AHDB September/October 2013, Vol 6, No 8

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ september/October 2013

Volume 6, Number 8

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

“Pharma Value” David B. Nash, MD, MBD

Fall Follies: The ACA Lurches into Operation Joseph R. Antos, PhD REGULATORY ™

Development of a Medicare Beneficiary Comprehension Test: Assessing Medicare Part D Beneficiaries’ Comprehension of Their Benefits Meghana V. Aruru, PhD, MBA, BPharm; J. Warren Salmon, PhD Stakeholder Perspective by Joseph R. Antos, PhD BUSINESS

The Economics of Biosimilars Erwin A. Blackstone, PhD; Joseph P. Fuhr, Jr, PhD Stakeholder Perspective by Grant D. Lawless, RPh, MD, FACP

The Incidence Rate and Economic Burden of Community-Acquired Pneumonia in a Working-Age Population Jonah Broulette, ASA, MAAA; Holly Yu, MSPH; Bruce Pyenson, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Reiko Sato, PhD Stakeholder Perspective by F. Randy Vogenberg, RPh, PhD Industry Trends

Technological Changes Can Transform Medicine by 2020: A Conversation with the Futurist Jim Carroll

ANNIVERSARY 6YEAR

EST. 2008

www.AHDBonline.com ©2013 Engage Healthcare Communications, LLC

For your members with COPD (chronic obstructive pulmonary disease)

The only once-daily ICS/LABA (inhaled corticosteroid/long-acting beta2-agonist) for the maintenance treatment of COPD. Contact your GlaxoSmithKline Account Manager to schedule a presentation.

Indications • BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2 -adrenergic agonist (ICS/LABA) indicated for the longterm, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

• BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

Important Safety Information for BREO ELLIPTA WARNING: ASTHMA-RELATED DEATH • Long-acting beta2-adrenergic agonists (LABAs), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including vilanterol.

• The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

CONTRAINDICATIONS • BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS • BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. • BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2 -agonist.

• BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

• Oropharyngeal candidiasis has occurred in patients treated with BREO ELLIPTA. Advise patients to rinse the mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

• An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal.

– In replicate 12-month studies of 3255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving BREO ELLIPTA 100/25 mcg (6% [51 of 806 subjects]), fluticasone furoate (FF)/vilanterol (VI) 50/25 mcg (6% [48 of 820 subjects]), and FF/VI 200/25 mcg (7% [55 of 811 subjects]) than in subjects receiving VI 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving VI or FF/VI 50/25 mcg.

There was fatal pneumonia in 1 subject receiving BREO ELLIPTA at the approved strength (100/25 mcg) and in 7 subjects receiving FF/VI 200/25 mcg (<1% for each treatment group).

• Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

• Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

• Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage of inhaled corticosteroids in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly.

Important Safety Information for BREO ELLIPTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur.

• If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy.

• Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. BREO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

• Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter.

• Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

• Be alert to hypokalemia and hyperglycemia.

ADVERSE REACTIONS • The most common adverse reactions (≥3% and more common than placebo) reported in two 6-month clinical trials with BREO ELLIPTA (and placebo) were nasopharyngitis, 9% (8%); upper respiratory tract infection, 7% (3%); headache, 7% (5%); and oral candidiasis, 5% (2%).

• In addition to the events reported in the 6-month studies, adverse reactions occurring in ≥3% of the subjects treated with BREO ELLIPTA in two 1-year studies included COPD, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia.

DRUG INTERACTIONS • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur.

• BREO ELLIPTA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists, such as vilanterol, on the cardiovascular system may be potentiated by these agents.

• Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with reversible obstructive airways disease.

• Use with caution in patients taking non–potassium-sparing diuretics, as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists.

USE IN SPECIFIC POPULATIONS • Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Fluticasone furoate exposure may increase in these patients. Monitor for systemic corticosteroid effects.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for BREO ELLIPTA on the following pages.

BREO ELLIPTA was developed in collaboration with

BRIEF SUMMARY BREOTM ELLIPTATM (fluticasone furoate and vilanterol inhalation powder) FOR ORAL INHALATION USE The following is a brief summary only; see full prescribing information for complete product information WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including vilanterol, an active ingredient in BREO ELLIPTA [see Warnings and Precautions (5.1)].

The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

1 INDICATIONS AND USAGE BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

Important Limitations of Use: BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

4 CONTRAINDICATIONS The use of BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions (5.11), Description (11) of full prescribing information].

5 WARNINGS AND PRECAUTIONS 5.1 Asthma-Related Death Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death.

Data are not available to determine whether the rate of death in patients with COPD is increased by LABA. A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthmarelated death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No study adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. BREO ELLIPTA has not been studied in patients with acutely deteriorating COPD. The initiation of BREO ELLIPTA in this setting is not appropriate.

BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.

Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA no longer controls symptoms of bronchoconstriction; the patientâ&#x20AC;&#x2122;s inhaled, shortacting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of BREO ELLIPTA beyond the recommended dose is not appropriate in this situation.

5.3 Excessive Use of BREO ELLIPTA and Use With Other Long-Acting Beta2Agonists BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving the fluticasone furoate/vilanterol combination, including BREO ELLIPTA 100 mcg/25 mcg, in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences

these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 6% [48 of 820 subjects]; 100 mcg/25 mcg: 6% [51 of 806 subjects]; or 200 mcg/25 mcg: 7% [55 of 811 subjects]) than in subjects receiving vilanterol 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving fluticasone furoate/vilanterol 100 mcg/25 mcg and in 7 subjects receiving fluticasone furoate/vilanterol 200 mcg/25 mcg (less than 1% for each treatment group).

5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.7 Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD symptoms during these episodes, in recommended doses it supplies less than normal physiological amount of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (mean forced expiratory volume in 1 second [FEV1]), beta-agonist use, and COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression) despite maintenance or even improvement of respiratory function.

5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic dose of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)]. Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD symptoms should be considered.

5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3) of full prescribing information].

5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA

can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

5.11 Hypersensitivity Reactions Hypersensitivity reactions may occur after administration of BREO ELLIPTA. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not take BREO ELLIPTA [see Contraindications (4)].

5.12 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12-fold higher systemic exposure than seen in patients with COPD) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered. In replicate 12-month trials in 3,255 subjects with COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 2% [14 of 820 subjects]; 100 mcg/25 mcg: 2% [19 of 806 subjects]; or 200 mcg/25 mcg: 2% [14 of 811 subjects]) than in subjects receiving vilanterol 25 mcg alone (less than 1% [8 of 818 subjects]).

5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. In replicate 12-month trials in 3,255 subjects with COPD, similar incidences of ocular effects (including glaucoma and cataracts) were reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: less than 1% [7 of 820 subjects]; 100 mcg/25 mcg: 1% [12 of 806 subjects]; 200 mcg/25 mcg: less than 1% [7 of 811 subjects]) as those receiving vilanterol 25 mcg alone (1% [9 of 818 subjects]).

5.15 Coexisting Conditions BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 6- and 12-month duration evaluating BREO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

6 ADVERSE REACTIONS LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. BREO ELLIPTA is not indicated for the treatment of asthma. [See Boxed Warnings and Warnings and Precautions (5.1).] Systemic and local corticosteroid use may result in the following: Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)]; Increased risk for decrease in bone mineral density [see Warnings and Precautions (5.13)].

6.1 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects have received at least 1 dose of BREO ELLIPTA 100 mcg/25 mcg, and 1,087 subjects have received higher doses of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6-month and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.

6-Month Trials: The incidence of adverse reactions associated with BREO ELLIPTA in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were Caucasian. They had a mean age of 62 years and an average smoking

history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/ vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.

Table 1. Adverse Reactions With ≥3% Incidence and More Common Than Placebo With BREO ELLIPTA in Subjects With Chronic Obstructive Pulmonary Disease

Adverse Event

a

BREO ELLIPTA 100 mcg/25 mcg (n = 410) %

Vilanterol 25 mcg (n = 408) %

Fluticasone Furoate 100 mcg (n = 410) %

Placebo (n = 412) %

9

10

8

8

Infections and infestations Nasopharyngitis Upper respiratory tract infection Oropharyngeal candidiasisa

7

5

4

3

5

2

3

2

Nervous system disorders Headache

7

9

7

5

Includes terms oral candidiasis, oropharyngeal candidiasis, candidiasis, and oropharyngitis fungal.

12-Month Trials: Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg. In addition to the events shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA (N = 806) for 12 months included COPD, back pain, pneumonia [see Warnings and Precautions (5.5)], bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia.

7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol, the individual components of BREO ELLIPTA, are both substrates of CYP3A4.

Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of BREO ELLIPTA with longterm ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) of full prescribing information].

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Vilanterol, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.3 Beta Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, a component of BREO ELLIPTA, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/ or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by betaagonists, especially when the recommended dose of the beta-agonist is exceeded.

Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with BREO ELLIPTA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women should be advised to contact their physicians if they become pregnant while

taking BREO ELLIPTA. Fluticasone Furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 9 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone furoate and vilanterol, alone or in combination, up to approximately 95 mcg/kg/day). Fluticasone Furoate: There were no teratogenic effects in rats and rabbits at approximately 9 and 2 times, respectively, the MRHDID in adults (on a mcg/ m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and postnatal development in rats at approximately 3 times the MRHDID in adults (on a mcg/m2 basis at maternal doses up to 27 mcg/kg/day). Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/ day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. There were no effects on perinatal and postnatal development in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

8.2 Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of BREO ELLIPTA during labor and delivery. Because beta-agonists may potentially interfere with uterine contractility, BREO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk.

8.3 Nursing Mothers It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk. However, other corticosteroids and beta2-agonists have been detected in human milk. Since there are no data from controlled trials on the use of BREO ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman.

8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of BREO ELLIPTA for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3) of full prescribing information].

8.7 Renal Impairment There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3) of full prescribing information].

10 OVERDOSAGE No human overdosage data has been reported for BREO ELLIPTA. BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA. 10.1 Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions (5.8)]. Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days.

10.2 Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/ min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.

Treatment of overdosage consists of discontinuation of BREO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below.

Fluticasone Furoate: Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (approximately equal to the MRHDID in adults on a mcg/m2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed

in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/ day, respectively (approximately 3 and 9 times, respectively, the MRHDID in adults on a mcg/m2 basis).

Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/ day (approximately 530 times the MRHDID in adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,000 times, respectively, the MRHDID in adults on a mcg/m2 basis).

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for Use) 17.1 Asthma-Related Death Patients should be informed that LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthmarelated death. BREO ELLIPTA is not indicated for the treatment of asthma.

17.2 Not for Acute Symptoms BREO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with a rescue inhaler such as albuterol. The physician should provide the patient with such medicine and instruct the patient in how it should be used. Patients should be instructed to notify their physicians immediately if they experience any of the following: Symptoms get worse; Need for more inhalations than usual of their rescue inhaler; Significant decrease in lung function as outlined by the physician. Patients should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.

17.3 Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed BREO ELLIPTA, other medicines containing a LABA should not be used.

17.4 Risks Associated With Corticosteroid Therapy Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with BREO ELLIPTA, but at times therapy with BREO ELLIPTA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth without swallowing after inhalation is advised to help reduce the risk of thrush.

Pneumonia: Patients with COPD who have received BREO ELLIPTA have a higher risk of pneumonia and should be instructed to contact their healthcare providers if they develop symptoms of pneumonia (e.g., fever, chills, change in sputum color, increase in breathing problems).

Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

Hypercorticism and Adrenal Suppression: Patients should be advised that BREO ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk.

Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered.

17.5 Risks Associated With Beta-Agonist Therapy Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

BREO and ELLIPTA are trademarks of GlaxoSmithKline.

BREO ELLIPTA was developed in collaboration with

Š2013, GlaxoSmithKline. All rights reserved.

Revised 05/2013 Š2013 GlaxoSmithKline group of companies.

All rights reserved. Printed in USA. MH3770R0 October 2013

BRE:1BRS

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Volume 6, number 8

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

™

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

Publishing Staff

REGULATORY

Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Directors, Client Services Joseph Beck Ron Gordon Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon

453 D evelopment of a Medicare Beneficiary Comprehension Test: Assessing Medicare Part D Beneficiaries’ Comprehension of Their Benefits

Meghana V. Aruru, PhD, MBA, BPharm; J. Warren Salmon, PhD

Projects Manager John Welz Senior Production Manager Lynn Hamilton

461 Stakeholder Perspective: Understanding the Options: An Essential Ingredient in Our Evolving Healthcare System by Joseph R. Antos, PhD

The Lynx Group

EDITORIAL

448 “Pharma Value”

David B. Nash, MD, MBD 483 Fall Follies: The ACA Lurches into Operation

Joseph R. Antos, PhD

business

469 The Economics of Biosimilars

Erwin A. Blackstone, PhD; Joseph P. Fuhr, Jr, PhD 478 Stakeholder Perspective: Modeling the Future Economic Impact of Biosimilars’ Entry into the US Market by Grant D. Lawless, RPh, MD, FACP 494 T he Incidence Rate and Economic Burden of Community-Acquired Pneumonia in a Working-Age Population Jonah Broulette, ASA, MAAA; Holly Yu, MSPH; Bruce Pyenson, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Reiko Sato, PhD 503 Stakeholder Perspective: CAP Is a Burden for All Ages—Prevention Strategies Are Key by F. Randy Vogenberg, RPh, PhD Continued on page 442

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.

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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.

© Pharmacyclics, Inc. 2013 © Janssen Biotech, Inc. 2013 04/13 K08BR13002

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Volume 6, number 8

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

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

(Continued)

DEPARTMENTs

491 Opinion

The Evolution of Cost-Plus Health Care: The Story of American Health Insurance Is Clearly Not a Story of Intelligent Design

By John Steel Gordon 510 Industry Trends

Technological Changes Can Transform Medicine by 2020: A Conversation with the Futurist Jim Carroll

By Rosemary Frei, MSc

CORRECTION In the article “Burden of disease: the psychological impact of rosacea on a patient’s quality of life” in the July/August 2013 issue, the author’s affiliation (page 348) and disclosure statement (page 353) were incorrectly listed. The correct statement in both cases is Tu T. Huynh, PhD, is a contract medical writer for Galderma Laboratories, LP.

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GE Healthcare Clarient Diagnostic Services

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JB15955US

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 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

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 Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy, University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD health & value promotion

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

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

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

HEALTH INFORMATION TECHNOLOGY

PATIENT ADVOCACY

GOVERNMENT

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX 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 Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX

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

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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

September/October 2013

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S E I G R E L L A D O O F * VE IN CHILDREN HA

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

(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 0

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

(Epinephrine) Auto-Injectors

(Epinephrine) Auto-Injectors 0.3/0.15mg

(Epinephrine) Auto-Injectors 0.3 mg

Editorial

“Pharma Value” David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Jefferson School of Population Health, Philadelphia, PA

A

ll healthcare consumers want to achieve value, namely, best outcome at the most affordable price. Certainly, as readers of American Health & Drug Benefits know, we have talked about value in the past, especially as it relates to the Affordable Care Act (ACA) and the future shape of our healthcare system.

