died than did patients receiving placebo treatment [see Warnings and Precautions]. Serious Infections: Patients should be advised that BENLYSTA may decrease their ability to fight infections. Patients should be asked if they have a history of chronic infections and if they are currently on any therapy for an infection [see Warnings and Precautions]. Patients should be instructed to tell their healthcare provider if they develop signs or symptoms of an infection. Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of anaphylaxis, including wheezing, difficulty breathing, peri-oral or lingual edema, and rash. Patients should be instructed to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of BENLYSTA [see Warnings and Precautions]. Depression: Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes. [see Warnings and Precautions]. Immunizations: Patients should be informed that they should not receive live vaccines while taking BENLYSTA. Response to vaccinations could be impaired by BENLYSTA [see Warnings and Precautions]. Pregnancy and Nursing Mothers: Patients should be informed that BENLYSTA has not been studied in pregnant women or nursing mothers so the effects of BENLYSTA on pregnant women or nursing infants are not known. Patients should be instructed to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations]. Patients should be instructed to tell their healthcare provider if they plan to breastfeed their infant [see Use in Specific Populations]. BENLYSTA is a registered trademark of Human Genome Sciences, Inc., used under license by GlaxoSmithKline. Manufactured by: Human Genome Sciences, Inc. Rockville, Maryland 20850 U.S. License No. 1820 Marketed by:

Human Genome Sciences, Inc. Rockville, MD 20850

GlaxoSmithKline Research Triangle Park, NC 27709

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Original Article

Perspectives of Quality Care in Cancer Treatment: A Review of the Literature Lisa M. Hess, PhD; Gerhardt Pohl, PhD Background: Approximately 1.7 million Americans are diagnosed with cancer annually. There is an increasing demand for high-quality cancer care; however, what constitutes quality care is not well defined. There remains a gap in our knowledge regarding the current perceptions of what defines quality care. Objective: To review the current understanding and perspectives of key stakeholders regarding quality cancer care for adult patients with cancer who are receiving chemotherapy-based treatment regimens. Methods: This systematic qualitative literature review involved a search of MEDLINE and PubMed databases for articles that were published between January 2009 and May 2013 using a predefined search strategy with specific Medical Subject Headings terms encompassing 3 core concepts—cancer, chemotherapy, and quality of healthcare. Articles were eligible to be included if they focused on adult cancers, discussed quality indicators of cancer care or quality of care in the article’s body, discussed treating cancer with chemotherapy, were conducted in the United States and with US respondents, and reported data about cancer quality that were obtained directly from stakeholders (eg, patients, caregivers, providers, payers, other healthcare professionals). Thematic analyses were conducted to assess the perspectives and the intersection of quality care issues from each stakeholder group that was identified, including patients, providers, and thought leaders. Results: The search strategy identified 542 articles that were reviewed for eligibility. Of these articles, 15 were eligible for inclusion in the study and reported perspectives from a total of 4934 participants. Patients with cancer, as well as providers, noted information needs, psychosocial support, responsibility for care, and coordination of care as important aspects of quality care. Providers also reported the importance of equity in cancer care and reimbursement concerns, whereas patients with cancer considered the timeliness of care an important factor. The perspectives of thought leaders focused on barriers to and facilitators of quality care. Conclusion: Thematic elements related to cancer quality were relatively consistent between patients and providers; no additional information was found regarding payer perspectives. The perspectives of these groups are important to consider as quality initiatives are being developed.

ccording to the American Cancer Society, more than 1.6 million people will receive a new diagnosis of cancer in 2013.1 It is also estimated that there were almost 14 million cancer survivors (ie, any living person who has ever received a diagnosis of cancer) in the United States in 2012.2 Although many agDr Hess is Principal Research Scientist, US Health Outcomes and Health Technology Assessment, Eli Lilly and Company, Indianapolis, IN, and Adjunct Professor, Schools of Medicine and Public Health, Indiana University, Indianapolis; Dr Pohl is Research Advisor, Statistics, Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, IN.

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Am Health Drug Benefits. 2013;6(6):321-329 www.AHDBonline.com Disclosures are at end of text

gressive forms of cancer still exist, individuals who receive a diagnosis of cancer today are less likely to die from their disease than in the past; the death rate from cancer has decreased by 20% since 1991.1 However, the number of cancer diagnoses is increasing, and it is expected that there will be more than 18 million cancer survivors in the United States in the next decade.2 Representing a set of heterogeneous diseases, the term “cancer” refers to a diagnosis that is increasingly becoming a chronic condition. Patient care is shifting from a model that was focused on the immediate need to treat the tumor to a more holistic approach in the care of the patient to ensure both quantity and quality of life. The consideration of these needs begins before the active

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Key Points With an increasing number of cancer diagnoses and the development of quality initiatives, there is a growing demand for high-quality cancer care. ➤ However, quality care is currently ill-defined, and a uniform understanding of what constitutes quality care is still lacking. ➤ This study sought to describe perspectives of various stakeholders about quality cancer care. ➤ Using search criteria that included cancer, chemotherapy, and quality healthcare, 15 articles published between January 2009 and May 2013 were eligible for inclusion, representing perspectives from a total of 4934 patients with cancer, providers, caregivers, and thought leaders. ➤ Information needs, psychosocial support, responsibility for care, and coordination of care were indicated by patients and providers as important components of quality cancer care. ➤ Providers also noted the importance of equity in cancer care and reimbursement concerns. ➤ Perspectives from thought leaders focused on barriers to and on facilitators of quality care. ➤ These themes can serve as a starting point for future initiatives designed to improve quality cancer care and help identify quality measures that are important to patients and providers. ➤

treatment phase and continues after the transition to long-term survivorship. This shift from acute cancer care to treating cancer as a chronic disease has corresponded with the more recent focus on quality cancer care; however, the relationship between these trends and general attitudes about cancer care is unclear. A number of cancer quality–focused initiatives are ongoing to ensure and assess the quality of cancer care in the United States. These range from legal requirements, such as the Quality Reporting Program for Prospective Payment System–Exempt Cancer Hospitals (Patient Protection and Affordability Care Act, Section 2701 includes mandatory quality reporting requirements, and Section 3005 is specific to cancer hospitals),3 to completely voluntary quality initiatives, such as the Quality Oncology Practice Initiative (QOPI) and its certification system,4 and initiatives led by the Institute of Medicine, such as Improving the Quality of Cancer Care: Addressing the Challenges of an Aging Population (www.iom. edu/Activities/Quality/QualityCancerCareAging.aspx). Cancer quality measures are being developed by many

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groups with different or overlapping goals. For example, the National Quality Forum (NQF) (www.quality forum. org) sets standards and recommends and endorses measures for quality performance in anticipation of the increase in pay-for-performance reimbursement systems. The Physician Quality Reporting System (PQRS), which is sponsored by the Centers for Medicare & Medicaid Services (www.cms.gov/PQRS), is focused on payment incentives and adjustments to enhance quality reporting measures.3 Measures may be coendorsed by the NQF and the PQRS. The National Committee for Quality Assurance (www.ncqa.org) is a not-for-profit organization that is focused on care structure and the process of care delivery, and it offers a variety of accreditation and certification programs to ensure quality care. The largest oncologist organization in the United States, the American Society of Clinical Oncology (ASCO), initiated the QOPI program to be a physician-led initiative that promotes improvement in cancer care by oncologists through self-assessment via specific retrospective chart review procedures.4 The National Comprehensive Cancer Network (NCCN) collaborated with ASCO to develop a set of measures that are now being used in the QOPI program. The Community Oncology Alliance (www.communityoncology.org) is a nonprofit organization that is designed to protect the community oncology care delivery system in the United States, with the primary goal of ensuring patient access to quality cancer care. Many other specialist organizations (eg, Society of Thoracic Surgeons, American Medical Association, College of American Pathologists) have measures that are focused on specific cancers that are not part of the larger disease site–specific measures that are already within the NQF and PQRS tools. As the measures are being developed, what is being measured will ultimately determine how quality is defined; hence the importance of efforts to develop the measures that will assess what is important to the key stakeholders in cancer care (ie, the patients, providers, and payers) cannot be understated. Patients, caregivers, providers, managed care organizations, payers, and other stakeholder groups have all communicated their interests in improving the quality of cancer care. However, what a patient defines as quality care may not always correspond with how the groups that are developing the key quality measures perceive as quality care. Improvement in quality care could have a very different inherent meaning across stakeholder groups, and discrepancies in values may not be reflected in the measures being created by the various groups. Therefore, it is important to understand the values of each stakeholder through their perceptions of quality in cancer care.

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As measures are being developed, it will be important that the patient voice, as well as the voices of others, be adequately represented, or there will be a risk of focusing quality-of-care improvement efforts in such a way as to have no meaning to the recipient of that care. A previous literature review was conducted by Eli Lilly and Company (Indianapolis, IN) and RTI Health Solutions (Research Triangle Park, NC) on perspectives of quality care in the published literature from 1996 through 2009.5 The study identified 25 published articles that assessed perspectives of quality care. The authors reported the key promoters to quality that were identified by patients (eg, communication, trust, caring behavior and comfort, social and spiritual support), barriers to quality care that were identified by patients (eg, getting health information, lack of coordinated care, lack of psychosocial care, delays in care, billing issues), concerns of providers (eg, workload or administrative burden, lack of coordinated care, bureaucracy of managed care, lack of processes to support treatment guidelines), and the strategies being implemented by managed care to address cancer quality (eg, decision support tools, pathways, guidelines, and cost reduction strategies).5 Each of these perspectives provides insight as to how quality care is interpreted and defined. However, the payer–provider–patient landscape has been changing rapidly in recent years, and trends and perspectives are likely to have changed since 2009. Therefore, we repeated the search strategy in this present study to provide a more current overview of the state of the science related to perspectives on quality in cancer care from January 2009 through May 2013.

Methods MEDLINE and PubMed databases were searched systematically for publications related to cancer that were published between January 2009 and May 2013. The PubMed Medical Subject Headings (MeSH) terms that were used in this study include “neoplasms/drug therapy,” “cancer care facilities,” and “oncology service, hospital.” The MeSH terms that were used to capture studies on quality of care are “quality of health care,” “quality assurance, health care,” and “quality indicators, health care.” Additional articles were obtained from the selected article bibliographies and from online searches informed by content from the selected articles. Each article obtained through the predefined MeSH terms search strategy and hand-searching method was reviewed for eligibility. Articles were eligible for inclusion if they met all the following criteria—(1) the article was focused on adult cancers, (2) quality indicators of cancer care or of quality of care were discussed in the article body, (3) the article discussed chemotherapy treatment for can-

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Figure 1 CONSORT Diagram 542 articles identified in search strategy Reasons for exclusion, N = 527 Case report, N = 3 Commentary/editorial, N = 7 End-of-life/palliative care, N = 9 No chemotherapy, N = 25 No data presented, N = 15 Not US study, N = 79 Pediatric cancer, N = 1 Not oncology, N = 12 Not about quality, N = 363 Review, N = 10 Screening focus, N = 3

15 eligible articlesa 1 article related to thought leaders 10 articles related to patients and caregivers

1 article addressed to both

3 articles related to providers

No new studies were identified that presented managed care or payer perspectives

References 6-20.

cer, (4) the study was conducted in the United States and with US respondents, and (5) the article reported data about cancer quality that were obtained directly from various stakeholder groups (ie, patients, caregivers, providers, payers, other healthcare professionals). An article was ineligible for inclusion if it did not present any perspectives on cancer quality care, if it focused on pediatric oncology, if it was not related to oncology or cancer, or if it did not include perspectives on the chemotherapy treatment period. To be consistent with the previous review by Colosia and colleagues,5 studies were also deemed ineligible if they only addressed quality of survivorship, end-of-life care, supportive care, or hospice care for patients with cancer; if they only addressed quality of preventive or screening services for cancer prevention or early detection; if they addressed quality-of-care delivery methods; if the article had been included in that earlier review5; or if the article type was a review, editorial or letter to the editor, case report, news report, meeting summary report, or a commentary.