As we get further down the road of reform, I was intrigued by a report from PricewaterhouseCoopers (PwC) titled, “Top Health Industry Issues of 2013—Picking up the Pace on Health Reform.”1 I am enamored of these periodic reports from the (remaining) big consulting companies. Typically, an army of researchers fan out across the country, interview hundreds of leading experts, and then they conduct more than 1000 telephone interviews with everyday consumers. That’s exactly the footwork that went into this most recent report.

Although space precludes my review of all 10 sections of the report, I was particularly interested in the section titled, “Meeting the New Expectations of Pharma Value.”

Let me summarize some of the key take-home messages from this report.

As a longtime member of our institution’s Pharmacy & Therapeutics Committee and Chair of the Medication Quality and Safety Subcommittee, the report “hit me between the eyes” when it noted that physicians may no longer be the key drivers of formulary design and construction. “If purchasers don’t see evidence that a new drug fills an unmet need or outperforms similar products at a more reasonable cost, the drug won’t receive preferred formulary placement and may not even be covered by insurance.”1 Regrettably, I would have to agree with this observation. Since the pharmaceutical industry has largely shielded customers from the true price of medication and has shifted these costs to others, the pharmaceutical companies will be under much greater pressure under the ACA to prove the value of their products.

We are also seeing the development of so-called outcomes-based contracts, where the value of drugs and devices must be demonstrated before reimbursement is forthcoming. The report outlines 2 examples—one is EMD Serono, a division of Merck that forged a separate contract with CIGNA, and the other is the pharmacy benefits manager Prime Therapeutics—to provide an

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adherence-based discount on interferon beta-1a (Rebif), an expensive therapy for multiple sclerosis. Published reports cited in a PwC document note that CIGNA has shown that interferon beta-1a helped reduce hospitalizations by 43% in the first year of its agreement with EMD Serono. If we accept these published findings at face value, then it does appear that an outcomes-based contract with a special “adherence rider” may truly be the wave of the future.

Although adherence-based contracts are intriguing, I prefer the “partnership model.” I am particularly familiar with one, which was also cited in the PwC report. This partnership is between Pfizer and Humana, who have forged a 5-year agreement focusing on improving the cost, quality, and access to appropriate care.1 According to experts at Humana, such as Kim Caldwell, Humana intends to do a deep analytic dive on certain products from Pfizer to help purchasers understand the cost-benefit and cost-effectiveness of these drugs. The goal, of course, is to improve the treatment and management of chronic conditions, including many treatments in the Pfizer portfolio for cardiovascular disease and Alzheimer’s disease. Are Pfizer and Humana “usual bedfellows”?

In my view, not really. They have an aligned economic incentive to encourage patients to take their medications, do well, and stay out of the hospital. I cannot think of other stakeholders at this moment whose economic incentives are more clearly aligned than a big pharmaceutical company and a national insurer bent on keeping people out of the hospital.

The PwC report also noted 2 overseas examples of “pharma value”; examples that I am sure are familiar to our readers, including how the United Kingdom’s NICE (National Institute for Health and Care Excellence) makes decisions based, at least in part, on a value proposition for every drug. And the same applies to Germany, where “if a company cannot demonstrate that a new therapy provides clinical benefit over established treatments, reimbursement starts at the same level as existing clinically equivalent medicines.”1 A very intriguing survey component of the PwC report was the question they posed to their policy experts, which focused on “how much do you agree with the following: our organization would benefit from a data sharing partnership with biopharmaceutical companies.”1

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Overall, 43% of the policy experts interviewed agreed with this provocative statement and only 17% disagreed.

The other experts were simply either not sure or had no strong views. If 43% of the surveyed policy experts believe that a partnership is a good idea, that gives me some hope, and I hope it gives our readers hope too, for a more collaborative approach to establishing “pharma value.”

This section of the report ended with 3 take-home messages. First, the pharmaceutical industry must provide robust and reliable data to purchasers on the cost-effectiveness of care, and mock formulary audits are needed, something I have been a proponent of for nearly 2 decades.

Second, the pharmaceutical industry and its partners “should monitor costs and outcomes as they aggregate and interpret data. Underused data from electronic health records, patient registries, medical devices, nutrition studies, and social media can often supplement claims and prescription information.”1 Yes, there is no question that there are other data sources that must be utilized. More on this will come in future editorials.

Finally, “drug and device makers can prove value by including a comparative effectiveness component in clinical trials and pairing products with diagnostics targeting patients who can benefit the most.”1 Well, we all support a broader platform for comparative effectiveness

research, and it is heartening to see it being highlighted in this PwC report.

The pharmaceutical industry must provide robust and reliable data to purchasers on the cost-effectiveness of care, and mock formulary audits are needed, something I have been a proponent of for nearly 2 decades.

Establishing “pharma value” in new levels and with greater clarity will be a challenge for everyone in the healthcare industry. In my view, collaborative agreements and better teamwork represent the “road to redemption.” I am excited to see reports such as this one from a major national consulting company, because as more people join the “value” conversation, I believe we will be able to make more progress together. As always, I am interested in your views, and you can reach me at david.nash@jefferson.edu. n

Reference

1. PwC Health Research Institute. Top health industry issues of 2013: picking up the pace on health reform. January 2013. www.pwc.com/us/en/health-industries/tophealth-industry-issues/download-publication.jhtml. Accessed February 28, 2013.

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The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage A t 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,544 per 3.5-mg vial as of July 2013 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVErsE rEACtIons Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

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

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

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

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group.

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively.

The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

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

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

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

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

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-12-0306a

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Original Research

Development of a Medicare Beneficiary Comprehension Test: Assessing Medicare Part D Beneficiaries’ Comprehension of Their Benefits

Meghana V. Aruru, PhD, MBA, BPharm; J. Warren Salmon, PhD Background: Medicare Part D, the senior prescription drug benefit plan, was introduced through the Medicare Modernization Act of 2003. Medicare beneficiaries receive information about plan options through multiple sources, and it is often assumed by consumer health plans and healthcare providers that beneficiaries can understand and compare plan information. Medicare beneficiaries are older, may have cognitive problems, and may not have a true understanding of managed care. They are more likely than younger persons to have inadequate health literacy, thereby demonstrating significant gaps in knowledge and information about healthcare.

Objective: To develop a Medicare Beneficiary Comprehension Test (MBCT) to evaluate Medicare beneficiaries’ understanding of Part D plan concepts, as presented in the 2008 Medicare & You handbook.

Methods: A 10-question MBCT was developed using a case-vignette approach that required beneficiaries to read portions of the Medicare & You handbook and answer Part D–related questions associated with healthcare decision-making. The test was divided into 2 sections: (I) insurance concepts and (II) utilization management/appeals and grievances to cover standard terminology, as well as newer utilization management and appeals and grievances procedures that are unique to Part D. The test was administered to 100 beneficiaries at 2 sites—a university geriatrics clinic and a private retirement facility. Beneficiaries were tested for cognition and health literacy before being administered the test.

Results: The mean score on the MBCT was 3.5 of a maximum of 5, with no statistical difference found between both sites. Ten faculty members and 4 graduate students assessed the content validity of the instrument using a 4-point Likert rating rubric. The construct validity of the instrument was assessed using a principal components analysis with varimax rotation.

The principal components analysis yielded 4 factors that were labeled as “Plan D concepts,” “managed care/utilization management,” “cost-sharing,” and “plan comparisons.” The factor analysis indicated that the test is multidimensional and did measure the construct.

Conclusions: Medicare beneficiaries’ understanding of Part D may play a key role in the management of their drug use and health and the associated outcomes. The MBCT and its pending revisions can be administered to beneficiaries with differing health outcomes.

Medicare beneficiaries are often faced with several pieces of information involving a complex array of choices amidst bewildering plan options. It is crucial that beneficiaries and/or their family members involved in the decision-making process understand the plan benefits to truly make an informed decision. As the number of Medicare beneficiaries increases over the coming years with the baby boomers, it becomes even more imperative that the elderly have improved access to treatments that can achieve desirable outcomes. Measuring comprehension by Medicare beneficiaries may be an initial step toward understanding more complex issues, such as treatment adherence, decision-making, and, ultimately, trends in healthcare utilization and outcomes.

Stakeholder Perspective, page 461

Am Health Drug Benefits.

2013;6(8):453-461 www.AHDBonline.com Disclosures are at end of text

Dr Aruru is Assistant Professor, Roosevelt University College of Pharmacy, Schaumburg, IL; and Dr Salmon is Professor of Health Policy and Administration, School of Public Health, University of Illinois at Chicago, IL. Vol 6, No 8

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I

n the United States, the elderly population is growing. More than 1 of 8 Americans (34.5 million adults) are aged ≥65 years, and most are facing chronic degenerative diseases and disabilities.1 By 2030, older adults are projected to outnumber those aged <18 years.1 Approximately 75% of the elderly have at least 1 chronic illness, whereas approximately 50% have at least 2 chronic illnesses.2 Medicare currently covers 49 million people.3 These numbers are projected to double to 70 million people by the year 2030.4 The Medicare expenditures were estimated to reach $536 billion in 2012, causing alarm to the mounting federal deficit debates.5 With the new healthcare reform act, the Medicare program faces several budget cuts, with fiscal expansion, thereby politically threatening its longterm viability. Given that numerous beneficiaries are living longer and therefore their utilization of healthcare services is increasing, their Medicare expenses are growing concurrently. This may indeed become problematic, and it needs to be addressed by the current, as well as future, administrations.

It is becoming increasingly important in the context of health policy to ensure that elderly Americans understand their healthcare options so that they can make informed choices. Changes in the policy sphere with the introduction of Medicare Part D, increasing options to finance healthcare, and the economic downturn all interact with each other, and Medicare beneficiaries face significant challenges in assimilating unfamiliar, complex volumes of information.

A primary objective of Healthy People 2020, the nation’s health promotion and disease prevention agenda, is to improve the quality of life and longevity of adults with chronic diseases. Nearly all chronic diseases, including hypertension, stroke, asthma, diabetes, and coronary artery disease, require medication management among the elderly. Supplemental drug coverage and drug utilization in Medicare beneficiaries are national concerns, given their multiple considerations, as well as their critical role in improving health status.

Medicare Part D From its origin Medicare did not cover prescription drugs for its enrollees (except while hospitalized), but that changed with the Medicare Modernization Act (MMA) of 2003. The Medicare Part D prescription drug benefit is a newer outpatient plan that was rolled out on January 1, 2006. With the Balanced Budget Act of 1997 and the MMA, Medicare has been directed away from its traditional fee-for-service structure to a managed care financing model.

Part D provides an array of prescription drug benefits to most beneficiaries, and it has met the expectation to

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Key Points Beneficiaries’ understanding of Medicare Part D can play a key role in the management of their drug use and the associated outcomes, but many beneficiaries have cognitive problems or language barriers that hinder comprehension of healthcare concepts. ➤ A new Medicare Beneficiary Comprehension Test (MBCT) was developed to evaluate beneficiaries’ understanding of Part D’s concepts outlined in the 2008 Medicare & You handbook. ➤ The MBCT is a 10-question test, which requires beneficiaries to read parts of the handbook and answer questions regarding Part D concepts and utilization. ➤ This study demonstrates the validity of the MBCT as an original instrument to shed light on Medicare beneficiaries’ comprehension of Part D benefits. ➤ The mean score on Section I of the test, which addresses cost-sharing, was 3.28 (of a possible 8) for the geriatrics clinic and 3.08 for the retirement community cohorts. ➤ The mean scores in Section II, which measures comprehension of managed care concepts, were 0.76 at both sites; a mean of 0.76 indicates that most beneficiaries did not understand these concepts from the Medicare & You handbook. ➤ The scores on the MBCT were significantly different by sex and by levels of education, indicating it may be beneficial to tailor reading materials to specific populations as opposed to a standardized handbook. ➤ Measuring comprehension by Medicare beneficiaries may be a step toward understanding treatment adherence, decision-making, and trends in healthcare utilization and outcomes. ➤ Policymakers should approach cautiously the introduction of new market mechanisms to control utilization and costs to the Medicare program. ➤

improve access to medications for millions of elderly Americans. Elderly state Medicaid recipients now receive their prescription medications through Part D.

CMS Communications to Medicare Beneficiaries In 1999, the Centers for Medicare & Medicaid Services (CMS), formerly known as the Health Care Financing Administration, initiated a National Medicare Education Program to inform and to educate beneficiaries about Medicare+Choice, and to provide them with general and comparative information about their health insurance options.1 “The specific objectives of this campaign were to

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ensure that beneficiaries have access to accurate and reliable information, are aware of different health plan choices available to them, understand the consequences of choosing different plans, and are able to use the information provided to them when making decisions.”6 CMS would like Medicare beneficiaries to view the Medicare program and its private-sector partners as trusted and reliable sources of information.7,8 CMS developed a consumer handbook (Medicare & You) to explain health plan options and to inform Medicare beneficiaries. The education campaign also provided a toll-free telephone helpline; an Internet information database; support and training; enhanced beneficiary counseling services; and state-, as well as community-based, outreach efforts (Table 1).6-8 Several newer concepts were introduced in Part D, including the donut hole, formulary management, step-therapy, quantity limits, copayments, coinsurances, and deductibles. Many elderly beneficiaries may not be familiar with these concepts and therefore unable to make properly informed decisions.9

Measuring Medicare Beneficiaries’ Understanding of Their Benefits Assessing reading materials typically involves measuring comprehension. Relatively few studies have examined the usefulness of the Medicare & You handbook and other materials in informing and educating beneficiaries adequately. Another study that analyzed data available from the Medicare Current Beneficiary Survey to evaluate the effectiveness of the Medicare educational campaign showed that awareness and knowledge of Medicare programs by beneficiaries was related to their level of education.7 Furthermore, among beneficiaries with access to the Internet, only a small percentage visited the Medicare website to seek further information.6 Some studies have addressed Medicare beneficiaries’ knowledge levels after reading the Medicare & You handbook and/or using other CMS educational tools.1,7-14 Few multivariate studies specifically address the factors that are associated with knowledge of health insurance among Medicare beneficiaries.15-20 Some studies found higher education to be significantly associated with greater health insurance knowledge.15-20 A study using the Health Insurance Experiment showed that higher knowledge was significantly associated with being offered a choice of health plans, longer term of enrollment in a plan, and the use of physician services.20 This study also reported that knowledge was adversely affected by plan complexity. Higher levels of knowledge were attributed to a younger age-group,20 whereas another study also reported the role of race (being white) as a factor that is associated with higher knowledge of health insurance plans.18

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omponents of the National Medicare Table 1 C Education Program • Beneficiary mailings that included the Medicare & You

handbook, which was mailed by the Centers for Medicare & Medicaid Services in October 2005

• Toll-free telephone helpline (1-800-Medicare) • Website portal (www.medicare.gov) • Alliances with national and local organizations • National train-the-trainer program • State- and community-based special information

campaigns

• Enhanced beneficiary counseling from State Health

Insurance Assistance programs

• Targeted and comprehensive assessment of outreach efforts

A study of 1600 Medicare beneficiaries suggested that their health insurance knowledge was clearly inadequate.14 The researchers reported that 47% of the respondents viewed the task of choosing a Part D plan, and a large majority did not understand the differences between traditional fee-for-service and managed care delivery systems.15 Researchers have reported modest gains in beneficiary knowledge after reading the Medicare & You handbook.13 However, such gains in knowledge may mean relatively little if the beneficiaries themselves are unable to retain such information.