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Table 1 Eligible Studies: 15 Publications, 4934 Participants Stakeholder group(s), N

Study design

Primary objective of study

Data source

Taplin et al, 20107

Patients, 6

Retrospective

To understand process of care and quality perspectives

Interview

Dulko and Mooney, 20108

Patients, 92

Cross-sectional

To understand patient perception of quality care

Survey

Scandrett et al, 20109

Patients, 159

Pre-/post-design

To compare quality of care with or without intervention

Survey

Teno et al, 200910

Patients, 206

Longitudinal

To measure quality-of-care concerns of patients

Survey

Roundtree et al, 201111

Patients, 33

Retrospective

To describe perceptions about care

Thind et al, 2010

Patients, 924

Cross-sectional

To identify factors in satisfaction related to quality care

Survey

Patients, 2018

Cross-sectional

To assess the relationship between quality and willingness to recommend

Survey

Tsianakas et al, 201214

Patients, 95

Cross-sectional

To compare interviews to surveys to understand priorities for quality improvement

Bickell et al, 201215

Patients, 374

Longitudinal

To describe perceptions of quality care

Survey

Landercasper et al, 201016

Patients, 234

Retrospective

To assess relationship between timeliness and patient satisfaction

Survey

Wagner et al, 201017

Patients/ caregivers, 39 Providers, 15

Retrospective

To assess barriers and facilitators to quality care

Focus group

Nelson, 201118

Providers, 20

Longitudinal

To describe perceptions of staffing for quality care

Interview

Bunnell et al, 2013

Providers, 74

Pre-/post-design

To measure changes in perceptions of quality care

Survey

Burg et al, 2010

Providers, 622

Cross-sectional

To describe barriers to quality patient care

Survey

Thought leaders, 23

Cross-sectional

To assess barriers and facilitators to quality care

Study

Lis et al, 2011

Aiello Bowles et al, 20086

Focus group

Survey/ interview

Interview

Figure 2 Patient Perspectives of Quality Cancer Care Lack of information

Information Psychosocial support system

Personalized care

Communication

Patients: what defines quality

Clarity in who has responsibility for care

Coordination of care

Providers who do not work as a team/coordination of care

Timeliness of care

Patients: barriers to quality

Lack of communication

Lack of attention to care

Source: References 7-17.

The following data were extracted from each eligible article or abstract: type of study, sample size, study population demographics, disease site(s), and survey instruments or questionnaires that were administered. The

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thematic qualitative data extraction initially focused on the themes within the earlier review by Colosia and colleagues.5 The articles were further culled for emerging themes that were not previously identified and were re-

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Table 2 Content of Patient-Reported Cancer Quality Themes Patient theme

Content

Information

Defining: help patients and families find reputable websites; navigators to help patients participate in decision-making; knowledge of how to manage side effects; care team helping patient to understand diagnosis; written information on what to expect during treatment, side effects, and what to do at home; knowing who to ask when there are questions Barriers: patients overwhelmed by amount of, complexity of, and conflicts in information; patient education provided after major decisions have been made; lack of awareness of what was going to happen, procedures not explained; not understanding test results; contradictory information; not knowing where to call after hours

Communication

Defining: high ratings of communication correspond to high ratings of quality care Barriers: inaccurate/contradictory information from interactions with providers; understandability of instructions or information given at diagnosis and during treatment decision-making

Coordination of care

Defining: find a “one-stop shopping” approach to cancer care; enhanced role of primary care provider during treatment; all providers working as a team Barriers: lack of teamwork among a variety of healthcare providers; disorganization between providers; lack of single source of information on treatment history, tests, and billing; primary care does not understand cancer and specialist is only familiar with cancer

Timeliness of care

Defining: patients getting a more rapid diagnosis and are more satisfied with care; timely care is in accordance with patient preferences, not just shorter time Barriers: problems with appointment systems or waiting times lead to missed appointments; takes too long to reach a provider when there is an urgent issue; delays during the diagnostic period increased distress; long wait times add to patient stress

Responsibility for care

Participatory decision-making associated with greater satisfaction; need to have clarity in who is responsible for which part of care; patients do not want to be left with the responsibility of making sure things are done correctly

Personalized care

Being cared for as a person rather than just as a patient; “whole person” approach to care; provider and staff knows you by name; high ratings of treatment by providers associated with willingness to recommend provider

Psychosocial support

Need for peer and professional psychosocial support for patients; need for emotional support from the healthcare provider; services need to be introduced earlier in the care plan; social support from family and friends

Lack of attention to care

Providers do not pay enough attention to the individual’s care; patients have insufficient amount of time with the provider; lack of attention during inpatient stay and lack of respect have an impact on recovery

Source: References 7-17.

lated to cancer care quality from each perspective. Finally, the qualitative analysis assessed the intersection of quality care issues from the various perspectives.

Results The search strategy identified 542 articles that were reviewed for eligibility (Figure 1, page 323). Of these articles, 15 were eligible for inclusion and reported perspectives from patients, providers, caregivers, and thought leaders (Table 1, page 324).6-20 The primary reasons for article ineligibility included a lack of information on cancer quality (N = 363), data from outside of the United States (N = 79), and not fo-

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cusing on quality of care during chemotherapy (N = 25). Of the eligible articles, 10 articles focused solely on the perspectives of patients and caregivers7-16; 3 articles focused on the perspectives of providers18-20; and 1 article covered both perspectives.17 One article presented the perspectives of thought leaders,6 and no new articles were identified that presented the perspectives of managed care or of payers.

Patient Perspectives Of the eligible articles, 11 included perspectives from 4180 patients with cancer and caregivers.7-17 Of the 5 studies that reported age, the mean age of patients was

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Figure 3 Provider Perspectives of Quality Cancer Care

Lack of psychosocial support for patients

Lack of clarity for who is accountable for care

Lack of coordination of care

Providers: barriers to providing quality care

Reimbursement policies

Provider workload

Patient access to care

Accountability for metrics Reimbursement supports patientcentered care

Patient psychosocial support programs

Timeliness of care

Multidisciplinary teams

Providers: suggestions to improve quality

Equitable access for rural/low-income populations

Patient education/ information needs

Collegial relationships

Online scheduling/electronic medical systems

Source: References 7-17.

55.7 years.9,11,13,15 Five studies were limited to patients with breast cancer,11,12,14-16 5 studies included various tumor types (primarily breast, colon, lung, prostate, cervical, pancreatic, and hematologic malignancies),7-10,13 and 1 study did not provide information on the tumor type of the patients who were included in the study.17 A number of key themes emerged related to the perspectives of patients with cancer regarding quality care (Figure 2, page 324). Examples of content from the eligible articles supporting these themes is provided in Table 2 (page 325).7-17 The themes defining quality care included information for patients, communication between patients and providers, coordination of care, timeliness of care, responsibility for care, personalized care, and psychosocial support. Three of these themes (ie, coordination of care, communication, and information) were also considered barriers to quality care if they were not met, along with the final theme of a lack of attention to care, which was a patient-reported barrier to healthcare quality.7,9-11,14,17

Provider Perspectives Provider perspectives were obtained from 731 physicians, nurses, social workers, and clinic staff. Their perspectives included recommendations to improve quality, such as accountability for metrics of care, the use of multidisciplinary teams, collegial relationships among the provider team, electronic medical and scheduling systems, equitable access to care, patient psychosocial support programs, and reimbursement programs that support the use of patient-centered care (Figure 3).17-20 Providers noted that barriers to quality care included a lack of clarity regarding who is responsible for the patientâ&#x20AC;&#x2122;s care, lack of coordination of care, provider work-

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load, challenges with the timeliness of care, patient education and information needs, barriers to patient access to care, reimbursement policies, and the lack of psychosocial support programs (Figure 3). Examples of the content that was associated with these themes is summarized in Table 3.17-20

Thought Leader Perspectives Perspectives were obtained from 23 thought leaders in one study.6 The barriers to quality care noted in this study included a lack of standardization and a lack of adherence to guidelines, difficulty in scheduling appointments, patient out-of-pocket costs, reimbursement policies, a lack of documentation, a lack of teamwork and care coordination, low provider awareness of new research, patient anxiety, and a lack of patient awareness and education.6 Some of the facilitators that were reported to improve quality care included real-world data, shared decision-making, interactive websites, electronic medical records and other information technology innovations, patient navigators and family or social support, outcomes-based performance measures, and risk-adjusted reimbursement policies.6 Discussion This study has updated an earlier review of perspectives of quality care in cancer, because there have been more recent initiatives and mandates related to quality healthcare.3 In the previous review, 25 sources were identified that reported perspectives of quality care over a 13-year period.5 The current study identified an additional 15 articles that were published within the past 4 years (from 2009 to 2013), representing a much shorter

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Table 3 Content of Provider-Reported Cancer Quality Themes Provider theme Access to care

Content Barrier: racial, ethnic, socioeconomic, and geographic disparities; childcare/eldercare needs; low income and uninsured difficulties in accessing services; inadequate insurance Recommendation: use of telemedicine for rural care; increased linkages between cancer centers and safety net hospitals

Reimbursement policies

Barrier: no reward for services that provide information or supportive care; reimbursement discourages patient-centered care Recommendation: financial incentives/changes in reimbursement that encouraged patientcentered services

Lack of psychosocial support services for patients

Barrier: patients experience fear, anxiety, depression, and distress; lack of systematic assessment of or attention to psychosocial issues

Accountability for care/ metrics of care

Lack of clarity in who guides patient care before and after therapy for cancer; integrated cancer care services will help support accountability; published performance measures

Coordination of care

Lack of coordination before and after treatment period; multidisciplinary care starts too late, after treatment is already initiated; no clear provider at time of arrival to oncology; difficulty communicating with off-site providers

Provider workload

Inadequate staffing leads to alteration, elimination, or delay in patient care and increases concerns about safety; nursing fills in for missing support services, thereby impacting quality care

Timeliness of care

Unclear accountability and inadequate staffing contributes to delays in care; care managers could facilitate this

Patient education/ information

Patient navigators to help them access information; care centers vary widely in emphasis and resources devoted to educating patients; key information provided after major decisions have already been made; provider time to answer patient questions and details needed by patient takes away providerâ&#x20AC;&#x2122;s time for care of the patient

Multidisciplinary teams

Multidisciplinary teams can improve the timeliness of care; a barrier when multidisciplinary care begins after the initiation of treatment

Collegial relationships

Quality care improves when collegial relationships and good communication exist between nurses and physicians

Electronic systems

Electronic systems can improve the timeliness of care; electronic health records and patient portals could inform/connect patients to information and services; shared electronic health records can help coordinate care, facilitate provider communication, support multidisciplinary care planning, and improve safety; online appointment scheduling

Recommendation: enhancing the quality of service provision by hiring more oncology social workers and educating them in cancer care; use of patient navigators to provide support

Source: References 17-20.

period, which indicates an increasing interest in and focus on the topic of quality cancer care. Some of the themes emerging from this update are consistent with the earlier review, such as patient information needs, the importance of social support, concerns with coordination of care, provider workload, reimbursement policies, and the need for improved patient interaction and communication with providers. However, new themes emerged in the new publications related to the perspectives of providers, such as accountability for care, the desire for multidisciplinary teams, and collegial relationships among providers to enhance quality care. There were no perspectives identified in the eligible

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articles that addressed improved outcomes associated with quality care. However, the ultimate goal of quality cancer care should not only be the short-term improvements in processes, but rather improvements in patient outcomes, such as reduced toxicity resulting from supportive care, fewer hospitalizations as a result of improved healthcare delivery that can help to address concerns before they become serious or life-threatening. Recent research has demonstrated that adherence to treatment guidelines, such as guidelines published by the NCCN, are associated with improved survival outcomes.21,22 However, quality measures remain largely process-oriented, and there is an expressed need to in-

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clude additional outcomes-oriented quality measures.23 The relationship between process improvements and outcomes measures has yet to be fully demonstrated, but it may help to address this concern. The common themes that emerge in this analysis in the 2 most researched stakeholder groups—patients and providers—suggest common perceptions of quality cancer care. Patients, their caregivers, and providers all express the need for better patient information, improvements in care coordination, and for multidisciplinary care that includes psychosocial support and the importance of timeliness of care. In addition, patients desire more personalized care, improved communication with providers, and additional clarity regarding who has responsibility for their care. Overall, these findings suggest that there may be a need to develop improved initiatives that address patient–provider communication and information sharing, as well as initiatives to provide multidisciplinary care at the point of an initial diagnosis. However, there may also be barriers to these initiatives as noted by providers: their workload and their time are already restricted; there is inequitable access to care among patients (as a result of healthcare disparities, insurance issues, rural location, and out-of-pocket costs); and there is a need for appropriate reimbursement to support patient-centered care.

Limitations Although the search strategy was designed to be comprehensive, it is possible that additional publications addressing the quality of cancer care were not identified. Although MEDLINE and PubMed databases were searched, there are other sources of information, such as meeting abstracts and organization reports, that were not explored as sources of information for this study. The summaries and themes cannot necessarily be considered representative of the views of these stakeholder groups, because many of the studies identified in the literature were designed to explore specific concepts, which contributed to the themes that were chosen. There is always the risk of a subjective interpretation of common themes in a qualitative review of the literature. Although the current study focused on quality care during chemotherapy, to be consistent with the methods of the earlier review,5 there is a need to understand the quality cancer care perspectives in the survivorship community, which is not represented in this present article. In addition, because 9 articles were identified that focused on end-of-life care and up to 25 other articles that dealt with other treatment or follow-up periods during survivorship, there may be sufficient information to evaluate the perspectives of cancer care for periods of

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cancer-related care beyond the chemotherapy treatment period. The full trajectory of care throughout the survivorship period is therefore recommended as a topic for future research.

Conclusion The themes identified in this study may serve as a starting point for initiatives or programs that are designed to improve quality of cancer care and to identify measures associated with factors that are important to patients and to providers. Initiatives that focus on enhancing the quality of cancer care may need to consider the limitations and barriers to care noted in this article, especially regarding the patient–provider communication and information sharing, as well as the need for reimbursement to support patient-centered care. To increase the likelihood of success, such initiatives should include strategies to mitigate these barriers. Future studies are warranted to address the full range of quality care throughout the survivorship period and through end-of-life care, as well as to better understand payer perspectives. n Author Disclosure Statement Dr Hess is an employee of Eli Lilly and Company. Dr Pohl is an employee of and a stockholder of Eli Lilly and Company.

References

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63:11-30. 2. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220-241. 3. Patel KK, Tran L. Opportunities for oncology in the patient protection and affordable care act. Am Soc Clin Oncol Educ Book. 2013;2013:436-440. 4. Campion FX, Larson LR, Kadlubek PJ, et al. Advancing performance measurement in oncology: quality oncology practice initiative participation and quality outcomes. J Oncol Pract. 2011;7(3 suppl):31S-35S. 5. Colosia AD, Peltz G, Pohl G, et al. A review and characterization of the various perceptions of quality cancer care. Cancer. 2011;117:884-896. 6. Aiello Bowles EJ, Tuzzio L, Wiese CJ, et al. Understanding high-quality cancer care: a summary of expert perspectives. Cancer. 2008;112:934-942. 7. Taplin SH, Rodgers AB. Toward improving the quality of cancer care: addressing the interfaces of primary and oncology-related subspecialty care. J Natl Cancer Inst Monogr. 2010;2010:3-10. 8. Dulko D, Mooney K. Effect of an audit and feedback intervention on hospitalized oncology patients’ perception of nurse practitioner care. J Nurs Care Qual. 2010;25: 87-93. 9. Scandrett KG, Reitschuler-Cross EB, Nelson L, et al. Feasibility and effectiveness of the NEST13+ as a screening tool for advanced illness care needs. J Palliat Med. 2010;13:161-169. 10. Teno JM, Lima JC, Lyons KD. Cancer patient assessment and reports of excellence: reliability and validity of advanced cancer patient perceptions of the quality of care. J Clin Oncol. 2009;27:1621-1626. 11. Roundtree AK, Giordano SH, Price A, Suarez-Almazor ME. Problems in transition and quality of care: perspectives of breast cancer survivors. Support Care Cancer. 2011;19:1921-1929. 12. Thind A, Hoq L, Diamant A, Maly RC. Satisfaction with care among low-income women with breast cancer. J Womens Health (Larchmt). 2010;19:77-86. 13. Lis CG, Rodeghier M, Gupta D. The relationship between perceived service quality and patient willingness to recommend at a national oncology hospital network. BMC Health Serv Res. 2011;11:46. 14. Tsianakas V, Maben J, Wiseman T, et al. Using patients’ experiences to identify priorities for quality improvement in breast cancer care: patient narratives, surveys or both? BMC Health Serv Res. 2012;12:271. 15. Bickell NA, Neuman J, Fei K, et al. Quality of breast cancer care: perception versus practice. J Clin Oncol. 2012;30:1791-1795. 16. Landercasper J, Linebarger JH, Ellis RL, et al. A quality review of the timeliness of breast cancer diagnosis and treatment in an integrated breast center. J Am Coll Surg. 2010;210:449-455. 17. Wagner EH, Aiello Bowles EJ, Greene SM, et al. The quality of cancer patient experience: perspectives of patients, family members, providers and experts. Qual Saf

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Health Care. 2010;19:484-489. 18. Nelson BA. Healthcare team members’ perception of staffing adequacy in a comprehensive cancer center. Oncol Nurs Forum. 2011;38:52-59. 19. Bunnell CA, Gross AH, Weingart SN, et al. High performance teamwork training and systems redesign in outpatient oncology. BMJ Qual Saf. 2013;22:405-413. 20. Burg MA, Zebrack B, Walsh K, et al. Barriers to accessing quality health care for cancer patients: a survey of members of the association of oncology social work. Soc Work Health Care. 2010;49:38-52.

21. Boland GM, Chang GJ, Haynes AB, et al. Association between adherence to National Comprehensive Cancer Network treatment guidelines and improved survival in patients with colon cancer. Cancer. 2013;119:1593-1601. 22. Bristow RE, Chang J, Ziogas A, Anton-Culver H. Adherence to treatment guidelines for ovarian cancer as a measure of quality care. Obstet Gynecol. 2013;121:1226-1234. 23. Kurian AW, Edge SB. Information technology interventions to improve cancer care quality: a report from the American Society of Clinical Oncology Quality Care Symposium. J Oncol Pract. 2013;9:142-144.

Stakeholder Perspective Quality of Cancer Care: Emerging Definition and Measurements, but Reimbursement Lagging By Craig Deligdish, MD Hematologist/Oncologist, Oncology Resource Networks, Orlando, FL

The article by Dr Hess and Dr Pohl in this issue of American Health & Drug Benefits examines quality care in cancer treatment. There has recently been much focus in the mainstream media on the quality of care that is delivered in the US healthcare system, specifically in hospitals. However, the challenges that organized medicine and the general public have with identifying, or even defining, quality are problematic. POLICYMAKERS: In the past several years, the Centers for Medicare & Medicaid Services (CMS) has invested a great deal of effort in defining and measuring quality. Some of the parameters that CMS has examined include the frequency of rehospitalization within 30 days postdischarge, hospital-acquired infections, adverse events, surgical errors, and mortality. These data have mostly been aggregated by the Agency for Healthcare Research and Quality and by CMS, and have been widely reported and used to rate hospitals. In recent months, publications and organizations such as Consumer Reports, US News & World Report, The Leapfrog Group, and others have used some of these data to formulate their own rating systems for quality. Transparency and the dissemination of this information can only help patients and payers identify which organizations are committed to improving the care they deliver to patients. Nevertheless, few, if any, of these analyses measure value, because they fail to impute the cost of care, which can vary from one hospital to another by several-fold. Quality care in the treatment of patients with cancer can be even more difficult to define and measure. The American Society of Clinical Oncology has invested tremendous effort in creating the Quality Oncology Practice Initiative, and CMS has created a similar program in its Physician Quality Reporting System. Although neither program has been widely adopted, both represent impor tant efforts toward measuring and improving care quality. PROVIDERS/PATIENTS: Dr Hess and Dr Pohl re-

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view cross-sectional retrospective and longitudinal studies measuring quality in cancer care from the perspectives of patients, physicians, and other stakeholders, but payer studies are lacking. The authors should be commended for their important and timely contribution to this discussion. However, their research is focused on quality that is associated with chemotherapy; in reality, only a subset of patients with cancer receive chemotherapy, and additional studies are needed to assess the full spectrum of cancer care, including survivorship, end-of-life care, supportive care, radiation, and hospice care. Recently, Halpern and colleagues examined quality parameters in patients with cancer at community hospitals, based on 5 National Quality Forum–approved quality-of-care measures for patients with breast or colon cancer.1 They found that quality improvements were related to hospitals’ participation in the National Cancer Institute Community Cancer Centers Program compared with nonparticipating hospitals.1 The Affordable Care Act has made a tremendous financial investment in defining, measuring, and improving the quality of care for patients with cancer and other chronic diseases. The expectation is that this investment and increasing focus by researchers will better define quality and help to improve the care that patients with cancer receive in the outpatient setting and at US hospitals. PAYERS: New ongoing initiatives highlight the importance of quality of care for patients and for providers. Quality measures are being introduced into the clinical setting, but few payers are willing to reimburse providers in any significant manner for improvement in quality or outcomes. Payers need to look more closely at quality and outcomes and reassess quality measures as important components of reimbursement. 1. Halpern T, Spain P, Holden DJ, et al. Association of increases in quality of care with the NCI Community Cancer Center Program (NCCCP) pilot. J Clin Oncol. 2012;30(suppl):Abstract 6046.

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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, 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 while reducing or controlling costs, enhancing 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: • Health Information Exchange • Health Plan Initiatives • Innovations in Healthcare • Literature Reviews • Managed Care • Medicare/Medicaid • Patient Outcomes/Advocacy • Pharmacoeconomics

• Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Comparative Effectiveness Research • Decision-Making Tools • Ethics in Medicine • Health Economics Research

• Pharmacogenomics • Policy Issues • Prevention Initiatives • Real-World Evidence • Reimbursement Strategies • Social Media in Healthcare • Survey Results • Value-Based Healthcare

Clinical Topics of High Interest: Aging—With the aging of the US population there is a growing need for early implementation of outcomes-based 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 emerging therapies is a key target for improving patient outcomes and reducing costs. Cancer care—The growing focus on high-cost biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management. Cardiovascular disease—Outcomes-based research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

Diabetes, Obesity—The growing epidemics of these twin metabolic conditions mandates a thorough examination of best therapies, adherence issues, access, and prevention strategies. 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, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, adherence, best practices, and reimbursement.

Pain Management—Chronic pain is associated with many 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@engagehc.com. For more information, call 732-992-1892.

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Introducing a

NEW INDICATION in relapsed or refractory mantle cell lymphoma REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS™ program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma receiving REVLIMID with dexamethasone.

For more information, please visit www.REVLIMID.com or call 1-888-423-5436. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on the following pages. REVLIMID® is a registered trademark of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 06/13 US-REV130004

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS™ Program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndrome (MDS) had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma (MM) who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy: • REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicated that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the “RevAssist®” Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Patients may require dose interruption and/or dose reduction. MCL: Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.