In 2006, the US Government Accountability Office (GAO) analyzed 6 of 70 CMS Part D documents indicating that reading levels for the analyzed passages ranged from seventh grade to postcollege.10 Approximately 40% of seniors read at or below the fifth-grade level, suggesting a significant scope for improvement.10 Findings from the GAO’s 2008 study indicate that CMS’s model annual notice of change did not communicate drug plan changes effectively to beneficiaries.12 The GAO further stated in its report that the language contained in the mailings was at a reading level that is too high for many beneficiaries and that it contained irrelevant information.12 It was also discovered that 30% of the Medicare & You 2008 handbook was written at grade levels higher than grade 12.9 Since 2008, there has been much need for improvement in CMS communications with Medicare beneficiaries.

The design of appropriate writing materials for elderly populations is particularly important in light of evidence that some older individuals face challenges in reading and retaining written information.10,12 Studies have found that, based on reading materials, individuals aged ≥65 years were less proficient than younger adults in locating information in documents and making health-related decisions.15,17 A 2003 national survey on adult literacy found

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that 27% of Medicare beneficiaries were unable to understand information in short, simple texts.21

Comprehension “Comprehension refers to the ability to go beyond words.”22 In the healthcare paradigm, comprehension would take on a different meaning and significance.

Readers of healthcare materials are often consumers or patients in the healthcare system. Therefore, comprehension of healthcare materials would involve analyzing and applying concepts. For example, giving informed consent depends on a person’s ability to understand the basic concepts of research design, to estimate personal risk, and to assess suitability for commitment to the procedure or clinical trial.

Part D beneficiaries have varying levels of income, age, education, mobility, cognitive competence, access to help from family members, and so on. Some beneficiaries may be eligible for subsidies for their prescriptions based on their income levels. Several low-income sub­ sidies options are available to Medicare beneficiaries; however, the onus is on the beneficiary to seek information and to access any available assistance, which may not be an easy task for the average elderly person. Low literacy and low health literacy are prevalent in the Medicare population, and healthcare materials designed to inform these beneficiaries are written at higher levels, thereby adding to the complexity and confusion surrounding the Part D plan. It remains unknown whether beneficiaries truly comprehend the benefit design to make their best decisions regarding Part D enrollment.

Measuring comprehension may perhaps be the first step toward understanding enrollment behavior with this particular population.

Therefore, the present study aimed to develop a comprehension test specifically for Medicare Part D beneficiaries (ie, the Medicare Beneficiary Comprehension Test [MBCT]) based on the Medicare & You handbook. The MBCT was tested with 100 seniors at 2 distinct locations, a senior retirement center and a university-based geriatrics clinic, to improve generalizability of the findings.

Study Methods Instrument Development The MBCT was developed specifically for this study to assess the comprehension of key concepts under the Medicare Part D plan as presented in the Medicare & You handbook. Because this test does not measure or assess Part D knowledge, beneficiaries were provided with the required information from the handbook (2008 English version) before being tested. Questions were developed based on the reading passages. Respondents were asked questions about their familiarity with and the perceived

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usefulness of the handbook in making their own Part D plan decisions.

The test was developed using a case-vignette approach. Case vignettes are often used in the health professions as a teaching tool. For the MBCT, a case study was developed using a fictional elderly beneficiary (Mary Poppins) who has a few questions about Medicare Part D. The questions are meant to help her enroll and utilize a Part D plan to make an informed decision. The test questions are listed in Table 2.

The test was divided into 2 parts. Section I includes standard insurance concepts, to help Mary Poppins select a plan, and Section II includes Part D concepts (CMS- and managed care–specific), to help her procure the necessary prescriptions.

The standard insurance concepts include questions on deductibles, premiums, copayments, and coinsurance.

The managed care concepts include questions on utilization management techniques, such as formulary restrictions, prior authorizations, quantity limits, and the appeals and exceptions process under Part D. At the end of Section I, beneficiaries were told that Mary Poppins decided to enroll in a particular plan and had a prescription for a medication for hypertension. They were then asked for their input in helping Mary procure her prescription in the following section.

Questions 7a and 7b address the concept of formularies. Beneficiaries were asked to read passages in the handbook and to respond to the question. Questions 8 and 9 address the concepts of prior authorization and quantity limits, both of which are utilization management techniques often used by managed care health plans. Beneficiaries were asked to read relevant passages and to respond to these questions.

It is important to note that Medicare Part D’s reliance on market mechanisms differs from previous Medicare operational assumptions instilled in its inception in 1965, which did not rely on the healthcare market so stringently. All of the questions were written and developed to simulate real-life situations that a beneficiary may encounter in selecting and signing up for a Part D plan. Sentence structure and wording were carefully developed to include lower grade level readability (tested using the Windows-­ based Flesch-Kincaid Grade Level reading program). The average grade level readability of the MBCT was determined to be grade 5 (Flesch-Kincaid readability).

Exclusion Criteria This study excluded beneficiaries who were visually impaired, blind, or who had severe vision problems that could not be corrected by the use of eyeglasses or contact lenses. This study also excluded individuals who were very ill (ie, hospitalized) and participants who did not

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Table 2 Medicare Beneficiary Comprehension Testa

SECTION I

Mary Poppins retired from her sales position in January 2008.

She wants to sign up for a Medicare Part D plan.

She is extremely confused about Medicare Part D. Mary has a few questions for you.

She needs your help to understand and sign up for a Medicare Part D plan.

Please read the following passages so that you can correctly answer Maryâ&#x20AC;&#x2122;s questions (marked Medicare & You handbook reading passages to be provided to participant).

Based upon the following information and the passage that you have just read, answer questions 1 and 2: Mary has a choice of 2 different drug plans: Plan X: $500 deductible Plan Y: $300 deductible

6. Mary signs up for Plan X. Mary paid the deductible for Plan X. Her doctor prescribes one (1) medication for her.

Her medication costs $100 for one (1)-month supply.

How much will Mary pay for one (1)-month medication supply? a) $10 b) $20 c) $30 d) $40

SECTION II

Mary Poppins considered her options and signed up for Plan X. Mary has high blood pressure.

Her doctor prescribed Drug BP for her high blood pressure.

The doctor says that she can only take Drug BP for her high blood pressure.

Mary needs your help to get Drug BP.

1. Who pays the deductible? a) Part D plan b) Mary Poppins c) Neither

7. Mary signed up for Plan X. Mary goes to the pharmacy to get Drug BP. Plan X does not include Drug BP in its formulary.

2. Which plan would make Mary pay more (of her own money) before the plan starts to pay? a) Plan X b) Plan Y c) Both are equal

7a. W hat is the first thing that Mary should do to get Drug BP? a) Ask the doctor to write a prescription for a similar drug b) Ask for a temporary 30-day supply c) Ask Plan X for an exception d) Do nothing

Mary has a choice of 2 different drug plans: Plan X: $25 premium each month Plan Y: $30 premium each month 3. Which plan will make Mary pay more (of her own money) each month? a) Plan X b) Plan Y c) Both are equal

7b. What is the second thing that Mary should do to get Drug BP? a) Ask the doctor to write a prescription for a similar drug b) Ask for a temporary 30-day supply c) Ask Plan X for an exception d) Do nothing

4. Mary signs up for Plan X. Mary also signs up for a State Pharmacy Assistance Program (SPAP).

The SPAP pays $10 toward her premium each month.

How much premium does Mary pay each month? a) $10 b) $15 c) $20 d) $25

8. Mary signed up for Plan X. Mary goes to the pharmacy to get Drug BP. Plan X requires prior authorization for Drug BP. The pharmacist informs Mary that Plan X denied the prior authorization for Drug BP.

Plan X: 20% coinsurance for one (1)-month medication supply 5. Mary signs up for Plan X. Mary paid the deductible for Plan X. Her doctor prescribes one (1) medication for her.

The medication costs $100 for one (1)-month supply.

How much will Mary pay for one (1)-month medication supply? a) $10 b) $20 c) $30 d) $40

Plan X: $30 copay for one (1)-month medication supply

What should Mary do to get Drug BP? a) Ask the doctor to write a prescription for a similar drug b) Ask for a temporary 30-day supply c) Ask Plan X for an exception d) Do nothing

9. Mary is going on vacation to Timbuktu for six (6) weeks.

She wants to carry a six (6)-week supply of Drug BP on vacation.

Her Plan X has set a quantity limit on Drug X for 30 days.

What should Mary do to get a six (6)-week supply of Drug BP? a) Ask the doctor to write a prescription for a similar drug b) Ask for a temporary 30-day supply c) Ask Plan X for an exception d) Do nothing

This test is still being finalized and revised. If you wish to use this test with your Medicare beneficiaries, please contact Dr Aruru via e-mail at maruru@roosevelt.edu for more information. a

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emographics for Respondents of the Medicare Table 3 D Beneficiary Comprehension Test Study Patients, % Mean MBCT ( N = 100) scores P value

Characteristics Age, yrs 65-84 ≥85

61 32

4.26 3.27

.666

Race/ethnicity Caucasian African American

54 36

3.91 4.31

.52

26 74

4.19 3.85

.396

Sex Male Female

44 56

4.59 3.43

.001a

Grade level education Less than high school High school graduate

81 19

3.74 4.79

.03a

Seen handbook Yes No

80 20

4.03 3.60

.372

Marital status Married Unmarried/separated/ divorced/widowed

The difference is significant (ie, P <.05).

MBCT indicates Medicare Beneficiary Comprehension Test.

a

edicare Beneficiary Comprehension Test Mean Table 4 M Scores for Respondents

Testing site

Section I MBCT Section II Total mean score range, mean MBCT MBCT minimumMBCT score,a score (SD) score (SD) mean (SD) maximum

University clinic

3.28 (1.6)

0.76 (1.2)

4.04 (1.8)

0-7

Retirement center

3.08 (1.6)

0.76 (1.1)

3.84 (2.0)

0-8

The difference is not significant (ie, P >.05).

MBCT indicates Medicare Beneficiary Comprehension Test; SD, standard deviation.

a

wish to cooperate or who were unwilling to complete the study. Individuals who did not understand or speak English, or those who were not fluent in the English language, were excluded from the study. Eligibility was determined based on responses to a generic sociodemographic questionnaire.

Study Results Data were analyzed using the PASW 17.0 statistical software. The MBCT was divided into 2 sections: Section I addressed standard insurance concepts (eg, premiums, copayments, coinsurance, and deductibles), and

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Section II addressed managed care and Part D concepts (eg, prior authorizations, quantity limits, and formularies in the context of filing for appeals and exceptions).

A total of 100 individuals were enrolled into the study—50 at a university-based geriatrics clinic and 50 at a retirement community in the Northwest suburbs of the Chicago area (Table 3).

Bivariate analyses were conducted using ordinal regression for each regressor. Responses obtained for all questions were recorded and are measured on an ordinal scale, with higher values indicating a better understanding of the reading material.

Table 4 shows the responses for the MBCT scores at both sites. The MBCT includes a total of 10 questions and therefore 10 possible points. Each question had only 1 correct response. In this sample, a minimum score of 0 and a maximum of 8 points could be achieved on both sections (Table 4). There was no significant difference between the scores (P >.05) at both sites.

Validity of the Medicare Beneficiary Comprehension Test The primary objective of this study was to conceptualize and develop a Medicare Part D comprehension test for beneficiaries and to test it in a small sample to assess its validity in further research.

Content validity. The MBCT was first tested for content validity utilizing 6 pharmacy administration faculty members, 4 graduate students (pursuing master’s and doctorate degrees), and 4 pharmacy practice faculty members. Experts were provided with the MBCT and a 4-point Likert rating scale to rank questions from highly appropriate to highly inappropriate. Each question was rated based on 3 characteristics: relevance to the study population, question properties (ie, wording, grammar), and answer choices (ie, wording, length). Experts were also asked to provide feedback on the length, relevance to the study questions, and the ability of the elderly population to answer these questions. The final revised version was administered to 100 beneficiaries at 2 locations.

Construct validity. To ascertain that the questionnaire indeed measures the construct for which it was originally intended, a factor analysis was carried out to search for underlying themes.23 The factor analysis was carried out using PASW 17.0 to determine if a simple method for summing all of the items into a total Medicare Part D comprehension score was possible.

Factor analysis. A principal components analysis with varimax rotation was run in PASW. The analysis yielded a total of 10 factors, of which 4 were retained (eigenvalue >1; Table 5). Four factors and variables loaded highly onto 1 factor. It is interesting to note that all 4 questions from Section II (managed care/utilization

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questions) of the MBCT loaded on the same factor.

The 4 questions (ie, questions 7a, 7b, 8, and 9) that loaded onto the first factor can be labeled as “Part D/ managed care concepts.” Question 1 also loaded onto factor 1. This question asked beneficiaries about who pays the deductible, and it may be construed as a managed care/insurance concept. The 2 questions (questions 2 and 3) that loaded highly on factor 2 asked about which plan would make Mary pay more (of her own) money monthly, and that plan is labeled as “plan comparison.” Question 4 that loaded onto factor 4 asked the beneficiary to calculate a premium based on a subsidy, and is labeled as “understanding of low-income subsidies.” Questions 5 and 6 are related to copayments and coinsurance and are labeled as “cost-sharing.”

This analysis revealed that the MBCT is actually composed of 4 subscales: (1) plan comparison, (2) understanding of low-income subsidies, (3) cost-sharing, and (4) Part D/managed care concepts. This was the intent behind the development of the questionnaire and testing it. This analysis demonstrates that the MBCT successfully measures readers’ comprehension of Medicare Part D from the Medicare & You handbook; however, because this was an exploratory study, with only 100 participants, further research, with larger sample sizes, may be needed to gain better clarity on the factors and to improve the internal consistency of this study.

Discussion The beneficiaries’ understanding of their choices in Medicare Part D and the concepts involved in Part D (including newer terminology) may play a role in influencing their health and wellness. For example, if standard benefit beneficiaries did not truly comprehend the concept of the donut hole and picked a Part D plan with no coverage in the donut hole, they may be unable to pay the full price of their medications when they fall into the coverage gap, and they may also be unable to refill prescriptions enough to reach the catastrophic coverage.

Enrollment in Part D is a complex issue that requires the ability to access, read, comprehend, and act on the information that is given. It also involves complex tasks, such as comparing plans and calculating costs for each individual beneficiary. Enrolling into and maintaining a Part D plan also requires knowledge about health insurance in general, as well as the ability to find information and use it to compare various plan offerings that may be appropriate for the individual’s financial situation and pharmacotherapy regimen. It also involves the ability to file appeals and/or exceptions when necessary.

This study demonstrates that the MBCT is a valid instrument, and perhaps one of the first, to shed light on beneficiaries’ comprehension of the newer Medicare

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edicare Beneficiary Comprehension Test Factor Table 5 M Analysis Componenta

Test question

Part D/ managed care Plan Cost- Low-income concepts comparison sharing subsidies

Q1. Deductible 1

0.711

Q2. Deductible 2

0.697

Q3. Premium 1

0.659

0.521

Q4. Premium 2

0.896

Q5. Coinsurance

0.819

Q6. Copayment

0.827

Q7a. Formulary

0.793

Q7b. Formulary

0.392

Q8. Prior authorization

0.724

Q9. Quantity limits

0.820

–0.698

Rotation converged in 6 iterations.

a

benefit. The mean score on Section I of the test that addressed cost-sharing (eg, premiums, copayments, coinsurance, deductibles) was 3.28 for the geriatrics clinic and 3.08 for the retirement community beneficiaries.

Section II means were the same at both locations (0.76).

This is an interesting finding, because Section II specifically asked questions about comprehension of managed care concepts (eg, formularies, quantity limits, step-therapy) and CMS’s appeals and grievances procedure.

A mean of 0.76 indicates that most beneficiaries did not understand these concepts from the Medicare & You handbook. Furthermore, it may be safe to say that beneficiaries may not have understood these concepts either because of their unfamiliarity with them or their inability to deal with them. This is alarming, because all managed care plans use utilization management, and at any given time beneficiaries may find themselves faced with a difficult situation that limits their access to their prescription medications.

Furthermore, the scores on the MBCT were significantly different by sex and by grade-level education, indicating that it may be useful to tailor reading materials to specific populations as opposed to a standardized handbook that may not be comprehensible to all.

Medicare beneficiaries are faced with a bewildering array of choices, some of which they may not truly understand. Beneficiaries must understand varied new managed care concepts to make informed decisions. This becomes especially important when beneficiaries have to seek and process such information by themselves, with-

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out the help of an employer, friends, or relatives who may be able to help them make informed decisions. Only few studies have assessed elderly beneficiaries’ knowledge about Medicare,15-20 and even fewer evaluated comprehension of the newer Part D concepts.9 As more and more beneficiaries qualify for Part D annually, they will need to evaluate their choices and make better decisions in their best interests. Existing beneficiaries also need to reevaluate their plan choices to ensure optimal outcomes from their plans.

Such disregard in policymaking can yield deleterious consequences in health outcomes and in the associated costs. Remedies to curtail the $536 billion in Medicare expenditures can be much better addressed than merely rolling back eligibility age, restricting benefits, and cutting provider reimbursements. n

Limitations A few limitations are recognized in this study. First, the study population was small (N = 100), with only the minimum number of participants enrolled by study completion.

In addition, the study populations were limited, using accessible populations from a public clinic and a private nursing home retirement community, and not a randomly obtained sample. These population characteristics preclude generalizations or inferences to nonsimilar populations.

Another limitation is the variety of factors that may affect comprehension that were neither measured nor controlled for in the study design and analysis, including the possibility that participants might have procured Part D informational materials from outside sources not addressed in this study. Because of time and resource constraints, every identifiable confounding independent variable could not have been controlled.

References

Conclusions The MBCT is perhaps one of the first instruments to shed light on Medicare beneficiaries’ comprehension of the Part D plan benefit. The mean score of 0.76 achieved in Section II indicates that most beneficiaries did not understand the managed care concepts from the Medicare & You handbook provided by CMS. As the number of Medicare beneficiaries increases over the coming years with the aging of the baby boomers, it becomes even more imperative that the elderly have improved access to their healthcare with treatments to achieve desirable health outcomes.

Measuring comprehension by Medicare beneficiaries may be an initial step toward understanding more complex issues, such as treatment adherence, decision-making, and, ultimately, trends in prescription drug utilization. Moreover, policymakers should approach the future introduction of market mechanisms to control utilization and costs to the Medicare program cautiously. Based on the research findings described in this article, the privatization of Medicare Part D appears to have complicated choices for beneficiaries, choices that were not considered by a CMS cognizance of varying health literacy levels among Part D participants.

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Author Disclosure Statement Dr Aruru and Dr Salmon have reported no conflicts of interest.

1. Harris-Kojetin LD, McCormack LA, Jaël EM, Lissy KS. Beneficiaries’ perceptions of new Medicare health plan choice print materials. Health Care Financ Rev. 2001; 23:21-35.

2. Calkins E, Boult C, Wagner EH, Pacala JT, eds. New Ways to Care for Older People: Building Systems Based on Evidence. New York, NY: Springer; 1999.

3. Kaiser Family Foundation. Total number of Medicare beneficiaries. 2012. www. statehealthfacts.org/comparemaptable.jsp?cat=6&ind=290#footnote1. Accessed September 27, 2013.

4. Administration on Aging. A profile of older Americans: 2000. www.aoa.gov/ AoAroot/Aging_Statistics/Profile/2000/profile2000.pdf. Accessed September 27, 2013.

5. Kaiser Family Foundation. Medicare spending and financing fact sheet. November 14, 2012. http://kff.org/medicare/fact-sheet/medicare-spending-and-financingfact-sheet/. Accessed October 2, 2013.

6. Berkman ND, Bann C, Kuo M, et al. Analysis of Medicare beneficiary knowledge data using the Medicare Current Beneficiary Survey (MCBS): phase 3.1: final report.

RTI International. July 19, 2002. www.cms.gov/Research-Statistics-Data-andSystems/Statistics-Trends-and-Reports/Reports/downloads/berkman_2002_7.pdf.

Accessed November 20, 2013.

7. Assessment of the National Medicare Education Program: supply and demand for information. Health Care Financ Rev. 1999;21:129-131.

8. Cronin C. Private sector coverage of Medicare beneficiaries: a forum for employers and unions. Presented at a conference sponsored by the Health Care Financing Administration; March 21-22, 2000; Baltimore, MD. 9. Aruru M, Salmon JW. Assessment of Medicare Part D communications to beneficiaries. Am Health Drug Benefits. 2010;3:310-317.

10. US Government Accountability Office. Medicare: quality of CMS communications to beneficiaries on the prescription drug benefit could be improved. May 4, 2006. www.gao.gov/assets/120/113801.pdf. Accessed September 27, 2013.

11. US Government Accountability Office. Medicare Part D low-income subsidy: SSA continues to approve applicants, but millions of individuals have not yet applied. May 22, 2008. http://aging.senate.gov/events/hr195bb.pdf. Accessed September 27, 2013.

12. US Government Accountability Office. Medicare Part D: opportunities exist for improving information sent to enrollees and scheduling the annual election period.

December 2008. www.gao.gov/new.items/d094.pdf. Accessed September 27, 2013.

13. McCormack LA, Garfinkel SA, Hibbard JH, et al. Health insurance knowledge among Medicare beneficiaries. Health Serv Res. 2002;37:41-61.

14. Bernstein J, Stevens RA. Public opinion, knowledge, and Medicare reform.

Health Aff (Millwood). 1999;18:180-193.

15. Hibbard J, Greene J, Tusler M. An assessment of beneficiary knowledge of Medicare coverage options and the prescription drug benefit. AARP. May 2006. http://assets. aarp.org/rgcenter/health/2006_12_medicare.pdf. Accessed September 27, 2013.

16. Cafferata GL. Knowledge of their health insurance coverage by the elderly. Med Care. 1984;22:835-847.

17. Hibbard JH, Jewett JJ, Englemann S, Tusler M. Can Medicare beneficiaries make informed choices? Health Aff (Millwood). 1998;17:181-193.

18. Lambert ZV. Elderly consumers’ knowledge related to Medigap protection needs.

J Consum Aff. 1980;14:434-451.

19. McCall N, Rice T, Sangl J. Consumer knowledge of Medicare and supplemental health insurance benefits. Health Serv Res. 1986;20(6 pt 1):633-657.

20. Marquis MS. Consumers’ knowledge about their health insurance coverage.

Rand Corporation; 1981. www.rand.org/content/dam/rand/pubs/reports/2007/R2753. pdf. Accessed September 27, 2013.

21. Kutner M, Greenberg E, Jin Y, Paulsen C. The health literacy of America’s adults: results from the 2003 National Assessment of Adult Literacy (NCES 2006– 483). US Department of Education. 2006. Washington, DC: National Center for Education Statistics.

22. McNamara DS, ed. Reading Comprehension Strategies: Theories, Interventions, and Technologies. Mahwah, NJ: Lawrence Erlbaum; 2007.

23. Engs RC. Construct validity and re-assessment of the reliability of the Health Concern Questionnaire. Adv Health Educ. 1996;4:303-313.

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Stakeholder Perspective Understanding the Options: An Essential Ingredient in Our Evolving Healthcare System

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

PATIENTS: Do seniors understand their options when they enroll in Medicare? For that matter, how well do people of any age understand how their health insurance works? Consumer educationâ&#x20AC;&#x201D;and more important, consumer comprehension about healthcare and health insuranceâ&#x20AC;&#x201D;is critically important in an era of expanding choices.

Medicare has long offered alternatives to traditional Medicare through Medicare Advantage plans (and their precursors, which have been available since the mid1980s) and, more recently, Medicare prescription drug plans under Part D. Initially, educational outreach to beneficiaries was limited to publications similar to Medicare & You, whose 2014 edition is 152 pages long.1 For most people, that is 151 pages too many. They need an immediate answer to their questions, without having to wade through other materials that address different issues. The long-standing challenge has been to find ways that cut through the murk of regulatory whys and wherefores without misleading beneficiaries.

The Centers for Medicare & Medicaid Services offers a plan finder at Medicare.gov that allows seniors to compare their alternatives, including traditional Medicare, Medicare Advantage plans, and stand-alone prescription drug plans. A search for plan alternatives serving Washington, DC, reveals that 11 comprehensive health plan choices (including traditional Medicare), 31 stand-alone drug plans, and 7 different categories of information about those alternatives are available.

Even so, the plan finder leaves out some important information. The most serious omission: Medigap plan information is left out. Those plans are purchased separately by enrollees in traditional Medicare and are considered by many to be an integral part of their coverage.

In its attempt to provide reasonably complete information about plan alternatives, the plan finder produces information overload. Many people are likely to be overwhelmed by the cacophony of insurance terms and conditions. The plan finder provides data, but it does not help seniors understand what to make of those data.

PAYERS/PROVIDERS: What many of us know from the introduction of Medicare Part D is that seniors, even those who are comfortable with computerized searches, often need to talk their choices over with a

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trusted individual before they are comfortable committing to a particular plan. Call centers and more sophisticated interactive responses can help fill that need, but informed family members and friends in the community are more likely to be relied on to help decide which plan to select.

Are there too many plan choices, making it difficult for seniors to select the best option?2 Should we limit the number of plan options, or should we improve the way we communicate with beneficiaries and make a greater investment in effective just-in-time education?

New evidence from Medicare Part D suggests that better education and communication can pay off in improving the decisions made by seniors about their plan choices. A study of more than 71,000 enrollees in standalone drug plans found that seniors often did not select the lowest cost option when they first enrolled in 2006.3 However, even with less than 1 year of experience in Part D, 81% of these individuals were able to reduce their overspending by an average of $298. The greatest gains went to those who switched plans.3 This demonstrates the importance of actual experience and the ability of seniors to learn from their mistakes in selecting health plans. It also shows that seniors are able to use information about plan choices if that information is provided in ways that can be understood by people who are not insurance experts.

The implications of this analysis extend well beyond the Medicare program. The Affordable Care Act created health insurance exchanges offering a choice of health plans to individuals who are not already covered by insurance. Large firms are increasingly moving to private exchanges to provide more plan choices for their employees.4 Better decisions by consumers will drive competition and will improve health system efficiency, and that depends in large measure on the way information about health plan options is presented.

1. Centers for Medicare & Medicaid Services. Medicare & You. 2014 edition. September 2013. www.medicare.gov/Pubs/pdf/10050.pdf. Accessed October 14, 2013.

2. The Incidental Economist. Too many choices. AcademyHealth Blog. September 25, 2013. http://blog.academyhealth.org/too-many-choices/. Accessed October 14, 2013.

3. Ketcham JD, Lucarelli C, Miravete EJ, Roebuck MC. Sinking, swimming, or learning to swim in Medicare Part D. Am Econ Rev. 2012;102:2639-2673.

4. McCann D. Aon Hewitt Scores 15 Big Private-Exchange Clients. CFO.com.

September 18, 2013. http://ww2.cfo.com/health-benefits/2013/09/aon-hewitt-scores15-big-private-exchange-clients/. Accessed October 14, 2013.

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR) 100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20%

ORR 7.4% (n=8)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

0%

POMALYST (N=108)

POMALYST + low-dose dex (N=113)

Study design: A Phase II, Stud multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception POMALYST is available only through a restricted program called the POMALYST REMS program.

VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. 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.

POMALYST is only available under a restricted distribution program, POMALYST REMS™.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy

• POMALYST can cause fetal harm and 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 a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide 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 POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST 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 POMALYST

POMALYST REMS Program

Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

WARNINGS AND PRECAUTIONS (continued) Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS

In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction.

• In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS

No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST 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 if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established.

Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 04/13 US-POM120033

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy.

POMALYST is a thalidomide analogue.

Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.

• Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].

POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)].

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Toxicity

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant.

Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis.

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.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST 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 POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST 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 POMALYST 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 Pomalidomide 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 POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST 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 POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST 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 POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements.

Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors.

5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia.

Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia.

Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)].

5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state.

Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy.

There were no cases of grade 3 or higher neuropathy adverse reactions reported.

5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma 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. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions.

The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction.

Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%).

Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112).

Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%).

Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112).

Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).

7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided.

7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided.

Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction.

Patients should be advised that smoking may reduce the efficacy of pomalidomide.

Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST 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. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis.

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. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels.

There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day.

Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption.

8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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 of POMALYST in patients below the age of 18 have not been established.

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8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST 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 POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST 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 POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. 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. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies.

Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.

In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.

17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide).

Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may 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 POMALYST and for at least 4 weeks after completing therapy.

• Initiate POMALYST 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 POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. 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 POMALYST 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 POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy.

• Advise male patients taking POMALYST 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 POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)].

• Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. 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)].

• POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product.

Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation.

Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown.

Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

• The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water.

• Instruct patients that if they miss a dose of POMALYST, 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 POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed.

Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)].

Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation.

U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

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BUSINESS

Review Article

The Economics of Biosimilars Erwin A. Blackstone, PhD; Joseph P. Fuhr, Jr, PhD Background: The high cost of pharmaceuticals, especially biologics, has become an impor­ tant issue in the battle to control healthcare costs. The Hatch-Waxman Act encourages gener­ ic competition but still provides incentives for pioneers to develop new drugs. The Biologics Price Competition and Innovation Act is intended to do the same for biologics and biosimilars.

Objective: To examine information related to biosimilars to determine their potential impact on competition in the biologic market.

Method: Using information concerning the European Union (EU) and the pharmaceutical industry, this article reviews and analyzes the experience of biosimilars in the EU, as well as the obstacles and opportunities that biosimilars face in the United States. Much of the analy­ sis is based on examining current trends in biologic drugs and the potential implications on the future of biosimilars.