Venous Thromboembolism: Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MCL treated with lenalidomide monotherapy. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after assessment of the individual patient’s underlying risk factors. Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Tumor Flare Reaction: Tumor flare reaction (TFR) occurred during investigational use of lenalidomide for chronic lymphocytic leukemia (CLL) and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL with lenalidomide outside of a well-monitored clinical trial is discouraged. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop Revlimid upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Second Primary Malignancies: Patients with MM treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. T:10.5”

B:11.125”

S:9.875”

ADVERSE REACTIONS

Mantle Cell Lymphoma • Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%) • Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia • Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%) • Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established. Geriatric Use: Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr <30 mL/min) and in patients on dialysis.

REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

REVLIMID [lenalidomide] capsules, for oral use The following is a brief summary; refer to full prescribing information for complete product information. WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2). Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s tollfree number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)]. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. 1.2 Myelodysplastic Syndromes REVLIMID is indicated for the treatment of patients with transfusiondependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. 1.3 Mantle Cell Lymphoma REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.1 Multiple Myeloma The recommended starting dose of REVLIMID is 25 mg once daily on Days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg once daily on Days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily orally on Days 1-4 every 28 days. Treatment is continued or modified based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID. Platelet counts Thrombocytopenia in MM When Platelets

Recommended Course

Fall to <30,000/mcL

Interrupt REVLIMID treatment, follow CBC weekly Restart REVLIMID at 15 mg daily

Return to ≥30,000/mcL For each subsequent drop <30,000/mcL Return to ≥30,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily

Absolute Neutrophil counts (ANC) Neutropenia in MM When Neutrophils

Recommended Course

Fall to <1000/mcL

Interrupt REVLIMID treatment, add G-CSF, follow CBC weekly Resume REVLIMID at 25 mg daily

Return to ≥1,000/mcL and neutropenia is the only toxicity Return to ≥1,000/mcL and if other toxicity

Resume REVLIMID at 15 mg daily

For each subsequent drop <1,000/mcL Return to ≥1,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily

Other Grade 3 / 4 Toxicities in MM For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MM: See Section 2.4. 2.2 Myelodysplastic Syndromes The recommended starting dose of REVLIMID is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MDS Treatment Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows: Platelet counts If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS If baseline ≥100,000/mcL When Platelets

Recommended Course

Fall to <50,000/mcL Return to ≥50,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at 5 mg daily

If baseline <100,000/mcL When Platelets

Recommended Course

Fall to 50% of the baseline value If baseline ≥60,000/mcL and returns to ≥50,000/mcL If baseline <60,000/mcL and returns to ≥30,000/mcL

Interrupt REVLIMID treatment Resume REVLIMID at 5 mg daily Resume REVLIMID at 5 mg daily

If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS When Platelets

Recommended Course

<30,000/mcL or <50,000/mcL with platelet transfusions Return to ≥30,000/mcL (without hemostatic failure)

Interrupt REVLIMID treatment Resume REVLIMID at 5 mg daily

Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows:

If thrombocytopenia develops during treatment at 5 mg daily in MDS When Platelets Recommended Course <30,000/mcL or <50,000/mcL Interrupt REVLIMID treatment with platelet transfusions Return to ≥30,000/mcL Resume REVLIMID at 2.5 mg daily (without hemostatic failure) Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows: Absolute Neutrophil counts (ANC) If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS If baseline ANC ≥1,000/mcL When Neutrophils Recommended Course Fall to <750/mcL Interrupt REVLIMID treatment Return to ≥1,000/mcL Resume REVLIMID at 5 mg daily If baseline ANC <1,000/mcL When Neutrophils Recommended Course Fall to <500/mcL Interrupt REVLIMID treatment Return to ≥500/mcL Resume REVLIMID at 5 mg daily If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS When Neutrophils Recommended Course <500/mcL for ≥7 days or <500/mcL Interrupt REVLIMID treatment associated with fever (≥38.5°C) Return to ≥500/mcL Resume REVLIMID at 5 mg daily Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows: If neutropenia develops during treatment at 5 mg daily in MDS When Neutrophils Recommended Course <500/mcL for ≥7 days or <500/mcL Interrupt REVLIMID treatment associated with fever (≥38.5°C) Return to ≥500/mcL Resume REVLIMID at 2.5 mg daily Other Grade 3 / 4 Toxicities in MDS For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MDS: See Section 2.4. 2.3 Mantle Cell Lymphoma The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to REVLIMID. Platelet counts Thrombocytopenia during treatment in MCL When Platelets Recommended Course Fall to <50,000/mcL Interrupt REVLIMID treatment and follow CBC weekly Return to ≥50,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Absolute Neutrophil counts (ANC) Neutropenia during treatment in MCL When Neutrophils Recommended Course Fall to <1000/mcL for at least Interrupt REVLIMID treatment and 7 days follow CBC weekly OR Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C OR Falls to < 500 /mcL Return to ≥1,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily

Other Grade 3 / 4 Toxicities in MCL For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MCL: See Section 2.4. 2.4 Starting Dose for Renal Impairment in MM, MDS or MCL Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MM, MDS or MCL are as follows: Table 1: Starting Dose Adjustments for Patients with Renal Impairment in MM, MDS or MCL Category

Renal Function (Cockcroft-Gault)

Moderate Renal CLcr 30-60 mL/min Impairment

Dose in MM or MCL

Dose in MDS

10 mg Every 24 hours

5 mg Every 24 hours

Severe Renal Impairment

CLcr < 30 mL/min 15 mg (not requiring dialysis) Every 48 hours

2.5 mg Every 24 hours

End Stage Renal Disease

CLcr < 30 mL/min (requiring dialysis)

2.5 mg Once daily. On dialysis days, administer the dose following dialysis.

5 mg Once daily. On dialysis days, administer the dose following dialysis.

After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described elsewhere (see section 2). 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)]. 4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.5)]. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy.

Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID. 5.2 REVLIMID REMS™ program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration (2.1, 2.2, 2.3)]. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration (2.2)]. In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)]. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous Thromboembolism Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

5.5 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. 5.6 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The 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. 5.7 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL with lenalidomide outside of a well-monitored clinical trial is discouraged. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 5.8 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop Revlimid upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.9 Second Primary Malignancies Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Allergic Reactions [see Warnings and Precautions (5.5)] • Tumor lysis syndrome [see Warnings and Precautions (5.6)] • Tumor flare reactions [see Warnings and Precautions (5.7)] • Hepatotoxicity [see Warnings and Precautions (5.8)] • Second Primary Malignancies [see Warnings and Precautions (5.9)] 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. 6.1 Clinical Trials Experience in Multiple Myeloma Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/ dexamethasone (350 patients).

In the REVLIMID/dexamethasone treatment group, 269 patients (76%) underwent at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse events were more frequent in patients who received the combination of REVLIMID/ dexamethasone compared to placebo/dexamethasone. Tables 2, 3, and 4 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups. Table 2: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex* Placebo/Dex * (n=353) (n=350) n (%) n (%) Blood and lymphatic system disorders Neutropenia % 149 (42.2) 22 (6.3) Anemia @ 111 (31.4) 83 (23.7) Thrombocytopenia @ 76 (21.5) 37 (10.6) Leukopenia 28 (7.9) 4 (1.1) Lymphopenia 19 (5.4) 5 (1.4) General disorders and administration site conditions Fatigue 155 (43.9) 146 (41.7) Pyrexia 97 (27.5) 82 (23.4) Peripheral edema 93 (26.3) 74 (21.1) Chest Pain 29 ( 8.2) 20 (5.7) Lethargy 24 ( 6.8) 8 (2.3) Gastrointestinal disorders Constipation 143 (40.5) 74 (21.1) Diarrhea@ 136 (38.5) 96 (27.4) Nausea @ 92 (26.1) 75 (21.4) Vomiting @ 43 (12.2) 33 (9.4) Abdominal Pain @ 35 (9.9) 22 (6.3) Dry Mouth 25 (7.1) 13 (3.7) Musculoskeletal and connective tissue disorders Muscle cramp 118 (33.4) 74 (21.1) Back pain 91 (25.8) 65 (18.6) Bone Pain 48 (13.6) 39 (11.1) Pain in Limb 42 (11.9) 32 (9.1) Nervous system disorders Dizziness 82 (23.2) 59 (16.9) Tremor 75 (21.2) 26 (7.4) Dysgeusia 54 (15.3) 34 (9.7) Hypoaesthesia 36 (10.2) 25 (7.1) Neuropathy ª 23 (6.5) 13 (3.7) Respiratory, Thoracic and Mediastinal Disorders Dyspnea 83 (23.5) 60 (17.1) Nasopharyngitis 62 (17.6) 31 (8.9) Pharyngitis 48 (13.6) 33 (9.4) Bronchitis 40 (11.3) 30 (8.6) Infectionsb and infestations Upper respiratory tract infection 87 (24.6) 55 (15.7) Pneumonia @ 48 (13.6) 29 (8.3) Urinary Tract Infection 30 (8.5) 19 (5.4) Sinusitis 26 (7.4) 16 (4.6) Skin and subcutaneous system disorders Rash c 75 (21.2) 33 (9.4) Sweating Increased 35 (9.9) 25 (7.1) Dry Skin 33 (9.3) 14 (4.0) Pruritus 27 (7.6) 18 (5.1) (continued)

Table 2: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term Metabolism and nutrition disorders Anorexia Hypokalemia Hypocalcemia Appetite Decreased Dehydration Hypomagnesaemia Investigations Weight Decreased Eye disorders Blurred vision Vascular disorders Deep vein thrombosis % Hypertension Hypotension

REVLIMID/Dex* (n=353) n (%)

Placebo/Dex * (n=350) n (%)

55 (15.6) 48 (13.6) 31 (8.8) 24 (6.8) 23 (6.5) 24 (6.8)

34 (9.7) 21 (6.0) 10 (2.9) 14 (4.0) 15 (4.3) 10 (2.9)

69 (19.5)

52 (14.9)

61 (17.3)

40 (11.4)

33 (9.3) 28 (7.9) 25 (7.1)

15 (4.3) 20 (5.7) 15 (4.3)

Table 3: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups System Organ Class/ Preferred Term REVLIMID/Dex# Placebo/Dex# (n=353) (n=350) n (%) n (%) Eye Disorders Cataract 6 (1.7) 1 (0.3) Cataract Unilateral 5 (1.4) 0 (0.0) Psychiatric Disorder Depression 10 (2.8) 6 (1.7) Table 4: Serious Adverse Reactions Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups System Organ Class/ Preferred Term REVLIMID/Dex& Placebo/Dex& (n=353) (n=350) n (%) n (%) Blood and lymphatic system disorders Febrile Neutropenia% 6 (1.7) 0 (0.0) Vascular disorders Deep vein thrombosis% 26 (7.4) 11 (3.1) Infectionsb and infestations Pneumonia @ 33 (9.3) 21 (6.0) Respiratory, thoracic, and mediastinal disorders Pulmonary embolism@ 13 (3.7) 3 (0.9) Cardiac disorders Atrial fibrillation @ 11 (3.1) 2 (0.6) Cardiac Failure Congestive @ 5 (1.4) 0 (0.0) Nervous system disorders Cerebrovascular accident @ 7 (2.0) 3 (0.9) Gastrointestinal disorders Diarrhea @ 6 (1.7) 2 (0.6) Musculoskeletal and connective tissue disorders Bone Pain 4 (1.1) 0 (0.0) For all tables above: n – Number of Patients * - All Treatment Emergent AEs with ≥5% of Patients in REVLIMID/ Dex and at Least 2% Difference in Proportion between the Two Arms - (Safety population) # - All Treatment Emergent Grades 3 and 4 AEs with ≥1% Patients in REVLIMID/ Dex and at Least 1% Difference in Proportion between the Two Arms - (Safety population) & - All Treatment Emergent Serious AEs with ≥1% Patients in REVLIMID/ Dex and at Least 1% Difference in Proportion between the Two Arms (Safety population) @ - ADRs with Death as an outcome % - ADRs which were considered to be life threatening (if the outcome of the event was death, it is included with death cases) ª - All PTs under the MedDRA SMQ of Neuropathy of a peripheral sensory nature will be considered listed b - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed c- All PTs under HLT of Rash will be considered listed Dex=dexamethasone Median duration of exposure among patients treated with REVLIMID/ dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse events between two treatment groups REVLIMID/dexamethasone vs. placebo/ dexamethasone. Venous Thromboembolism Deep Vein Thrombosis and Pulmonary Embolism [see Warnings and Precautions (5.3)] Deep vein thrombosis (DVT) was reported as a serious adverse drug reaction (7.4%) or Grade 3/4 (8.2%) at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively. Discontinuations due to DVT adverse reactions were reported at comparable rates between groups.