Discussion: This article reviews the mixed success of biosimilars in the EU and the implica­ tions for the United States. Because biologics are produced from living organisms, manufac­ turing issues are more important than in the chemical drug market. The barriers to biosimilar entry into the marketplace are much more difficult to overcome than challenges generic man­ ufacturers typically face and are similar to obstacles specialty injectable producers encounter.

The competitive responses by pioneers are also likely to be more important. The capital costs and risk issues with biosimilars make alliances and partnering arrangements very likely.

Biosimilars often enter emerging markets, where the barriers to entry are easier to overcome.

Nevertheless, the United States represents the greatest opportunity for biosimilar producers, in part because it is the largest biologics market and has high prices for biologics. As the United States enters the biosimilar market, the pharmaceutical industry is likely to grow at an accelerated pace. Automatic substitution is likely to be slow to develop, because of safety and quality concerns. The beneficial impact of biosimilars is likely to take a long time to be realized and to be fraught with more difficulties than was the case for small-molecule generics.

Conclusion: Various factors, such as safety, pricing, manufacturing, entry barriers, physician acceptance, and marketing, will make the biosimilar market develop different from the gener­ ic market. The high cost to enter the market and the size of the biologic drug market make entry attractive but risky.

T

he high cost of pharmaceuticals, especially biologics, has become an important issue in the battle concerning ever-increasing healthcare costs. The average daily cost of a biologic in the United States is $45 compared with only $2 for chemical (small-molecule) drugs.1 The Hatch-Waxman Act encourages generic competition but still provides incentives for pharmaceutical innovators to develop new drugs. The Biologics Price Competition and Innovation Act (BPCIA) of 2009 is intended to do the same for biologics and biosimilars. Now that the US Food and Drug Administration (FDA) can approve biosimilars, it is impor­ tant to consider whether biosimilars are likely to have Dr Blackstone is Professor of Economics, Temple University, Philadelphia, PA; Dr Fuhr is Professor of Economics, Widener University, Chester, PA.

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2013;6(8):469-478 www.AHDBonline.com Disclosures are at end of text

the same impact in the biologic drug market that generics have had in the chemical drug market.

The experience in the European Union (EU), where biosimilars were first marketed in 2007, is instructive.

This article reviews the obstacles that biosimilar manufacturers face, as well as the opportunities, and evaluates the probable impact of biosimilars on the healthcare market. The potential impact of the BPCIA on prices and access in the biologic market are addressed.

Terminology and Definitions The biologic market is composed of large-molecule drugs that are produced in living organisms. Biosimilars, unlike small-molecule generics, are not identical to the reference product. A biosimilar is “highly similar” to a branded drug, which is referred to as the “reference product.”2 The Affordable Care Act (ACA),

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Key Points The high cost of pharmaceuticals, especially biologics, has an increasing impact on healthcare costs. ➤ Biosimilars have been available in the European Union since 2007 but are only now being considered for approval by the FDA. ➤ Biosimilars have the advantage of being able to extrapolate and “piggyback” on the branded drug to get approval for all the original drug’s indications. ➤ The barriers to market entry for biosimilars are much more difficult to overcome than is typically seen with small-molecule generic drugs. ➤ Safety, pricing, manufacturing, market entry barriers, physician acceptance, and marketing will make the biosimilar market develop different from the generics market. ➤ As of mid-January 2013, the FDA received 13 inquiries about potential biosimilar application, but no applications have been filed. ➤ The first biosimilar marketed in the United States is likely several years away at least. ➤ Pharmaceutical alliances will be common, because of the need to share the risk inherent in biologic and biosimilar development; the possible extension of a patent for the original biologic is inherent in the risk of entering the biosimilar market. ➤ Large, well-established companies are expected to dominate that market. ➤

which includes the BPCIA, defines biosimilars as having “no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.”2 The implementation of the ACA (the new healthcare law) requires many decisions by the FDA, such as the extent of clinical trials that will be required and developing guidelines for biosimilar entry.2 Because different countries have various regulatory requirements, the term “biosimilar” is often misused. Bio­ similars that do not meet the requirements of being similar to the original drug are referred to as “noncomparable biologics.” In this article we consider biosimilars to be those that were approved in the United States, EU, Canada, or Australia, and one should be cautious in referring to other countries’ noncomparable drugs as biosimilars. Biobetters are biologics that exhibit superiority over the branded biologic in dimensions such as efficiency or clinical specificity.2

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Biologics and Incentives for Innovation The BPCIA recognizes the importance of encouraging innovation, but it also provides a pathway for competition once monopoly protection ends. Biologics can obtain patent protection, which lasts for 20 years from the date the patent application is filed.3 Questions exist about the degree of protection afforded by biologic patents.3 Accordingly, the BPCIA provides a 12-year market exclusivity and a 4-year data exclusivity beginning when the biologic drug receives FDA marketing approval. Each exclusivity can be extended 6 months for pediatric applications. A biosimilar cannot be marketed until the 12-year exclusivity expires.3 These exclusivity protections are intended to encourage biologic research and development (R&D). Patents can be challenged in court, but exclusivity cannot.

There is often a lag of many years between patent approval and FDA approval to market a drug; therefore, a patent may run out before the exclusivity expires. By contrast, it is important that the data exclusivity expire before the market exclusivity, so that a biosimilar manufacturer can begin development work to ensure rapid market entry on the expiration of a biologic’s market exclusivity. Furthermore, biosimilar entry would be encouraged by predictable approval requirements from the FDA and market acceptance, among other factors. This would decrease risk, leading to more entry and greater price discounting. The 12-year market exclusivity is a type of insurance policy, given the uncertainty of patent litigation, and is probably necessary to encourage innovation.

Biologics Market The biologics market is growing rapidly, especially compared with the small-molecule chemical market whose revenues actually decreased in 2012. The future for many pharmaceutical firms is in biologics. Several biologics have sales of more than $1 billion annually. For example, in 2011, global sales were $7.19 billion for Remicade (infliximab) and $5.98 billion for Avastin (bevacizumab).4 In addition, many of these very profitable drugs are scheduled to come off patent, providing the opportunity and incentive for biosimilar entry. Specifically, Herceptin (trastuzumab), Humalog (insulin lispro), Rituxan (and MabThera in Australia; rituximab), Remicade, and Aranesp (darbepoetin alfa) will lose patent protection within 5 years.5 It is also estimated that 32 biologics, with a combined $51 billion of sales in 2009, will lose patent protection by 2015.4 The opportunity exists, but unlike the generic market, where market entry is fairly simple and well established, there are substantial barriers to entry into the biosimilar market.

The investment needed to develop and market a biosimilar is considerably higher than the $1 million to $4

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million that is required in the generic market. It takes 7 to 8 years to develop a biosimilar, at a cost of between $100 million and $250 million.6 Moreover, the complexity of monoclonal antibodies makes their development and manufacturing costs much higher than for the biosimilars that are currently on the market in the EU. The US market is by far the largest and potentially most lucrative market for biosimilars. It has attracted the interest of various companies. At the same time, other companies have been discouraged by the lack of definitive standards for approval and the concerns about adequate profitability given the greater risk. In any event, biosimilar entry is probable only for the biologics with substantial sales and profits.

The EU Experience The first biosimilar was approved in the EU in 2006.7 However, although the EU market has grown over time, it is still relatively small. Only 16 biosimilars in 3 classes—human growth factor, short-acting erythropoietin, and daily granulocyte colony-stimulating factor (GCSF)—have been approved. These 3 classes represent approximately 11% of the total patient volume and approximately 18% of all biologic sales.7 For the year ending June 2011, biosimilars accounted for approximately 10% of the available market, and biosimilars make up <1% of the total biologic sales in the EU.7 However, the EU has approximately 80% of the global biosimilar market.1 Long-acting erythropoietin and G-CSF are not included in the biosimilar market, because the patents have not expired for these products. Biosimilar prices in the EU have been on average approximately 30% less expensive than their reference products.8 In June 2013, Celltrion and Hospira received permission from the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use, and have recently received approval from the European Commission to market a biosimilar version of Johnson & Johnson’s Remicade.9 This is the first approval of a monoclonal antibody biosimilar. The biosimilar, called Remsima, will not be marketed in most of the EU until the EU patent for Remicade expires in February 2015, but it will be marketed in some countries in 2014. However, Johnson & Johnson has many secondary patents on Remicade and may file a patent infringement case to prevent the marketing of the biosimilars.9 EU countries generally prefer lower costs than increased access.10 Automatic substitution at the pharmacy level has not occurred: the EMA advises against such substitution.11 No European country (except Germany) has been willing to give preferential reimbursement treatment, which is important to long-term success.10 In the EU, penetration rates for different biosimilars vary

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iosimilar Differences: European Union versus Table 1 B United States Biosimilar parameters

European Union

United States

Exclusivity for first interchangeable drug

None

1 year

Efficacy and safety

Patient benefit

Yes

Likely

10 years

12 years

Same as pioneer drug

Not yet determined

Regulatory application must show: Decisions related to “biosimilarity” determined on case-by-case basis Exclusivity period Postmarketing requirements

considerably between and within countries. In terms of companies, Sandoz has 3 biosimilars and has 50% of the total biosimilar market in the EU.12 In the EU, the major players are large, well-established companies, such as Teva, Sandoz, and Hospira. One would expect the same to occur in the United States.

The experience of the EU does not particularly bode well for the initial success of biosimilars in the United States. The lack of automatic substitutability, the relatively small price savings, and the reluctance of physicians to use biosimilars explains the situation (Table 1).

Nevertheless, biosimilars have not had substantial safety issues in the EU. Despite the lack of safety problems in the EU, the United States is likely to err on the side of caution when it approves biosimilars. After all, one safety problem could stifle the industry’s development. Moreover, the relatively low price discounts may be viewed as desirable for the biosimilar firms, and the experience in terms of market shares and sales in the EU is similar to that of specialty injectables and nonoriginal drugs in general. Therefore, the implications for biosimilars in the United States must be viewed cautiously.

Barriers to Market Entry Biosimilars will encounter substantial barriers in their efforts to compete with branded biologics. These obstacles are more substantial than those encountered by small-molecule generics. Specifically, biosimilars have to overcome the particular barriers that are associated with manufacturing, marketing, storage (cold) and other distribution issues, delivery devices, immunogenicity (ie, patient adverse reactions because of live organisms), and special requirements for pharmacovigilance (ie, postsale monitoring).2 Complexity of Expertise One of the major barriers is the complexity of manu-

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facturing biologics and biosimilars. Companies with experience in manufacturing, especially in manufacturing biologics, such as Amgen and Biogen Idec, will have a considerable advantage over new companies with no such manufacturing experience. Therefore, experienced companies should dominate the market, which is one reason for the various alliances that enable these companies to be stronger competitors.

Biologics and biosimilars are sensitive to and altered by changes in their manufacturing process. The FDA must approve even minor changes in the production process. Achieving a sufficiently uniform product is difficult and costly even in different batches of the same product, which can make market entry risky and can discourage some potential entrants.5 Manufacturing biosimilars, or biologics for that matter, requires scientific expertise and experience. There is a steep learning curve, which gives companies such as Amgen and Hospira an effective and substantial cost advantage.5 In 2009, Samsung announced a $389-million investment in biosimilars over 5 years.13 Samsung believes that it has a competitive advantage in the manufacturing of biosimilars.14 Giles Cottler, President of SAFC, stated, “existing larger biopharma players that are entering the biosimilar space, as well as continuing in the innovative space, probably have a better chance because of the complexity of the IP [intellectual property], the complexity of the processes, and the complexity of making a biosimilar.”15 Large pharmaceutical companies will likely dominate the market, because they bring “marketing, sales, R&D, and manufacturing expertise to the table.”12

Legal Issues Other barriers to market entry involve legal factors, such as patents and trade secrets arising from the ACA. An official at a biologics and biosimilars company stated that the uncertainty is preventing companies without “deep pockets” from entering into the industry.5 The FDA has received 13 inquiries from companies considering possible biosimilar entry as of mid-January 2013, but no applications have been submitted; even after an application is submitted to the FDA, there is no guarantee that it will be approved.16 There will be a considerable lag between application and approval. Therefore, the first biosimilar marketed in the United States may be at least several years away.

Lack of Automatic Substitution The lack of essentially automatic substitution and interchangeability has helped make entry difficult for biosimilars. The generic market gained market share with automatic substitution at the pharmacy level.

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Other factors such as efforts by insurance companies were also important. Presently, 84% of the small-molecule chemical market consists of generic drugs, but it was a long process to achieve this market share.17 It took some time for physicians and payers to accept generics, as will be the case for biosimilars.

The lack of identical products will make automatic substitution much more difficult to achieve for biosimilars. However, many biologics are administered by physicians; therefore, more emphasis will have to be directed at the physicians than was the case with small-molecule generics, thereby reducing the significance of automatic substitution to some extent. Greater biosimilar market shares should occur as physicians and patients become more familiar with them, in part because of the emphasis on decreasing healthcare costs.

Clinical Trials Another barrier is the difficulty in attracting patients to clinical trials of biosimilars. Patients may be reluctant to participate in the trials, especially for serious diseases, because only some of them will receive the biosimilar rather than being confident of receiving the branded biologic outside of a clinical trial. A patient with breast cancer, for example, is unlikely to participate in a trial in which the choice is Herceptin or a biosimilar, which may or may not work.18 Because many companies may be attempting to develop the same biosimilar, it may be difficult to get enough volunteers because they are competing for the same limited population.9 Based on discussions with people in the pharmaceutical industry, some biosimilar companies have encountered difficulties in obtaining the reference product for the trials, and when they do, it is often quite expensive.

Competition Another factor leading to great risk is the uncertainty associated with other potential biologic or biosimilar competitors. For example, a study by the Biotechnology Information Institute reported that companies are working on 21 biosimilars and 12 biobetters for Herceptin and 21 biosimilars and 13 biobetters for Rituxan.5 An approved biosimilar could therefore enjoy a large market share for a short time or perhaps not at all, because of the successful entry of another biosimilar or biobetter.

Also, the first entrant in the United States will not receive a 180-day exclusivity period that exists under the Hatch-Waxman Act for the first successful generic challenger, and the added cost of potential litigation may lead to a disadvantage for the first mover. A company could spend millions of dollars, only to find that its funds were wasted if a pioneer drug succeeds in obtaining a patent extension or a license for a biobetter.

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Market Opportunities Even given the uncertainty surrounding biosimilars, there are considerable commercial opportunities. The global sales of biologics amounted to $157 billion in 2011 and are estimated to reach more than $200 billion by 2016.16 According to the IMS Institute for Healthcare Informatics, the US drug market shrank for the first time in 2012, but spending on specialty drugs (mostly biologics) increased by nearly 20%, and growth in this segment is forecasted to be 40% through 2014.17 There are more than 45 monoclonal antibodies worldwide on the market, with revenues in excess of $40 billion.19 There are currently no monoclonal antibody biosimilars marketed in the EU; however, 2 have received approval from the EMA, and marketing could begin in 2015, when their EU patent is expected to expire. Manufacturer SAFC estimates that approximately 860 biosimilars are in development.15 Biologics with estimated sales of $100 billion will come off patent by 2020.20 Between 2009 and 2019, $50 billion of the market value of biologics in the United States alone will lose patent protection.21 For example, Genentech is at risk of losing $10.7 billion in sales with patent expiration for Avastin, Herceptin, and Rituxan.22 Because it is easier to copy than create, biosimilars have a better chance to make it to market and are therefore less risky than branded biologics. In addition, the investment in biologics is much greater than in biosimilars, and the probability of success is lower. The R&D record of pharmaceutical companies shows that approximately 95% of all drug projects never make it to market.23 The average cost of developing a new biotechnology drug as of December 2012 was estimated to be approximately $1.9 billion.4 Furthermore, only 1 in 10 approved drugs become a commercial success, and the average time to obtain approval to market a drug is 13.5 years.4 Only 9% of the drugs entering phase 1 clinical trials between 2004 and 2010 achieved regulatory approval, and only 22% of the biologic drugs entering phase 2 clinical trials have achieved approval.4 Because the market for many reference products is large, especially for monoclonal antibodies, there is an incentive for biosimilars to enter the market—a 5% share of a $1-billion market can lead to a good return on an investment: “Despite the inherent risk, biosimilars have the potential to exceed benchmark returns from any other form of R&D, a primary reason for increased alliances in the last 5 years.”21 Nevertheless, companies will need to spend considerably more on biosimilars than on small-molecule generics to enter the market; because they are not identical, presently no automatic substitution exists, and they must compete like a branded drug.21 Furthermore, manufacturers must spend substantial sums to market the drug to physicians and to hospitals.

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To the extent that the reference products have lower costs, as a result of economies of scale, the profit-maximizing strategy for the branded companies may well be to practice limit pricing; that is, price just high enough to deter the entry of biosimilars. However, to the extent that some originators’ facilities are older and use outdated technology, their costs may be higher, and thus limit pricing would not work.

Because biosimilars are using newer technology, the cost of manufacturing them may be lower. Some biosimilars have been developed using plants, which can decrease their cost significantly. The Canadian company PlantForm has created a plant-based biosimilar version of Roche’s Herceptin.24 Because plants only require water and sunlight, PlantForm’s manufacturing cost could be as much as 90% lower, and could result in a substantial decrease in price. Clinical trials for this biosimilar are expected to begin in 2014, and the launch is planned for 2016. Herceptin can cost as much as $100,000 annually per patient and has sales of more than $6 billion. Roche’s patent runs out in 2014 in the EU and in 2017 in the United States. PlantForm is developing 2 additional biosimilar cancer drugs, which have global sales of more than $11 billion.24 In addition, monoclonal antibody biosimilars for palivizumab (Synagis) and rituximab were produced by using nontransgenic green plants. Illinois Biotechnology Industry Organization (iBIO) has developed the plant technology for rituximab, and its senior vice president believes that “the production of functional rituximab in plants suggests that many if not all monoclonal antibodies can be produced using the iBioLaunch system.”25 Whether regulatory authorities would consider these plant-based products biosimilars, and whether these companies in the United States must go through the Biologics License Application (BLA) route instead of the abbreviated BLA (aBLA; ie, biosimilar) route is an issue that has to be decided. Table 2 compares the ap­ plication requirements for BLAs and aBLAs. Companies of branded drugs may be reluctant to switch to entirely new technology, because it may be very difficult to get the biosimilar approved by the FDA as it was for its pioneer biologic. For example, Genzyme opened a new large plant in an attempt to produce Myozyme (alglucosidase alfa), but the FDA did not consider the product in the new plant to be the same as Myozyme.26 Instead, Genzyme had to get approval from the FDA through a BLA for an entirely new biologic, Lumizyme (alglucosidase alfa), which was produced at the new plant. This resulted in a better biologic with new exclusivity.27 The cost of obtaining approval for biosimilars will decrease significantly if a new EMA guideline is passed

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omparison of Biologics License Applications versus Table 2 C Biosimilars Applications Drug application parameters

BLAs

aBLAs

Interchangeability

Not possible

Possible

Exclusivity period

Possible

Not possible

Patent licensing

Possible

Not possible

Larger

Smaller

Nondisclosure

Disclosure if challenged

Only indications for which it is approved by the regulatory agency

All indications of reference drug

Sample size Proprietary data Indications

aBLA indicates abbreviated Biologics License Application; BLA, Biologics License Application.

and is eventually adopted by the FDA. The EMA states that “with the aim of facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials, it may be possible for an applicant to compare the biosimilar in certain clinical studies and in vivo nonclinical studies (where needed) with a non–EEA (European Economic Area)-authorized comparator (ie, a non–EEA-authorized version of the reference medicinal product) which will need to be authorized by a regulatory authority with similar scientific and regulatory standards as EMA (ie, ICH [International Conference on Harmonisation] countries).”28 If this is adopted by the EU and by the FDA, then all the biosimilars currently approved in the EU would potentially be automatically approved in the United States.

The cost of biosimilar entry would decrease significantly when only 1 clinical trial is needed. The flip side of this is that easier market entry could lead to greater price discounts, which could reduce the incentives for R&D and innovation in the area of biosimilars.

Competitive Response The reference product companies have not sat idly by, and have responded in different ways to the potential entry of biosimilars. They have followed strategies such as “improvements to the first-generation products, reducing the frequency of dosing schedules, and providing more convenient administration technologies [that] may extend patent protection” or achieve new exclusivity.14 Other strategies include price decreases, patent defenses, and extensions, as well as the use of trade secrets.

Companies of branded drugs “are focusing on ways to expand and improve formulations, expression systems, dosing, delivery methods, and overall perception of superiority of branded innovator drugs over their biosimilar

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counterparts.”14 For example, Roche is developing a new subcutaneous formulation for MabThera that cuts treatment time from 2.5 hours to 5 minutes.17 Another example is Amgen’s first-generation epoetin alfa (Epogen), which has multiple weekly doses, whereas its second-generation epoetin alfa (Aranesp) has only weekly injections. This can improve healthcare outcomes, by improving patient adherence with once-weekly dosing.

Inherent in the risk of entering the biosimilar market is the possible extension of a patent. For example, Amgen was able to receive a 16-year patent extension on Enbrel (etanercept), which is now set to expire in the United States in October 2028. Therefore, companies that invested substantial amounts of R&D on an “Enbrel biosimilar” will not be able to recoup any return on their investment in the United States until at least 2028; given the constantly changing environment, those companies may never be able to get a return. Indeed, at a fairly modest 10% discount rate, $1 invested in 2012 will require more than $4 in net revenue in 2028. The EU patent for Enbrel is expected to expire in 2015.

Another important form of intellectual property is trade secrets. However, the BPCIA “may expose trade secrets of both originators and biosimilar applicants.”29 For example, there are “many aspects that could be kept as trade secrets, including precise cell growth conditions, analytical processes, purification process, and even characteristics of the cells that produce the drug.”26 Abbott has filed a citizen petition with the FDA, claiming that the BPCIA violates pharmaceutical companies’ legal rights by forcing them to divulge trade secrets.30 Abbott claims that “an innovator’s resulting license application typically reflects more than a decade of research and contains analytical, preclinical, and clinical data, as well as detailed manufacturing information, most of which qualifies as trade secrets.”30 It further argues that even the federal government cannot try to control healthcare costs by taking private property.30 The claim is that branded companies should have reasonable expectations that their trade secrets will not be used to help their competitors.31 If Abbott’s claim is upheld, all biologics that were approved before the BPCIA was enacted would be exempt from the law, and no biosimilar will enter the United States until 2022.

The biotechnology companies AbbVie and InterMune have sued the EMA in an attempt to block publication of their clinical trial data.32 AbbVie states that it “does not support the disclosure of commercially confidential information ‘that does not meaningfully contribute to the scientific review or evaluation of products.’ ”32 The General Court of the EU has issued an interim order that stops the EMA from releasing information on drugs from AbbVie and InterMune.33 The issue concerns re-

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leasing “commercially confidential information,” and is similar to the trade secrets issues that are being challenged in the United States; however, this ruling in the EU only applies to the data of the 2 companies.33 Under US law, if a biosimilar attempts to enter and the innovator claims that its patent is infringed on, both the branded drug and the biosimilar may be required to reveal trade secrets.30 This may also lead to antitrust issues. If trade secrets must be divulged, the result may be that pharmaceutical companies are less willing to spend R&D on life-saving innovative biologics.30 Roche decided to stay out of biosimilars and to focus on improved versions of patented medicines. Herceptin’s patent expires in the EU in 2014 and in the United States in 2019.14 The company developed 2 new drugs, Perjeta (pertuzumab) and Kadcyla (ado-trastuzumab emtansine), to replace Herceptin. The typical course of Perjeta costs $188,000.18 And its new drug has recently shown good results—obinituzumab (GA101), which significantly decreased the risk of disease progression or death from chronic lymphocytic leukemia.34 This could be the next-generation biosimilar for Rituxan; the FDA has designated it a breakthrough therapy and has given obinituzumab a priority review. This drug could be on the market before biosimilar competition for Rituxan arrives in a few years.34 Furthermore, some branded drug companies have responded in the market by lowering prices and creating second-generation biologics that are an improvement over the original agent and give the companies new patent and exclusivity rights. Branded biologics with annual sales of $1 billion to $2 billion and that are profitable will fight competition. For example, the price of Aranesp was cut when biosimilars entered the EU market.35 The availability of a superior second-generation biosimilar could significantly decrease the demand for an inferior first-generation biosimilar.14 Also, the pricing of a second-generation biosimilar near that of a first-generation biosimilar could help the branded drug to control the market.14 For example, Neulasta, a second-generation of Neupogen (filgrastim), has a single treatment cycle cost of $3400 compared with Neupogen’s cost of $6000.36 This is an approximate 40% cost reduction.

Biosimilars could not compete with such a second generation if the biosimilar is priced only 30% less.

Biosimilar Developments Uncertainty over the impending regulatory framework and defense strategies by branded drugs has caused delays and has prompted some companies to halt drug development.37 Lonza is reviewing whether it is still worth investing in its biosimilar joint venture with Teva.37 It suspended its late-stage trial for MabThera in

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October 2012. Lonza’s chief executive Richard Ridinger stated, “I would like absolute clarity before we make a large investment. The quality of decisions is more important than speed.”37 He also states that the biosimilar development cost would exceed the $105.6 million that was estimated in 2009.37 Similarly, Merck, Teva, and Samsung have encountered severe setbacks and have suspended some biosimilar projects.38 Jeff George, a division head of generics at Sandoz, states, “There are emerging signs of a shakeout in biosimilars and only the strong will survive.” Richard Murray, PhD, vice president of Merck’s biologics and vaccines unit added, “There has been a little bit of volatility.”38 Such a shakeout is common in the early days of an industry, but it indicates the risk involved.

Celltrion may be third in the race to develop a biosimilar for Rituxan.39 It will finish a phase 1 trial before it revives its phase 3 trial, which it has altered after discussion with regulators.40 Sandoz and Boehringer Ingelheim are already conducting phase 3 trials for biosimilars of Rituxan. Rituxan loses patent protection in the EU in 2013.

Samsung and Teva have suspended their phase 3 trial.40 Given the high cost of phase 3 clinical trials of biosimilars and the uncertain regulatory environment, the risk is so high that some companies are reluctant to proceed.

In 2013, Celltrion was seeking a major pharmaceutical company to buy a controlling interest from its chief executive officer, indicating that it may be having financial difficulties.40 It recently received approval by the EMA for a Remicade biosimilar. Celltrion is aiming for approval of a biosimilar for Herceptin in Korea and in the EU. Its phase 3 trial is completed, but it has not filed for approval yet in the EU.40 Sandoz has 7 ongoing phase 3 studies across 5 biosimilar molecules.12 Teva’s Tevagrastim, a biosimilar for Neupogen, will be marketed in November 2013 as a bio­ logic in the United States under an agreement with Amgen.39 While defending its 12 biologics, Amgen is also entering the biosimilar industry with 6 biosimilars of its competitors.41 Hospira “doesn’t expect biosimilars to become key to its financial forecasts for at least 5 years.”35 Humira (adalimumab) has more than 200 patents, and AbbVie will defend them all.38 “You have scientific complexity but also patent attorneys that influence market.”16 Merck gave up its biosimilar project on Enbrel when Amgen got its expanded patent life.38 Dr Murray of Merck stated that “its portfolio is shifting away from the copies.”16 Merck dissolved a dedicated biosimilar unit; however, it started over by forming a partnership with Samsung. Also, if Abbott prevails in the trade secret issue, the biosimilar market will not open in the United States until 2022. Companies may turn to the BLA instead of following the aBLA route.

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BLA versus aBLA In the United States, even though the FDA has the legal right to approve biosimilars, there are presently no approved guidelines established for an aBLA approval.

Some companies may enter through the BLA route.

Teva and its partner Lonza received FDA approval in 2012 for a BLA for tbo-filgrastim, which competes with Neupogen.42 The same drug is a biosimilar in the EU under the name of Tevagrastim. Once the FDA opens the aBLA route, the choice will not be obvious, because there are advantages and disadvantages to each route.

A new biologic approved under the BLA would never get interchangeability, but it can be marketed as a competing brand, or even as a biobetter, which would get exclusivity and maybe even patent rights. Furthermore, “the difference in the amount of data the FDA requires under the 2 routes may be very small.”43 Even with the larger sample required for the BLA, the cost may be lower as a result of the company using only its product and not that of its competitors (which could be very costly). Unless the patent has expired, patent infringement issues are still valid; however, the company does not need to disclose proprietary data.34 The advantage of using the biosimilar route (ie, aBLA) allows the company to extrapolate and “piggyback” on the branded reference product, which will also get approval for all the indications for which the reference product is approved. The BLA can only be marketed for the indication for which the new biologic is approved.

Therefore, if a product has only 1 indication, it may be better to use the BLA. However, with many indications, the better strategy may be a biosimilar. In addition, under the biosimilar route, the drug may eventually be able to be interchangeable and be substituted for the reference product, without having to perform comprehensive clinical trials. This cannot occur under the BLA. Conclusions The characteristics of biosimilars, along with the competitive aspects of the pharmaceutical industry, suggest that large, well-established companies will dominate the market. It is likely that alliances will continue to be prevalent to share the risk and uncertainty of biologic and biosimilar development. However, some companies have been successful by themselves.

The best strategy for a biosimilar entrant may be to enter emerging markets, which have lower entry barriers, to develop strong postmarketing data to show that the product is truly a biosimilar, and then to enter more stringently regulated areas with an established record.

“Early market entry, state funding, and low costs make biosimilars an attractive opportunity in emerging markets and a rise of such products has been seen in these

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markets.”19 An added advantage is the less intellectual property protection, lower periods of exclusivity, and lower development and manufacturing costs in these markets, which could lead to 50% price reductions.19 For example, Dr Reddy’s strategy involves “Launching products in emerging markets 4 to 5 years ahead of the United States,”22 which will allow it to gather data in India before entering the US market. Such economies associated with learning by doing will permit it to be a more effective competitor in developed markets.