Pulmonary embolism (PE) was reported as a serious adverse drug reaction including Grade 3/4 (3.7%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% in the placebo/dexamethasone group. Discontinuations due to PE adverse reactions were reported at comparable rates between groups. Other Adverse Reactions In these clinical studies of REVLIMID in patients with multiple myeloma, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation 6.2 Clinical Trials Experience in Myelodysplastic Syndromes A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse event was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions. Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events. The next most common adverse events observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 5 summarizes the adverse events that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. Table 6 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. Table 5: Summary of Adverse Events Reported in ≥5% of the REVLIMID Treated Patients in del 5q MDS Clinical Study System organ class/Preferred term [a]

10 mg Overall (N=148)

Patients with at least one adverse event

148 (100.0)

Blood and Lymphatic System Disorders Thrombocytopenia Neutropenia Anemia Leukopenia Febrile Neutropenia

91 87 17 12 8

(61.5) (58.8) (11.5) (8.1) (5.4)

Skin and Subcutaneous Tissue Disorders Pruritus Rash Dry Skin Contusion Night Sweats Sweating Increased Ecchymosis Erythema

62 53 21 12 12 10 8 8

(41.9) (35.8) (14.2) (8.1) (8.1) (6.8) (5.4) (5.4)

Gastrointestinal Disorders Diarrhea Constipation Nausea Abdominal Pain Vomiting Abdominal Pain Upper Dry Mouth Loose Stools

72 35 35 18 15 12 10 9

(48.6) (23.6) (23.6) (12.2) (10.1) (8.1) (6.8) (6.1) (continued)

Table 5: Summary of Adverse Events Reported in ≥5% of the REVLIMID Treated Patients in del 5q MDS Clinical Study System organ class/Preferred term [a]

10 mg Overall (N=148)

Respiratory, Thoracic and Mediastinal Disorders Nasopharyngitis Cough Dyspnea Pharyngitis Epistaxis Dyspnea Exertional Rhinitis Bronchitis

34 29 25 23 22 10 10 9

General Disorders and Administration Site Conditions Fatigue 46 Pyrexia 31 Edema Peripheral 30 Asthenia 22 Edema 15 Pain 10 Rigors 9 Chest Pain 8

Table 6: Most Frequently Observed Grade 3 and 4 Adverse Events [1] Regardless of Relationship to Study Drug Treatment 10 mg (N=148)

Preferred term [2] Rash

(23.0) (19.6) (16.9) (15.5) (14.9) (6.8) (6.8) (6.1) (31.1) (20.9) (20.3) (14.9) (10.1) (6.8) (6.1) (5.4)

(6.8)

Anemia

(6.1)

Leukopenia

(5.4)

Fatigue

(4.7)

Dyspnea

(4.7)

Back Pain

(4.7)

Febrile Neutropenia

(4.1)

Nausea

(4.1)

Diarrhea

(3.4)

Pyrexia

(3.4)

Sepsis

(2.7)

Dizziness

(2.7)

Granulocytopenia

(2.0)

Chest Pain

(2.0)

Pulmonary Embolism

(2.0)

Respiratory Distress

(2.0)

Pruritus

(2.0)

Pancytopenia

(2.0)

Muscle Cramp

(2.0)

Respiratory Tract Infection

(1.4)

Musculoskeletal and Connective Tissue Disorders Arthralgia Back Pain Muscle Cramp Pain in Limb Myalgia Peripheral Swelling

32 31 27 16 13 12

(21.6) (20.9) (18.2) (10.8) (8.8) (8.1)

Nervous System Disorders Dizziness Headache Hypoesthesia Dysgeusia Peripheral Neuropathy

29 29 10 9 8

(19.6) (19.6) (6.8) (6.1) (5.4)

Upper Respiratory Tract Infection

(1.4)

Asthenia

(1.4)

Multi-organ Failure

(1.4)

Epistaxis

(1.4)

Infections and Infestations Upper Respiratory Tract Infection Pneumonia Urinary Tract Infection Sinusitis Cellulitis

Hypoxia

(1.4)

22 17 16 12 8

(14.9) (11.5) (10.8) (8.1) (5.4)

Pleural Effusion

(1.4)

Pneumonitis

(1.4)

Pulmonary Hypertension

(1.4)

Vomiting

(1.4)

Sweating Increased

(1.4)

Arthralgia

(1.4)

Pain in Limb

(1.4)

Headache

(1.4)

Syncope

(1.4)

Metabolism and Nutrition Disorders Hypokalemia Anorexia Hypomagnesemia

16 15 9

(10.8) (10.1) (6.1)

Investigations Alanine Aminotransferase Increased

(8.1)

Psychiatric Disorders Insomnia Depression

15 8

(10.1) (5.4)

Renal and Urinary Disorders Dysuria

(6.8)

( 6.1)

(6.8)

(5.4)

Vascular Disorders Hypertension Endocrine Disorders Acquired Hypothyroidism Cardiac Disorders Palpitations

[1] Adverse events with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2. [2] Preferred Terms are coded using the MedDRA dictionary. A patient with multiple occurrences of an AE is counted only once in the Preferred Term category. In other clinical studies of REVLIMID in MDS patients, the following serious adverse events (regardless of relationship to study drug treatment) not described in Table 5 or 6 were reported: Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia, refractory anemia

[a] System

organ classes and preferred terms are coded using the MedDRA dictionary. System organ classes and preferred terms are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an AE is counted only once in the AE category. Table 6: Most Frequently Observed Grade 3 and 4 Adverse Events [1] Regardless of Relationship to Study Drug Treatment 10 mg (N=148)

Preferred term [2] Patients with at least one Grade 3/4 AE

131

(88.5)

Neutropenia

(53.4)

Thrombocytopenia

(50.0)

Pneumonia

(7.4)

Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardio-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, ventricular dysfunction Ear and labyrinth disorders: vertigo Endocrine disorders: Basedow’s disease Gastrointestinal disorders: gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage

(continued)

General disorders and administration site conditions: disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death Hepatobiliary disorders: hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure Immune system disorders: hypersensitivity Infections and infestations infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcal infection, urosepsis Injury, poisoning and procedural complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture Investigations: blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia Musculoskeletal and connective tissue disorders: arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate Neoplasms benign, malignant and unspecified: acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate cancer metastatic Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal cord compression, subarachnoid hemorrhage, transient ischemic attack Psychiatric disorders: confusional state Renal and urinary disorders: renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass Reproductive system and breast disorders: pelvic pain Respiratory, thoracic and mediastinal disorders: bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration, wheezing Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis Vascular system disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis 6.3 Clinical Trials Experience in Mantle Cell Lymphoma In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years. Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events. Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma System Organ Class/Preferred Term

All AEs1 (N=134)

Grade 3/4 AEs2 (N=134)

n (%)

General disorders and administration site conditions Fatigue 45 (34) Pyrexia$ 31 (23) Edema peripheral 21 (16) Asthenia$ 19 (14) General physical health deterioration 3 (2) Gastrointestinal disorders Diarrhea$ 42 (31) Nausea$ 40 (30) Constipation 21 (16) Vomiting$ 16 (12) Abdominal pain$ 13 (10)

9 (7) 3 (2) 0 4 (3) 2 (1) 8 (6) 1 (<1) 1 (<1) 1 (<1) 5 (4) (continued)

Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma System Organ Class/Preferred Term

All AEs1 (N=134)

Grade 3/4 AEs2 (N=134)

n (%)

Musculoskeletal and connective tissue disorders Back pain 18 (13) 2 (1) Muscle spasms 17 (13) 1 (<1) Arthralgia 11 (8) 2 (1) Muscular weakness$ 8 (6) 2 (1) Respiratory, thoracic and mediastinal disorders Cough 38 (28) 1 (<1) Dyspnea$ 24 (18) 8 (6) Pleural Effusion 10 (7) 2 (1) Hypoxia 3 (2) 2 (1) Pulmonary embolism 3 (2) 2 (1) Respiratory distress$ 2 (1) 2 (1) Oropharyngeal pain 13 (10) 0 Infections and infestations Pneumonia@ $ 19 (14) 12 (9) Upper respiratory tract infection 17 (13) 0 Cellulitis$ 3 (2) 2 (1) Bacteremia$ 2 (1) 2 (1) Staphylococcal sepsis$ 2 (1) 2 (1) Urinary tract infection$ 5 (4) 2 (1) Skin and subcutaneous tissue disorders Rash + 30 (22) 2 (1) Pruritus 23 (17) 1 (<1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia% $ 48 (36) 37 (28) Anemia$ 41 (31) 15 (11) Leukopenia$ 20 (15) 9 (7) Lymphopenia 10 (7) 5 (4) Febrile neutropenia$ 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (<1) Hypokalemia 17 (13) 3 (2) Dehydration$ 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure$ 5 (4) 2 (1) Vascular disorders Hypotension@ $ 9 (7) 4 (3) Deep vein thrombosis$ 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin$ 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects @ - AEs where at least one resulted in a fatal outcome % - AEs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed + - All PTs under HLT of Rash will be considered listed The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma.

General disorders and administration site conditions: Chills Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysguesia, headache, neuropathy peripheral Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma. Respiratory, Thoracic and Mediastinal Disorders: Chronic obstructive pulmonary disease Infections and Infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (incl cysts and polyps): Basal cell carcinoma Cardiac Disorder: Supraventricular tachycardia 6.4 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/ cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.5 to 5.8)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions.

In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp). 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-â&#x2C6;&#x17E; were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 7.3 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone [see Warnings and Precautions (5.4)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1)]

Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 8.3 Nursing mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age. Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients â&#x2030;¤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.

REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation. Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)]. 8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route.

10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg. In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats. A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility. 17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindicatons (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product. Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)]. Venous Thromboembolism Inform patients that REVLIMID/dexamethasone has demonstrated significant increased risk of DVT and PE in patients with multiple myeloma [see Boxed Warnings and Warning and Precautions (5.4)]. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.

Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Secondary Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for:

Celgene Corporation Summit, NJ 07901

REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,281,230; 6,315,720; 6,555,554; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 7,119,106; 7,189,740; 7,468,363; 7,465,800; 7,855,217; 7,968,569 ©2005-2013 Celgene Corporation, All Rights Reserved. REV_COMBO_HCP_BSv.001 06/13

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American Health & Drug Benefits

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July/August 2013

Vol 6, No 6

S E I G R E L L A D FOO * IN CHILDREN HAVE

INCREASED BY

18% 1

Take a closer look at who should carry an EpiPen® (epinephrine) Auto-Injector As food allergies rise, the risk of anaphylaxis may also increase.1-3 Which is why it’s important to identify patients at risk for anaphylaxis and help them create an action plan: avoid the allergen first, and always carry an EpiPen 2-Pak®.3 For more than 20 years, EpiPen has been the #1 prescribed epinephrine auto-injector,4† with over 41 million units dispensed.5‡ There is no FDA-approved therapeutic equivalent.6 Indications EpiPen® (epinephrine) 0.3 mg and EpiPen Jr® (epinephrine) 0.15 mg Auto-Injectors are indicated in the emergency treatment of type 1 allergic reactions, including anaphylaxis, to allergens, idiopathic and exercise-induced anaphylaxis, and in patients with a history or increased risk of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to body weight. Important Safety Information EpiPen Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK, OR INTRAVENOUSLY.

underlying cardiac disease or taking cardiac glycosides or diuretics. Patients with certain medical conditions or who take certain medications for allergies, depression, thyroid disorders, diabetes, and hypertension, may be at greater risk for adverse reactions. Other adverse reactions include transient moderate anxiety, apprehensiveness, restlessness, tremor, weakness, dizziness, sweating, palpitations, pallor, nausea and vomiting, headache, and/or respiratory difficulties.

EpiPen and EpiPen Jr Auto-Injectors are intended for immediate self-administration as emergency supportive Epinephrine should be used with caution in patients with therapy only and are not intended as a substitute for certain heart diseases, and in patients who are on drugs immediate medical or hospital care. that may sensitize the heart to arrhythmias, because it You are encouraged to report negative side effects may precipitate or aggravate angina pectoris and produce of prescription drugs to the FDA. Visit www.fda.gov/ ventricular arrhythmias. Arrhythmias, including fatal medwatch, or call 1-800-FDA-1088. ventricular fibrillation, have been reported in patients with Please see Brief Summary of the full Prescribing Information on the adjacent page. * Reported prevalence from 1997 through 2007. † As of December 2011. ‡ Since 1990. References: 1. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics. 2009;124(6):1549-1555. 2. Simons FER. Anaphylaxis. J Allergy Clin Immunol. 2010;125(suppl 2):S161-S181. 3. Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-Sponsored Expert Panel. J Allergy Clin Immunol. 2010;126(6):S1-S58. 4. Data on file. Mylan Specialty L.P. 5. Data on file. Mylan Specialty L.P. IMS data as of June 2012. 6. U.S. Department of Health and Human Services Food and Drug Administration. Approved Drug Products With Therapeutic Equivalence Evaluations. 32nd ed. Washington, DC: U.S. Department of Health and Human Services; 2012.

epipen.com

EpiPen®, EpiPen Jr®, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned subsidiary, Mylan Specialty L.P. © 2012 Mylan Specialty L.P. All rights reserved. 9/12 EPI12-1046/EPI500320-01

EpiPen® 0.3 mg EPINEPHRINE AUTO-INJECTOR EpiPen Jr® 0.15 mg EPINEPHRINE AUTO-INJECTOR BRIEF SUMMARY. See package insert for full Prescribing Information. DO NOT REMOVE ACTIVATION CAP UNTIL READY FOR USE. THIS UNIT CONTAINS NO LATEX. INDICATIONS AND USAGE: EpiPen and EpiPen Jr Auto-Injectors are indicated in the emergency treatment of allergic reactions (Type I) including anaphylaxis to stinging insects (e.g., order Hymenoptera, which include bees, wasps, hornets, yellow jackets and fire ants) and biting insects (e.g., triatoma, mosquitos), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g., radiocontrast media) and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. EpiPen and EpiPen Jr Auto-Injectors are intended for immediate administration in patients, who are determined to be at increased risk for anaphylaxis, including individuals with a history of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to patient body weight (See DOSAGE AND ADMINISTRATION section of the full Prescribing Information). Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria or angioedema. EpiPen and EpiPen Jr Auto-Injectors are intended for immediate selfadministration as emergency supportive therapy only and are not a substitute for immediate medical care. CONTRAINDICATIONS: There are no absolute contraindications to the use of epinephrine in a life-threatening situation. WARNINGS: EpiPen and EpiPen Jr Auto-Injectors should only be injected into the anterolateral aspect of the thigh. DO NOT INJECT INTO BUTTOCK. Injection into the buttock may not provide effective treatment of anaphylaxis. Advise the patient to go immediately to the nearest emergency room for further treatment of anaphylaxis. Since epinephrine is a strong vasoconstrictor, accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area. Treatment should be directed at vasodilation in addition to further treatment of anaphylaxis. (see ADVERSE REACTIONS). Advise the patient to go immediately to the nearest emergency room and to inform the healthcare provider in the emergency room of the location of the accidental injection. DO NOT INJECT INTRAVENOUSLY. Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to sharp rise in blood pressure. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration. Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium metabisulfite, a sulfite that may, in other products, cause allergictype reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations even if the patient is sulfite-sensitive. Epinephrine should be administered with caution in patients who have heart disease, including patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In such patients, or in

patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. It should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, lifethreatening situation. Epinephrine is light sensitive and should be stored in the carrier tube provided. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (See USP Controlled Room Temperature). Do not refrigerate. Protect from light. Before using, check to make sure the solution in the auto-injector is not discolored. Replace the auto-injector if the solution is discolored or contains a precipitate. PRECAUTIONS: (1) General EpiPen and EpiPen Jr Auto-Injectors are not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek immediate medical or hospital care. More than two sequential doses of epinephrine should only be administered under direct medical supervision. Epinephrine is essential for the treatment of anaphylaxis. Patients with a history of severe allergic reactions (anaphylaxis) to insect stings or bites, foods, drugs, and other allergens as well as idiopathic and exercise-induced anaphylaxis should be carefully instructed about the circumstances under which epinephrine should be used. It must be clearly determined that the patient is at risk of future anaphylaxis, since the following risks may be associated with epinephrine administration (see DOSAGE and ADMINISTRATION section of the full Prescribing Information). Epinephrine should be used with caution in patients who have cardiac arrhythmias, coronary artery or organic heart disease, hypertension, or in patients who are on drugs that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, quinidine, or other anti-arrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors. Some patients may be at greater risk of developing adverse reactions after epinephrine administration. These include: hyperthyroid individuals, individuals with cardiovascular disease, hypertension, or diabetes, elderly individuals, pregnant women, pediatric patients under 30 kg (66 lbs.) body weight using EpiPen Auto-Injector, and pediatric patients under 15 kg (33 lbs.) body weight using EpiPen Jr Auto-Injector. Despite these concerns, epinephrine is essential for the treatment of anaphylaxis. Therefore, patients with these conditions, and/or any other person who might be in a position to administer EpiPen or EpiPen Jr Auto-Injector to a patient experiencing anaphylaxis should be carefully instructed in regard to the circumstances under which epinephrine should be used. (2) Information for Patients Complete patient information, including dosage, direction for proper administration and precautions can be found inside each EpiPen/ EpiPen Jr Auto-Injector carton. Epinephrine may produce symptoms and signs that include an increase in heart rate, the sensation of a more forceful heartbeat, palpitations, sweating, nausea and vomiting, difficulty breathing, pallor, dizziness, weakness or shakiness, headache, apprehension, nervousness, or anxiety. These symptoms and signs usually subside rapidly, especially

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors 0.3/0.15mg

(Epinephrine) Auto-Injectors 0.3 mg

with rest, quiet and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson’s disease may notice a temporary worsening of symptoms. In case of accidental injection, the patient should be advised to immediately go to the emergency room for treatment. Since the epinephrine in the EpiPen Auto-Injector is a strong vasoconstrictor when injected into the digits, hands or feet, treatment should be directed at vasodilation if there is such an inadvertent administration to these areas. (see ADVERSE REACTIONS). (3) Drug Interactions The carrier tube is not waterproof. The blue safety release helps prevent accidental injection and should be kept on until it will be used. Patients who receive epinephrine while concomitantly taking cardiac glycosides or diuretics should be observed carefully for the development of cardiac arrhythmias. The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, levothyroxine sodium, and certain antihistamines, notably chlorpheniramine, tripelennamine and diphenhydramine. The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta-adrenergic blocking drugs, such as propranolol. The vasoconstricting and hypertensive effects of epinephrine are antagonized by alpha-adrenergic blocking drugs, such as phentoloamine. Ergot alkaloids may also reverse the pressor effects of epinephrine. (4) Carcinogenesis, Mutagenesis, Impairment of Fertility Epinephrine and other catecholamines have been shown to have mutagenic potential in vitro and to be an oxidative mutagen in a WP2 bacterial reverse mutation assay. Epinephrine had a moderate degree of mutagenicity, and was positive in the DNA Repair test with B. subtilis (REC) assay, but was not mutagenic in the Salmonella bacterial reverse mutation assay. Studies of epinephrine after repeated exposure in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted. This should not prevent the use of epinephrine under the conditions noted under INDICATIONS AND USAGE. (5) Usage in Pregnancy Pregnancy Category C: There is no study on the acute effect of epinephrine on pregnancy. Epinephrine has been shown to have developmental effects when administered subcutaneously in rabbits at a dose of 1.2 mg/kg daily for two to three days (approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg daily for 10 days (approximately 7 times the maximum daily subcutaneous or intramuscular dose on a mg/m2 basis) and in hamsters at a subcutaneous dose of 0.5 mg/kg daily for 4 days (approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg daily for 10 days (approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). Although, there are no adequate and well-controlled studies in pregnant women, epinephrine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known if epinephrine passes into breast milk.

ADVERSE REACTIONS: Adverse reactions to epinephrine include transient, moderate anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache; and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism. Arrhythmias, including fatal ventricular fibrillation, have been reported in patients with underlying cardiac disease or certain drugs [see PRECAUTIONS, Drug Interactions]. Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Angina may occur in patients with coronary artery disease. The potential for epinephrine to produce these types of adverse reactions does not contraindicate its use in an acute life-threatening allergic reaction. Accidental injection into the digits, hands or feet may result in loss of blood flow to the affected area (see WARNINGS). Adverse events experienced as a result of accidental injections may include increased heart rate, local reactions including injection site pallor, coldness and hypoaesthesia or injury at the injection site resulting in bruising, bleeding, discoloration, erythema or skeletal injury. OVERDOSAGE: Epinephrine is rapidly inactivated in the body and treatment following overdose with epinephrine is primarily supportive. If necessary, pressor effects may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measure, it may be necessary to administer another pressor drug. Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients.

(Epinephrine) Auto-Injectors

Overdosage may also result in pulmonary edema because of peripheral vascular constriction together with cardiac stimulation. Treatment consists of a rapidly acting alpha-adrenergic blocking drug and/or respiratory support. Epinephrine overdosage can also cause transient bradycardia followed by tachycardia and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta-blocking drug such as propranolol.