The possibility of using plants to produce biologics could reduce prices substantially, leading to greater acceptance of biosimilars. The complexity of biosimilars requires substantial expertise for survival; it also explains why there are so many alliances. Smaller companies that may develop a biosimilar will probably need an established firm to sell it in developed markets. Brand names along with established companies may be necessary to overcome physician resistance. Automatic substitution may arise after some considerable time, as experience is gained with biosimilars, but because many biologics are administered by physicians, this issue may be less impor­ tant than with small-molecule generics.

The business of biosimilars has not developed as quickly as expected. Despite all the current difficulties, it is expected that the market will develop, given the potential profits with patent expiration. Moreover, the mandate to decrease healthcare costs and to increase access to these life-saving pharmaceuticals will increase the biosimilar market. Appropriate public policy should encourage biosimilars but should also ensure that they are safe. The experience in the EU shows that biosimilars have been proved safe. Once the US market is open for biosimilars, regulatory and antitrust authorities should ensure that competition from biosimilars is allowed to develop, but also ensure that pioneer drug firms have sufficient incentives to develop new biologics. The 12year market exclusivity is probably adequate. The biosimilar market will become more prominent, but this will take considerable time and effort. n Author Disclosure Statement Dr Blackstone has reported no conflicts of interest. Dr Fuhr was on the expert stakeholder panel of NeoTract.

References

1. Emerton DA. Profitability in the biosimilars market: can you translate scientific excellence into a healthy commercial return? BioProcess Int. 2013;11(6 suppl):6-14,23.

2. Blackstone EA, Fuhr JP. The future of competition in the biologics market. Temple J Sci Technol Environ Law. 2012;31:1-30.

3. Heled Y. Why primary patents covering biologics should be unforceable against generic applicants under the Biologics Price Competition and Innovation Act. Ann Health Law. 2012;21(spec ed):211-221.

4. Silver S. Industry surveys: biotechnology. Standard & Poor’s. February 2013.

5. Palmer E. Conquering the complexities of biologics to get to biosimilars. Fierce PharmaManufacturing. March 26, 2013. www.fiercepharmamanufacturing.com/specialreport/conquering-complexities-biologics-get-biosimilars. Accessed September 19, 2013.

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6. Van Arnum P. Biosimilars: market weaknesses and strengths: biosimilars represent an emerging niche in the biopharmaceutical market, but how strong is their true potential? PharmaTech.com. July 11, 2012. www.pharmtech.com/pharmtech/ Most+Viewed+Articles/Biosimilars-Market-Weaknesses-and-Strengths/Article Standard/Article/detail/780563. Accessed September 20, 2013.

7. European Commission. What you need to know about biosimilar medicinal products. Consensus information paper. 2013. http://ec.europa.eu/enterprise/sectors/ healthcare/files/docs/biosimilars_report_en.pdf. Accessed September 20, 2013.

8. IMS Health. Shaping the biosimilars opportunity: a global perspective on the evolving biosimilars landscape. December 2011. www.imshealth.com/ims/Global/ Content/Home%20Page%20Content/IMS%20News/Biosimilars_Whitepaper.pdf.

Accessed September 20, 2013.

9. Kitamura M, Kang S. First copy of J&J’s $6 billion Remicade wins EMA backing.

Bloomberg. July 1, 2013. www.bloomberg.com/news/2013-06-28/first-copy-of-j-j-s-6billion-remicade-wins-ema-backing.html. Accessed September 20, 2013.

10. Tapella M. Biosimilars have arrived. ScientiaAdvisors Blog. January 6, 2012. www.scientiaadv.com/blog/2012/01/06/biosimilars-have-arrived/. Accessed March 28, 2013.

11. Declerck PJ, Simoens S. A European perspective on the market accessibility of biosimilars. Biosimilars. 2012;2:33-40.

12. ViewPoints: has Sandoz got the biosimilars race all tied up? FirstWord Pharma.

June 26, 2013. www.firstwordpharma.com/node/1112747#axzz2fRXgaw4B. Accessed September 20, 2013.

13. Eun-kyung S, So-eui R. Samsung to invest $389 million in biosimilars: report.

Reuters. July 15, 2009. www.reuters.com/article/2009/07/15/us-samsung-bio-idUSTRE 56E0ZP20090715. Accessed September 20, 2013.

14. Lovenworth SJ. The new biosimilar era: the basics, the landscape, and the future.

Bloomberg Law. 2012. http://about.bloomberglaw.com/practitioner-contributions/ the-new-biosimilar-era-the-basics-the-landscape-and-the-future/. Accessed September 20, 2013.

15. Brennan Z. Biosimilars: is the market getting too much attention? BioPharmaReporter.com. March 6, 2013. www.biopharma-reporter.com/Markets-Regulations/ Biosimilars-Is-the-Market-Getting-Too-Much-Attention. Accessed September 20, 2013.

16. Weaver C, Whalen J, Rockoff JD. Biotech drugs still won’t copy. Wall Street Journal. February 26, 2013. http://online.wsj.com/article/SB10001424127887323864 304578318111144984632.html. Accessed September 20, 2013.

17. IMS Institute for Healthcare Informatics. Declining medicine use and costs: for better or worse? A review of the use of medicines in the United States in 2012. May 2013. www.imshealth.com/deployedfiles/ims/Global/Content/Insights/IMS%20Institute %20for%20Healthcare%20Informatics/2012%20U.S.%20Medicines%20Report/ 2012_U.S.Medicines_Report.pdf. Accessed September 30, 2013.

18. Copley C. Analysis: Roche stays a step ahead of copycat drugmakers. Reuters.

March 25, 2013. www.reuters.com/article/2013/03/25/us-roche-biosimilars-idUSBRE 92O0EH20130325. Accessed September 20, 2013.

19. Aris R. Biosimilars 2012—what does the current landscape look like? pharmaphorum. March 8, 2012. www.pharmaphorum.com/articles/biosimilars-2012-–-what-doesthe-current-landscape-look-like. Accessed September 20, 2013.

20. PR Newswire. The road ahead for biosimilars in Europe, says Frost & Sullivan: huge market opportunity from impending patent expiry of blockbuster biologics. Press release. March 21, 2012. www.prnewswire.co.uk/news-releases/the-road-ahead-forbiosimilars-in-europe-says-frost-sullivan-144597775.html. Accessed September 20, 2013.

21. Grant Thornton India. Bio-dynamism: insights into the biosimilars market: an overall perspective. 2013. www.grantthornton.in/assets/BioAsia_2013.pdf. Accessed September 20, 2013.

22. Hernandez R. Implications of biosimilar use: a market perspective. Spec Pharm Times. Epub 2013 March 13.

23. Leaf C. Do clinical trials work? New York Times Sunday Review. July 13, 2003. www.nytimes.com/2013/07/14/opinion/sunday/do-clinical-trials-work.html?pagewanted =all&_r=0. Accessed September 20, 2013.

24. Biosimilar trastuzumab made in tobacco plants. GaBi Online. January 18, 2013.

http://gabionline.net/Biosimilars/News/Biosimilar-trastuzumab-made-in-tobaccoplants. Accessed September 20, 2013.

25. Rituximab biosimilar successfully produced in plants. GaBi Online. October 10, 2011. www.gabionline.net/Biosimilars/News/Rituximab-biosimilar-successfully-producedin-plants. Accessed September 20, 2013.

26. Wallack T. FDA rejects Genzyme request for Myozyme. April 22, 2008. The Boston Globe. www.boston.com/business/healthcare/articles/2008/04/22/fda_rejects_ genzyme_request_for_myozyme/. Accessed September 20, 2013.

27. Genzyme receives FDA approval for Lumizyme for Pompe disease. Business Wire.

May 25, 2010. www.businesswire.com/news/home/20100525006514/en/GenzymeReceives-FDA-Approval-Lumizyme-Pompe-Disease. Accessed September 20, 2013.

28. Gaffney A. New EMA guideline establishes framework for biosimilars, use of international comparator studies. Regulatory Focus. May 2, 2013. www.raps.org/ focus-online/news/news-article-view/article/3354.aspx. Accessed September 20, 2013.

29. Graeser D. Industry voices: biosimilars and trade secrets. FierceBiotech. October 24, 2012. www.fiercebiotech.com/story/industry-voices-biosimilars-and-trade-secrets/ 2012-10-24. Accessed September 20, 2013.

30. Zuhn D. WLF submits comments on Abbott’s citizen petition on biosimilars.

Patent Docs. March 6, 2013. www.patentdocs.org/2013/03/wlf-submits-commentson-abbotts-citizen-petition-on-biosimilars.html. Accessed September 20, 2013.

31. Gaffney A. Data submitted before 2010 shouldn’t be used to approve biosimilars, group says. Regulatory Focus. April 19, 2013. www.raps.org/focus-online/news/newsarticle-view/article/3234. Accessed September 20, 2013.

32. Pharma companies sue EMA to block release of data. GaBi Online. March 15, 2013. www.gabionline.net/Biosimilars/General/Pharma-companies-sue-EMA-to-blockrelease-of-data. Accessed September 20, 2013.

33. Gaffney A. In major reversal, EMA ordered by EU court to halt clinical trials transparency initiative. Regulatory Focus. April 30, 2013. www.raps.org/focus-online/ news/news-article-view/article/3309. Accessed September 20, 2013.

34. Carroll J. Roche’s next-gen Rituxan candidate impresses in first look at PhIII data.

FierceBiotech. May 16, 2013. www.fiercebiotech.com/story/roches-next-gen-rituxancandidate-impresses-first-look-phiii-data/2013-05-16. Accessed September 20, 2013.

35. Gryta T; for Dow Jones Newswires. Hospira learning valuable lessons in European biosimilar market. Press release. October 1, 2009. http://english.capital.gr/news. asp?id=824518. Accessed September 20, 2013.

36. Dinwoodie N. Biobetters and the future biologics market BioPharm. November 1, 2011. www.biopharminternational.com/biopharm/Upstream+Processing/Biobettersand-the-Future-Biologics-Market/ArticleStandard/Article/detail/746281. Accessed September 20, 2013.

37. Copley C. Lonza CEO says reviewing biosimilar venture with Teva. Reuters.

March 30, 2013. www.reuters.com/article/2013/03/30/us-lonza-teva-biosimilars-id USBRE92T02L20130330. Accessed September 20, 2013.

38. Carroll J. Biosimilars face big delays as blockbuster knockoffs hit a roadblock.

FierceBiotech. February 27, 2013. www.fiercebiotech.com/story/biosimilars-face-bigdelays-blockbuster-knockoffs-hit-roadblock/2013-02-27. Accessed September 20, 2013.

39. Barnes K, Kim K, Park SY. Celltrion slides to third in race for Roche rituximab biosimilar with planned 2H13 phase III trial start. Financial Times. April 19, 2013. www.ft.com/cms/s/2/dcad130c-a8fb-11e2-a096-00144feabdc0.html#axzz2fSCIazDQ. Accessed September 20, 2013.

40. McBride R. Report: don’t count Celltrion out of Rituxan biosim race. FierceBiotech. April 19, 2013. www.fiercebiotech.com/story/report-dont-count-celltrion-outrituxan-biosim-race/2013-04-19. Accessed September 20, 2013.

41. Amgen’s biosimilar plans. GaBi Online. April 5, 2013. www.gabionline.net/ Biosimilars/News/Amgen-s-biosimilar-plans. Accessed September 20, 2013.

42. Kitamura M, Wainer D. Biosimilars lure major drugmakers into the generics biz.

BloombergBusinessweek. March 21, 2013. www.businessweek.com/articles/2013-03-21/ biosimilars-lure-major-drugmakers-into-the-generics-biz. Accessed September 20, 2013.

43. Questions over US biosimilars pathway in light of Teva’s BLA. GaBi Online. May 20, 2011. www.gabionline.net/Biosimilars/General/Questions-over-US-biosimilarspathway-in-light-of-Teva-s-BLA. Accessed September 20, 2013.

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BUSINESS

Stakeholder Perspective Modeling the Future Economic Impact of Biosimilarsâ&#x20AC;&#x2122; Entry into the US Market

By Grant D. Lawless, RPh, MD, FACP Associate Professor of Clinical Pharmacy and Pharmaceutical Economics and Policy, University of Southern California, Los Angeles

RESEARCHERS: This comprehensive overview

by Blackstone and Fuhr of the process and implications of how biosimilars may enter the US market should serve as the foundation for all future planning and thinking about the future direction of biosimilars.

Using the experience from the European Union and coverage and utilization data from other industrialized countries, including reference pricing and reimportation, this article offers valuable insights into any future financial impact projections or modeling. Many of the current and future actions of the US Food and Drug Administration are well documented and are delineated by Blackstone and Fuhr, ranging from new requirements in clinical trials research to pharmacovigilance, establishing the readerâ&#x20AC;&#x2122;s expectations of what hurdles will likely lay ahead of biosimilars in an attempt to mitigate the high cost of entry into the US market.

PAYERS: Many payers from both public and private organizations view biosimilars with mixed feelings. This profile of the barriers to biosimilars entering the US market outlined in this article, and what implications that may bring to both therapeutic pricing categories as well as to formulary selections, offers deeper insights into the multiple challenges facing the future use of biosimilars.

The cautions suggested by the authors help to temper any expectations of a rapid uptake similar to small-molecule generic drugs, and paints a more sobering rate of approval and utilization resulting from multiple key factors, including safety, quality, manufacturing standards,

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substitution, and physician preference.

On balance, the opportunities that biosimilars can offer in helping to control costs within current therapeutic categories through more competitive pricing are clear. Lower-cost products, as pointed out, will likely improve the range of treatment options when making formulary selections, without necessarily overstretching already thin budgets. New and novel business practices may emerge that will help biosimilars find their footing, and may likely include emerging risk concepts agreements that target clinical outcomes, cost-effectiveness guarantees, and patient adherence measures.

PATIENTS: Patients may see the greatest impact of biosimilars as new products are introduced to a much wider international audience on a country-by-country basis. The greatest impact may come from novel manufacturing and distribution partnerships in third-world countries and to populations that are currently denied access to specialty drugs. Blackstone and Fuhr challenge the concept that biosimilars may discourage innovation, offering a small glimpse into what may drive a new business model for new product development and profit margins.

The challenge presented by the authors will inevitably evolve into improved pathways of reaching a much wider and diverse set of low-income patients and cultures, while at the same time successfully delivering care under the mandate of decreasing operating budgets and shrinking margins.

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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.

©2013 GlaxoSmithKline group of companies.

All rights reserved. Printed in USA. BN2289R0 August 2013

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

Editorial

Fall Follies: The ACA Lurches into Operation

By Joseph R. Antos, PhD Dr Antos is the Wilson H. Taylor Scholar in Health Care and Retirement Policy, American Enterprise Institute, Washington, DC

O

ctober is the first time the public will see the Affordable Care Act (ACA) in action. At least that is what the schedule says.

On October 1, 17 state-run exchanges and 34 federal exchanges have begun accepting applications for health insurance. Things may not go well that day—or that month—but any bad news will be drowned out by a congressional uproar over the budget, the debt limit, and the war in the Middle East.