(Epinephrine) Auto-Injectors

Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis and kidney failure. Suitable corrective measures must be taken in such situations. Rx only. MANUFACTURED FOR Mylan Specialty L.P., Basking Ridge, NJ 07920, USA by Meridian Medical Technologies, Inc., Columbia, MD 21046, USA, a Pfizer company. EpiPen®, EpiPen Jr ®, EpiPen 2-Pak®, and EpiPen Jr 2-Pak® are registered trademarks of Mylan Inc. licensed exclusively to its wholly-owned affiliate, Mylan Specialty L.P. of Basking Ridge, NJ 07920, USA. © 2012 Mylan Specialty L.P. All rights reserved. 03-500-04C August 2012

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(Epinephrine) Auto-Injectors 0.3/0.15mg

(Epinephrine) Auto-Injectors 0.3 mg

CLINICAL

Review Article

Burden of Disease: The Psychosocial

Impact of Rosacea on a Patient’s Quality of Life Tu T. Huynh, PhD

Stakeholder Perspective, page 354

Am Health Drug Benefits. 2013;6(6):348-354 www.AHDBonline.com Disclosures are at end of text

Background: Rosacea is a chronic skin disorder that adversely affects patients’ quality of life. Current studies focus on the therapies that treat the clinical signs and symptoms of rosacea, but the impact of this disease on patients’ emotional health and quality of life is often overlooked. Objectives: To describe the disease burden of rosacea and the psychosocial implications on patients’ quality of life and to review the current understanding of the disease and the available therapies. Discussion: The facial skin manifestations of rosacea have significant implications on patients’ well-being and social and emotional health. The 4 clinical subtypes of this disease include erythematotelangiectatic, papulopustular, phymatous, and ocular, and patients may present with more than 1 subtype. Patients with rosacea have reported a negative burden of their disease, such as low self-esteem, low self-confidence, and decreased social interactions. Improvement of the clinical symptoms of rosacea improves the patient’s emotional well-being and quality of life. Several topical medications and 1 oral medication have been approved for the treatment of rosacea. Although current therapies do not cure the disease and do not treat the facial erythema associated with it, they do treat the papules and pustules associated with this condition. Proper management of the signs and symptoms of rosacea has been shown to improve patients’ quality of life. Conclusion: The self-perception of disease severity varies among patients with rosacea, so physicians should carefully consider each patient’s concerns when prescribing a treatment regimen. Although no cure exists, effective treatment options aid in the management of signs and symptoms of rosacea. New therapies that treat the broad range of rosacea symptoms are needed.

osacea is a common and chronic skin disorder with characteristic signs and symptoms, including flushing, facial erythema, inflammatory papules and pustules, telangiectasia, edema, and watery or irritated eyes.1 Four clinical subtypes of rosacea have been characterized, including erythematotelangiectatic, papulopustular, phymatous, and ocular.2 It is common for patients to present with more than 1 subtype. The erythematotelangiectatic subtype of rosacea has been described as the most difficult subtype to treat.3 The clinical features of this subtype include flushing and persistent central facial erythema, and telangiectasia may also be present (Figure 1).3 The papulopustular subtype of rosacea has been sometimes described as resembling acne vulgaris. The Dr Huynh is a contract medical writer for Galderma Laboratories, LP, Fort Worth, TX.

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clinical features of this subtype include persistent central facial erythema and transient papules and pustules, and facial edema may be present (Figure 2).3 The phymatous subtype of rosacea, which is more common in men, includes thickening skin and irregular surface nodularities (Figure 3). Rhinophyma is the most common type of phymatous rosacea.3 Although no exact prevalence data exist, the symptoms and signs of the ocular subtype of rosacea are estimated to affect nearly 60% of patients with rosacea.3 The clinical features of this subtype include watery or bloodshot eyes, telangiectasia of the conjunctiva and lid margin, and lid and periocular erythema (Figure 4). The common clinical presentations of this subtype include blepharitis, conjunctivitis, and keratitis. Patients with ocular rosacea experience discomfort in the eye including foreign body sensation, light sensitivity, and blurred vision.3

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Figure 1 S ubtype 1: Erythematotelangiectatic Rosacea

Figure 3 Subtype 3: Phymatous Rosacea

Figure 2 Subtype 2: Papulopustular Rosacea

Epidemiology and Triggers of Rosacea Rosacea is more prevalent in fair-skinned people of Northern European and Eastern European descent, but it has also been reported in people of other ethnicities.3-5 Women are more frequently affected than men, with onset of this condition generally occurring between the ages of 30 and 50 years, although rosacea has been reported in the teenaged years.6,7 Heredity has also been implicated as a factor leading to the development of rosacea.8 A National Rosacea Society survey of 600 patients with rosacea showed that

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nearly 52% of survey respondents also had a family member with the disease, and 42% reported that they were of Irish, German, or English descent.8 The factors that are believed to trigger or to exacerbate rosacea include sun exposure, stress, hot and cold weather, the consumption of hot beverages or alcohol, and eating spicy foods.3 Rosacea affects more than 16 million people in the United States.1 Between 1990 and 1997, there were approximately 1.1 million outpatient visits, annually, for rosacea in the United States.9 Based on data compiled by Galderma Laboratories, LP, on office visits for rosacea, between October 2011 and September 2012 there were 1.67 million office visits in the United States, with 75% of the visits conducted with dermatologists.10 Although this is a relatively small patient population, patients with rosacea seek treatment because of the burden of their disease and their poor quality of life. The goal of current therapies is to manage the clinical signs and the physical symptoms of rosacea, but the impact

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Key Points Rosacea is a chronic facial skin disorder that affects patients’ emotional health and quality of life, but these factors are often overlooked in the management of symptoms. ➤ The pathophysiology of rosacea is not fully understood but is believed to be an inflammatory disorder. ➤ The 4 clinical subtypes of rosacea include erythematotelangiectatic, papulopustular, phymatous, and ocular; the clinical manifestations include flushing, facial erythema, inflammatory papules and pustules, telangiectasia, edema, and watery or irritated eyes. ➤ Although there is no cure for this disorder, current treatments can aid in the management of some signs and symptoms and improve patients’ quality of life. ➤ Available therapies do not address the persistent facial erythema associated with rosacea; ongoing research is focused on this symptom. ➤ Physicians need to consider the patient’s selfperception of rosacea when prescribing a treatment regimen. ➤

of rosacea on patients’ emotional health and quality of life is sometimes overlooked. It is important for physicians to consider each patient’s self-perception when prescribing a treatment regimen for this chronic condition.

The Pathophysiology of Rosacea The pathophysiology of rosacea is poorly understood, and many mechanisms have been implicated in this disease.11 Multiple intrinsic and extrinsic factors, such as climatic exposure, vasculature, dermal matrix degeneration, chemical and ingested agents, pilosebaceous unit abnormalities, genetic susceptibility, and interactions with microbial organisms, may play a role in the pathogenesis of this disease.12 Inflammation is believed to be one of the main underlying factors leading to the signs and the symptoms of rosacea.13,14 Antimicrobial peptides, processing enzymes, and toll-like receptors may be involved in the promotion of inflammation.15 Elevated epidermal serine protease activity and the deposition of cathelicidin-derived peptides in the skin have been identified in inflammatory lesions of rosacea.16 A proposed mechanism of action for inflammation in rosacea may involve the production of neuropeptides, which may play a role in generating and maintaining inflammation.1,15 Some of these neuropeptides have been found to be in higher amounts in the skin of patients with rosacea.17,18

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Rosacea may be a vascular disorder because of its association with flushing, redness, and visible blood vessels. The supportive data suggest that mast cells may participate in a complex multifactorial process to promote localized vasodilation, angiogenesis, and tissue fibrosis.15 Physicians have also speculated that flushing may involve the nervous system, because rosacea is often either triggered or aggravated when patients are under emotional stress.19-21 The microscopic mite Demodex folliculorum has been considered a potential contributor to the pathogenesis of rosacea.22,23 D folliculorum are normal inhabitants of the human skin that consume cast-off cells. They reside predominantly in the lumina of sebaceous follicles and use sebum for nourishment.24 These mites were found to be substantially more common in patients with rosacea than in control individuals.25-27 The treatment of rosacea with systemic retinoids inhibited the production of sebum and the number of mites was subsequently reduced.28,29

Psychosocial Impact of Rosacea The clinical severity of rosacea does not correlate with the level of psychosocial distress experienced by the patient. This psychosocial impact has been documented with studies reporting increased depression rates among patients with rosacea.30,31 One analysis revealed that 65.1% of patients with rosacea who had a comorbid psychiatric diagnosis also had a diagnosis of depression.31 This is a much higher proportion than the 29.9% prevalence of depression reported for all psychiatric patient visits.31 The clinical signs and symptoms of rosacea occur predominantly in the facial region and therefore affect the patients’ physical appearance. It has been observed in other dermatologic conditions that patients can suffer from emotional stress if the areas that are affected are visible.32 Physical appearance as perceived by patients with rosacea can negatively influence their emotional health, resulting in psychological comorbidities such as anxiety disorders and social phobias.33 A survey conducted by the National Rosacea Society with more than 400 patients with rosacea revealed that 75% of respondents reported that their rosacea had lowered their self-esteem.34 In addition, the majority of respondents reported that their rosacea made them feel embarrassed (70%) and frustrated (69%). More than 50% of respondents reported that they felt robbed of pleasure or happiness because of their rosacea.34 Patients with rosacea have also reported having depression and anxiety because of their disease.33 The effect of rosacea on quality of life was described to be similar to leg ulcers, vitiligo, and occupational contact dermatitis.35 Body dysmorphic disorder is a psychiatric condition that describes the preoccupation with a defect in physical appearance.36 Symptoms of body dysmorphic disorder can

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significantly disrupt daily function and have been reported in patients with acne.36 Although body dysmorphic disorder has not been examined in patients with rosacea, this may also be applicable to patients with rosacea based on the similarities between the symptoms of acne vulgaris and the symptoms of rosacea in some patients and should be considered when evaluating patients with rosacea. Patients with rosacea are affected by emotional and social stigmas, including being viewed as abusers of alcohol or as having poor hygiene.14 One survey conducted by Kelton Research evaluated patients’ self-perception and the perception of others regarding patients with rosacea.37 This online “perception survey” contrasted images of women with and without rosacea.37 More than 1000 members of the general population and 502 women with rosacea completed the online survey between October 29, 2009, and November 9, 2009. Women with rosacea were perceived to be more insecure, not as healthy, not as intelligent, and not as successful as women with clear skin. Overall, respondents with and without rosacea had negative first impressions of women with rosacea.37

Burden of Disease Collectively, skin diseases are one of the top 15 groups of medical conditions for which prevalence and healthcare spending increased the most between 1987 and 2000.38 The economic burden of skin disease on the US healthcare was approximately $96 billion in 2004.38 Willingness to pay is a monetary- and preference-based measurement that is used to evaluate an individual’s burden of disease by focusing on the amount of money that patients would be willing to pay for a hypothetical cure. In addition to evaluating the burden of disease, willingness to pay is a measure that has been used to indirectly evaluate quality of life in patients with skin diseases.39-41 In one study by Beikert and colleagues, data from questionnaires completed by 475 patients with rosacea were analyzed and willingness to pay was examined.42 This population consisted of 79.9% women with a mean age of 56.3 years. When asked to pay a percentage of their monthly income for a complete healing (relative willingness to pay), more than half (60.3%) of the patients reported that they would invest 0% to 10% of their monthly income, 28.3% would invest 10% to 20% of their monthly income, and 11.4% would invest more than 20% of their monthly income.42 Women between the ages of 21 to 30 years showed the greatest relative willingness to pay. Beikert and colleagues reported that patients in this study showed a “moderate willingness to pay”; according to the authors, this suggests that these patients perceived their disease to be a major burden affecting their quality of life and that they were willing to pay for their treatment.42

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A retrospective claims database study sponsored by Galderma Laboratories, LP, using the IMS LifeLink health plan claims database, which encompasses more than 79 managed care health plans covering more than 70 million lives, examined patients with at least 1 diagnosis of rosacea.43 The 99,894 patients included in this study were at least 29 years of age and had continuous eligibility for medical and pharmacy services for 12 months after an initial prescription for a drug to treat rosacea. Most patients (73.2%) were women with a mean age of 52.4 years. The all-cause mean annual total cost was $6707, of which $4510 was for medical costs and $2197 was for pharmaceutical costs.43 The mean total rosacea-related cost was $347 (5.2% of all-cause costs), with a mean annual rosacea-related medical cost of $56 (1.2% of all-cause medical costs) and a mean annual rosacea-related pharmacy cost of $291 (13.3% of all-cause pharmacy costs).43 The patients averaged 1.1 physician visits annually, and 58% of them saw a dermatologist during the 12-month study period.43 A national survey conducted in 2006 aimed to gain insight into patients’ experiences with rosacea therapies and patients’ relationships with their healthcare providers.44 The patients reported that their relationship with their physicians was important, and that it played a role in the management of their disease.44 Patient education about the chronic nature of rosacea is also important. Understanding that daily treatment can improve the symptoms of this chronic disease may increase patient adherence to prescribed treatment regimens. Patient education, along with a continued patient–physician relationship, can promote treatment adherence and improve patient satisfaction.44,45

Quality of Life The Dermatology Life Quality Index (DLQI), which was developed in 1994, was the first dermatology-specific quality-of-life instrument. The DLQI is a validated 10item questionnaire that has been used to evaluate quality-of-life issues in more than 33 skin conditions. In a study of 308 patients with rosacea, 164 patients completed the DLQI after treatment.7 The results of this study suggested that rosacea affects quality of life to a moderate extent and that improvement in quality of life after treatment may be related to the patients’ sex, type of treatment modality, development of side effects, improvement of rosacea, rosacea severity, and self-reported ease of living with rosacea.7 In another study, 22 patients with erythematotelangiectatic rosacea completed the DLQI questionnaire before and after 3 pulsed dye laser treatment sessions.46 A significant improvement was observed in the DLQI score after 3 sessions, and all patients were judged by the investigators to have improved facial erythema.46

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Currently, no validated rosacea-specific quality-of-life instrument exists. In a preliminary study, one rosacea- specific instrument, RosaQoL, was found to be reliable.47 This pilot instrument consists of a 21-item rosacea-specific questionnaire.47 In a large 12-week trial of more than 1400 patients, RosaQoL was used to evaluate their quality of life.48 This study demonstrated that the impaired quality of life in subjects with rosacea was substantially improved during a 3-month period with effective treatment.48

Treatment Options Currently, there is no cure for rosacea.49 Available treatments are aimed at managing the signs and symptoms, which can worsen without treatment. Appropriate treatment can minimize the psychosocial impact of rosacea on the patient. The 3 topical agents approved by the US Food and Drug Administration (FDA) for the topical treatment of rosacea are metronidazole, azelaic acid, and sodium sulfacetamide-sulfur.49,50

It is important to consider the self-perception of rosacea by patients when prescribing a treatment regimen. The impact of rosacea on the patient’s emotional health and quality of life has been underestimated or overlooked. Currently, doxycycline 40 mg (30 mg immediate-release and 10 mg delayed-release) is the only FDA-approved oral drug indicated for the treatment of the inflammatory lesions (ie, papules and pustules) of rosacea.50 No approved treatment is currently available for the facial erythema that is associated with rosacea. Metronidazole gel 1% is a nitroimidazole indicated for the topical treatment of the inflammatory lesions of rosacea. Although the mechanism of action in rosacea is unknown, metronidazole has antioxidant and anti- inflammatory effects. Significant decreases in the inflammatory lesions of rosacea have been reported in multiple clinical studies.51-54 The most common adverse reactions (incidence, >2%) are nasopharyngitis, upper respiratory tract infection, and headache.51-54 Azelaic acid gel 15% is indicated for the topical treatment of the inflammatory papules and pustules of mild-to-moderate rosacea. The exact mechanism of action of azelaic gel is also unknown. Several studies indicated that azelaic acid may exert anti-inflammatory effects in patients with rosacea.55-59 The adverse events reported in a 15-week clinical trial of azelaic gel included burning; stinging or tingling; dryness, tightness, or scaling; itching; and erythema, irritation, or redness.57

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Tetracycline, the mainstay of oral antibiotic therapy, has been used as an off-label treatment for rosacea since the 1950s.60-62 Tetracycline is believed to affect inflammation, immunomodulation, cell proliferation, and angiogenesis.60,63 One concern with the long-term use of tetracycline has been antibacterial resistance.63 The common adverse reactions observed in patients receiving tetracyclines at higher, antimicrobial doses include nausea, vomiting, diarrhea, dysphagia, and inflammatory lesions (with vaginal candidiasis) in the anogenital region.60,63 Doxycycline 40 mg (30 mg immediate-release and 10 mg delayed-release) is indicated for the treatment of only inflammatory lesions (ie, papules and pustules) of rosacea in adult patients. Doxycycline 40 mg provides anti-inflammatory activity at a subantimicrobial dose with a reduced risk of bacterial resistance compared with higher doses of doxycycline.62-66 It has been demonstrated that administration of this subantimicrobial dose of doxycycline (40 mg) once daily for 9 months did not lead to the development of antibiotic resistance in patients with periodontal disease.67 The most common adverse reactions reported in clinical trials (incidence, >2%; more common than with placebo) are nasopharyngitis, sinusitis, diarrhea, hypertension, and an increase in aspartate aminotransferase.64-66

Conclusions Rosacea is a lifelong condition that adversely affects the emotional health and quality of life of patients. Although only a small percentage of patients with rosacea will seek professional advice and treatment, studies and national surveys have indicated that these individuals perceive their disease to be a burden, and they are motivated to address the adverse effects of this condition on their quality of life. Physicians need to be reminded of the psychosocial aspects of rosacea. It is important to consider the self-perception of rosacea by patients when prescribing a treatment regimen. The impact of rosacea on the patient’s emotional health and quality of life has been underestimated or overlooked. Surveys conducted by the National Rosacea Society and by Kelton Research have indicated that people have a negative impression of patients with rosacea.34,37 Regarding symptoms, including symptoms of persistent erythema predominantly in the central facial region, patients with rosacea have reported avoiding social interactions and their workplace productivity may be impacted. In addition, patients with rosacea are willing to pay for their treatments, suggesting that they perceive their disease to be a burden. The visible facial erythema and blemishes that are associated with rosacea can negatively affect patients’ emotional health. The improvement of the clinical

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symptoms of rosacea improves the patients’ emotional well-being. Current therapies treat the papules and pustules that are associated with rosacea, but no approved therapies target persistent facial erythema. There is no evidence that current therapies have a direct effect on erythema. This suggests an unmet medical need for treatments that will specifically target the persistent facial erythema associated with rosacea. Nevertheless, the treatment of the papules and pustules characteristic of rosacea by approved therapies improves patient quality of life. New therapies currently in development may be able to treat the broad range of symptoms of rosacea. n Acknowledgments The author would like to thank Thomas J. Greene, MD; Jim Kendall, PharmD; and Robert Kling for their editorial assistance. Funding Source Funding for the preparation of this manuscript was provided by Galderma Laboratories, LP. Author Disclosure Statement Dr Huynh is a contract medical writer for Galderma Laboratories, LP.

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patients with rosacea. Cutis. 1998;61:44-47. 54. Jorizzo JL, Lebwohl M, Tobey RE. The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: a double-blind clinical trial. J Am Acad Dermatol. 1998;39:502-504. 55. Gollnick H, Layton A. Azelaic acid 15% gel in the treatment of rosacea. Expert Opin Pharmacother. 2008;9:2699-2706. 56. Thiboutot DM, Fleischer AB Jr, Del Rosso JQ, Graupe K. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7:541-546. 57. Elewski BE, Fleischer AB Jr, Pariser DM. A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003;139:1444-1450. 58. Thiboutot D, Thieroff-Ekerdt R, Graupe K. Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies. J Am Acad Dermatol. 2003;48:836-845. 59. Azelaic acid (Finacea) for rosacea. Med Lett Drugs Ther. 2003;45:76. 60. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54:258-265. 61. Griffin MO, Fricovsky E, Ceballos G, Villarreal F. Tetracyclines: a pleitropic

family of compounds with promising therapeutic properties: review of the literature. Am J Physiol Cell Physiol. 2010;299:C539-C548. 62. Alikhan A, Kurek L, Feldman SR. The role of tetracyclines in rosacea. Am J Clin Dermatol. 2010;11:79-87. 63. Sloan B, Scheinfeld N. The use and safety of doxycycline hyclate and other second-generation tetracyclines. Expert Opin Drug Saf. 2008;7:571-577. 64. McKeage K, Deeks ED. Doxycycline 40 mg capsules (30 mg immediate-release/10 mg delayed-release beads): anti-inflammatory dose in rosacea. Am J Clin Dermatol. 2010;11:217-222. 65. Webster GF. An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate- release and 10-mg delayed-release beads). Cutis. 2010;86(5 suppl):7-15. 66. Theobald K, Bradshaw M, Leyden J. Anti-inflammatory dose doxycycline (40 mg controlled-release) confers maximum anti-inflammatory efficacy in rosacea. Skinmed. 2007;6:221-226. 67. Preshaw PM, Novak MJ, Mellonig J, et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planing in subjects with periodontal disease. J Periodontol. 2008;79:440-452.

Stakeholder Perspective The Psychosocial Impact of Skin Disorders: Time for a Closer Look? By Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services, SelectHealth, Salt Lake City, UT

The article by Dr Huynh on the psychosocial aspects of rosacea in this issue of American Health & Drug Benefits introduces a topic that is not at the forefront of healthcare concerns for policymakers, payers, or even primary care physicians. However, as this article makes clear, the emotional toll and impact on a patient’s quality of life merits a renewed look at this condition. PAYERS: Dermatology is not a clinical area that is top of mind for most payers, particularly for skin conditions that do not require specialty medications. Unlike psoriasis, which is on the payer’s radar, with annual treatment costs in the $30,000 range, treatment options for acne and rosacea may not carry as much priority for payers, or the risk for potentially high costs associated with inappropriate drug use. However, drug therapies for dermatologic conditions, particularly oral therapies, have not been completely off the radar for payers. Increasing numbers of oral and topical medications for dermatologic conditions, including rosacea, have become more costly and can place a financial burden on patients, and eventually on payers. Monthly costs can reach between $100 and $900, which can amount to a considerable copayment or coinsurance for some patients, especially for those who are underinsured or who have a large coinsurance amount. PATIENTS: Several studies and patient surveys have zeroed in on the psychological distress, social stig-

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ma, and reduced quality of life that are characteristic of patients with rosacea.1-5 Moreover, a small study has documented 16 patients with dermatologic conditions, including acne and rosacea, who committed suicide after presenting to their physician with skin problems, prominently facial skin disorders,6 shedding light on the potential for severe depression that could accompany a chronic skin condition, which nevertheless is often being misperceived as mainly a cosmetic problem. PROVIDERS: Providers should consider the psychosocial impact of rosacea on the patient when choosing the best approach to therapy. Various therapeutic options are available today, but cost may become a consideration as well. Providers should work closely with patients, and, if necessary, with payers, to ensure that proper management is available to all patients with this chronic and potentially debilitating disorder. 1. Roosta N, Black DS, Peng D, Riley LW. Skin disease and stigma in emerging adulthood: impact on healthy development. J Cutan Med Surg. 2010;14:285-290. 2. Su D, Drummond PD. Blushing propensity and psychological distress in people with rosacea. Clin Psychol Psychother. 2012;19:488-495. 3. National Rosacea Society. Coping with rosacea: managing psychosocial aspects of rosacea. www.rosacea.org/patients/materials/coping/managing.php#Managing. Accessed July 24, 2013. 4. Kini SP, Nicholson K, DeLong LK, et al. A pilot study in discrepancies in quality of life among three cutaneous types of rosacea. J Am Acad Dermatol. 2010;62:1069-1071. 5. Bowe WP, Leyden JJ, Crerand CE, et al. Body dysmorphic disorder symptoms among patients with acne vulgaris. J Am Acad Dermatol. 2007;57:222-230. 6. Cotterill JA, Cunliffe WJ. Suicide in dermatological patients. Br J Dermatol. 1997; 137:246-250.

www.AHDBonline.com

July/August 2013

Vol 6, No 6

ANNUAL CONFERENCE

"! ! !

! Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

* 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management â&#x20AC;˘ Reimbursement Challenges â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

www.globalbiomarkersconsortium.com

*Agenda is subject to change.

P O

PERSONALIZED MMEDICINE IN ONCOLOGY

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