Despite repeated claims that the ACA is on track, the Obama Administration has missed deadlines and delayed implementing major provisions of the law. The most significant admission that all is not proceeding smoothly was the July announcement that the employer mandate would be delayed 1 year. This action undermines the logic of the ACA and sets up the precedence for additional delays of this and other requirements in the coming years. This is not simply a matter of needing more time to solve technical problems. These issues drive the core of healthcare reform and the lack of public support for the President’s signature accomplishment.

Opponents of the ACA see a train wreck around every bend. Supporters see victory—in the 2014 elections and in the healthcare sector. Both will be disappointed.

Delaying the Employer Mandate: Promise of Things to Come The ACA’s employer mandate requires midsize and large firms to offer coverage to all of their employees or to pay thousands of dollars in penalties.1 An employer with 50 or more employees that does not offer insurance that meets federal standards will pay $2000 in fines per full-time employee, excluding the first 30 employees. A company with 50 employees would pay $40,000 in fines; a company with 100 employees would pay $140,000. An employer who offers coverage would be subject to a fine of $3000 for every employee who opted instead for subsidized coverage through the exchange.1 Although the 40-hour workweek remains the norm in most industries, the ACA says that a full-time employee is someone who works 30 hours or more weekly.2 This was meant to ensure that most workers in larger firms would be covered by their employer’s plan.

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Employers can minimize the amount of the fine by reducing work hours to below 30 and by cutting back on hiring to remain having less than 50 employees. Perversely, the brunt of those changes will be borne by the low-wage workers, who were supposed to have been helped by the mandate. Rather than making it possible for those workers to be covered by what is often a generous health plan, the mandate will result in lost wages and will send more people into the exchanges, for insurance.

The recent decision by the Obama Administration to delay the employer mandate by 1 year3 does not change the incentive that some firms have to cut back on their workforces. In fact, it gives firms more time to map out a strategy to avoid the steep penalty that will be levied if even 1 of the company’s employees receives an exchange subsidy.

The penalty is a real threat for many companies. Even with the employer paying a substantial part of the premium, low-income workers often cannot afford to buy into the company plan. ADP Research Institute’s 2012 survey of companies with more than 1000 employees found that 63% of workers earning $15,000 to $20,000 annually declined their employer’s health coverage compared with 20% or less of workers earning at least $35,000.4,5 Many of these workers would be eligible for heavily subsidized insurance through the exchange, which triggers the employer penalty.

There is growing evidence that employers are shifting to part-time workers and shorter hours where they can.

In October 2012, Darden Restaurants, one of the 30 largest employers in the United States, with brands that include Olive Garden and Red Lobster restaurants, stopped offering full-time schedules to its hourly employees in some locations.6 In February 2013, thousands of part-time state workers in Virginia were told that their hours would be cut to no more than 29 hours weekly.7 In March 2013, Regal Entertainment Group, which operates more than 500 theaters in 38 states, rolled back the hours of its nonsalaried workers to 30 hours weekly.8 The White House insists that these are merely anecdotes, but some of the biggest supporters of healthcare reform are beginning to worry.9 Joseph Hansen, President of the United Food and Commercial Workers In-

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ternational Union, which has 1.2 million members, says that the problem is real. “Wait a year. You’ll see tremendous impact as workers have their hours reduced and their incomes reduced.”9 Indeed, wait a year. The administration will no longer be able to deny that the problems caused by the employer mandate are serious. An additional year will not make the politics any easier for the President, and will not make it easier for many firms to report accurately to each employee whether the plan they can get through their job is affordable. An additional 1-year delay is virtually certain next fall, just before the midterm congressional election.

What about the individual mandate? If business gets a break, why not consumers? From an insurer’s standpoint, the argument is simple. Unless you force healthy young people to buy coverage, the cost of insuring those who need health services will skyrocket. But this is an argument for protecting insurers, who have been in the Democrats’ crosshairs for some time. Perhaps next fall’s announcement of a suspension of any penalties on individuals will be justified by the newness of the program and the (political) need to give people more time to do the “right” thing.

Exchange Coverage Is No Bargain Consumers going to the exchanges looking for insurance will find out the hard way that the plan they want will not be cheap. That is likely to be true even for a person who is eligible for a big subsidy.

The subsidies are substantial. Based on the Kaiser Family Foundation’s subsidy calculator, an individual with an annual income of $17,000 will pay approximately $55 monthly, or $660 annually, for “silver” plan coverage. A person with a $20,000 income will pay $85 monthly, or $1020 annually.10 But this is not just any silver plan. The advocates and online premium calculators that back them up overlook an important fact: a more expensive plan will cost more, regardless of whether one receives an exchange subsidy.10 The exchange subsidy is tied to the silver plan offering the second-lowest premium. If your doctor is not in 1 of the 2 lowest-cost silver plans, which cover 70% of the health costs for an average person, you may want to buy a more expensive plan.

In New York State, for example, state regulators report that the unsubsidized premium for the second lowest-cost silver plan is $349.14 monthly.11 An individual with an annual income of $17,000 will pay approximately $55 monthly, or $660 annually, for silver coverage.10,12 The remaining $294.14 will be paid by the exchange subsidy.

The New York State plan that falls in the middle of the range of costs has a premium of $466.81 monthly.11 The premium paid by the same person with a $17,000

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income is the subsidized $55 monthly plus the full difference between the 2 unsubsidized rates, which comes to $172.67 monthly, or $2072 annually—not the $660 promised by state officials.12 For most people with low incomes, higher-cost plans that offer better access will be out of reach financially, despite the exchange subsidy. If consumers cannot afford the plan they want, they may buy a plan they do not want just because it is cheaper.

That is the reason for the individual mandate. But the penalty is far less than the cost of insurance, even with the subsidy. Next year, scofflaws are liable for a $95 penalty, or 1% of their income. In later years, the penalty grows to 2.5% of income, which will still look like a bargain compared with insurance premiums that will be higher in the future.

Buying health insurance on a wait-and-see basis will be a good strategy for many people. Insurers cannot turn people down if they skip a year, and the premiums cannot be increased either. The exchange subsidy is tied to one’s income, not whether a person has followed the rules. And there is a good chance that the Internal Revenue Service will not be able to collect the penalty, because it is limited to taking the money out of a person’s tax refund.13 American households that do not file federal income tax returns are not subject to the penalty, and the rest can adjust their withholding to avoid the penalty.

The individual mandate will cause some people to buy exchange coverage who otherwise would not have done so, but not because of the penalty. The mandate is an attempt to establish a new social norm that remaining uninsured is unacceptable. Will it work? We will have some idea in a few months.

Can Republicans Exploit the ACA’s Unpopularity?

The ACA is remarkable for remaining consistently unpopular with the public. A recent NBC News-Wall Street Journal poll taken in July 2013 shows that 47% of those polled think that the new law is a bad idea compared with 34% who support it.14 According to a June 2013 survey, only 19% of respondents think their families will be better off under the reform,15 which is the worst showing for the President’s program since it was enacted.

The problem is not that the public does not know how good the ACA will be.16 The problem, if we can call it a problem, is that 85% of Americans already have health insurance, most through their employers.17 Few of them will be eligible for lower premiums or for larger subsidies in the exchanges.

Offering the status quo—“if you like your healthcare plan, you can keep your healthcare plan”18—will not make the majority of the public “fall in love” with one of the most complex pieces of US legislation in modern times, especially if that promise cannot be kept.

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The coverage that employees have today will soon be a thing of the past. Employers have already begun to change their health plans and restructure their workforces to avoid some of the higher health costs arising from the ACA. As a result, workers will pay more for a less generous employer coverage.

The prospect of new taxes and higher costs has caused many employers to take a second look at the way they manage their employee benefits. The “Cadillac tax” penalizes employer health plans whose total premiums exceed $10,200 for an individual or $27,500 for families.19 Although that tax does not start until 2018, companies are beginning to take steps to lower the cost of their plans.

The United Parcel Service (UPS) hit the headlines with its decision to exclude 15,000 working spouses from its health plan beginning in January 2014.20 Those spouses have access to insurance at their own jobs, but having to buy a separate policy increases the family’s cost to maintain the same level of coverage. This action lowers UPS’s benefit costs and reduces the average insurance premium that determines whether the plan is liable for the Cadillac tax.

This is not an isolated incident. In its recent survey of midsize and large employers, benefits consulting firm Towers Watson found that nearly 40% of firms are changing their employee health plans for 2014, in part prompted by the ACA.21 Even more employers will adopt new strategies to cut costs in 2015 and 2016 to avoid having to pay the Cadillac tax.21 If the ACA is as unpopular as surveys show,14,15 and if employers are citing the ACA as the reason for aggressively cutting back benefits, why are Republicans having such little luck rallying the public to their side?

The problem, at least in part, is the apparent lack of empathy in Republican policy positions. “Repeal and replace” sounds like “repeal without resolving the real problems.” The Democratic message of universal coverage (which translates into an implicit promise of security, regardless of the cost) has a greater surface appeal.

The details, as Representative Nancy Pelosi (D-CA) said, can be sorted out later.22 Republicans have an opportunity to regain the high ground in this debate, but only if they offer a positive vision for healthcare reform as well as a practical way to get there.

Beyond October Experts on both sides agree that the ACA has substantial flaws. A host of new problems will be uncovered as the exchange process gets under way over the next year. Some of those problems arise from a poorly constructed law; others, from poorly thought-out changes that are promulgated by subsequent regulations and administrative actions.

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Under less contentious political circumstances than we find with the healthcare reform, many of those problems would have been taken care of through a House– Senate conference committee before the final vote in Congress. That did not happen, because of the surprise election of Scott Brown (R-MA) to replace the late Senator Ted Kennedy (D-MA), giving Republicans 41 Senate seats.23 Democratic leaders feared that Senate Republicans could filibuster a conference report and prevent enactment.

The legacy of that decision is gridlock on Capitol Hill.

Small technical issues remain unresolved that under other circumstances would have been addressed through an uncontroversial corrections bill. Larger issues that could have been the subject of public debate remain outstanding.

The administration has not let political gridlock get in the way of shaping the law to fit political needs and business realities. Regulations and informal guidance have been used to make changes that in normal times would have been acted on by Congress. Deadlines have been changed when the administration needed more time to get the results it wants.24 The mandate on employers to offer coverage was delayed in response to opposition from the business community, even though the ACA does not allow for such an action.25 It now appears that the Obama Administration wants to extend to union members insurance subsidies that were intended to help the uninsured buy coverage.26 Those workers already have employer-sponsored insurance that is subsidized through the US tax system. Such a proposal would prompt a bitter political fight if it were introduced in Congress, something the White House can avoid by implementing the policy through regulation.

Except in the unlikely event that Republicans gain a sizable Senate majority in the 2014 midterm election, this aggressive regulatory process, which is controlled by the Executive Branch, will continue to play out for the next 3 years. That will solidify the federal government’s dominant role in the healthcare sector, which, thanks to the ACA, now extends well beyond Medicare and Medicaid.

That does not mean everything will go smoothly.

Perhaps the biggest danger to the President’s agenda comes from the overzealous actions of its strongest supporters. Premium rates that have been approved thus far in several major states are substantially below the levels that health plans requested. In many cases, those rates can be expected to rise sharply in future years. Insurers have an incentive to underprice their products initially to attract market share, and they are well aware of the prevailing political climate that demands low premium increases in the exchanges. But at some point they have to make a profit or drop out of the market.

That is the reason that Aetna, the third largest insur-

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er in the country, has pulled out of the exchange markets in Maryland, Connecticut, Ohio, Georgia, and New York.27 Other large national health insurers have planned limited entries into the new exchanges, giving them a chance to see whether they operate smoothly and whether enough healthy people sign on to offset the costs of sicker new members. If healthy people fail to enroll, that will drive up costs that will not be reflected in already-approved rates for next year.

The ACA will not be the success its supporters want it to be. It will also not be the disaster its opponents think it will be. It will cause permanent changes—some good, some bad—in the way health insurance is purchased in this country.

There will be a shakeout of the insurance industry over the coming years, as more experience is gained about exchange operations and regulators face business reality. Consequently, the ACA will not be the success its supporters want it to be. It will also not be the disaster its opponents think it will be. It will cause permanent changes—some good, some bad—in the way health insurance is purchased in this country. It also will add to the growing fiscal burden that threatens to damage the health of the economy. Congress and the President will not be able to ignore those facts indefinitely. n Author Disclosure Statement Dr Antos reported no conflicts of interest.

References

1. Cigna. Employer mandate fact sheet. July 2013. www.cigna.com/assets/docs/ about-cigna/informed-on-reform/employer-mandate-fact-sheet.pdf. Accessed September 13, 2013.

2. Automatic Data Processing. Determining full-time employees under the Affordable Care Act: implications of Notice 2012-58. Eye on Washington. Updated October 4, 2012. www.adp.com/tools-and-resources/adp-research-institute/insights/~/media/696C 3879BDB14C56A98BE58C1F85E363.ashx. Accessed September 5, 2013.

3. Carey MA. Employers to get an extra year to implement health law requirement on coverage. Kaiser Health News. July 2, 2013. www.kaiserhealthnews.org/stories/ 2013/july/02/employer-mandate-delayed.aspx. Accessed September 5, 2013.

4. Automatic Data Processing. ADP’s 2012 study of large employer health benefits: benchmarks for companies with 1,000+ employees. 2013. www.adp.com/tools-and-­ resources/adp-research-institute/research-and-trends/research-item-detail.aspx?id= 656665F4-5D63-47D1-8114-57D11D837F60. Accessed September 5, 2013.

5. Kliff S. Obamacare requires employers to offer insurance. What if it’s too expensive? Wonkblog. March 4, 2013. www.washingtonpost.com/blogs/wonkblog/wp/2013/ 03/04/obamacare-requires-employers-to-offer-insurance-what-if-its-too-expensive/.

Accessed September 5, 2013.

6. Pedicini S. Darden tests limiting worker hours as health-care changes loom.

Orlando Sentinel. October 7, 2012. http://articles.orlandosentinel.com/2012-10-07/ business/os-darden-part-time-workers-20121007_1_darden-restaurants-health-­

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insurance-olive-gardens. Accessed September 5, 2013.

7. Sizemore B. Va. workers’ part-time hours capped due to health law. PilotOnline.com.

February 8, 2013. http://hamptonroads.com/2013/02/state-workers-parttime-hourscapped-due-health-law. Accessed September 5, 2013.

8. Chiaramonte P. Nation’s biggest movie theater chain cuts workweek, blaming Obamacare. FoxNews.com. April 15, 2013. www.foxnews.com/us/2013/04/15/nationbiggest-movie-theater-chain-cuts-workweek-blaming-obamacare/. Accessed September 5, 2013.

9. Myers L, Mears CA. Businesses claim Obamacare has forced them to cut employee hours. NBC News Investigations. August 13, 2013. http://investigations.nbcnews. com/_news/2013/08/13/20010062-businesses-claim-obamacare-has-forced-them-tocut-employee-hours?lite. Accessed September 5, 2013.

10. Kaiser Family Foundation. Subsidy calculator: premium assistance for coverage in exchanges. http://kff.org/interactive/subsidy-calculator/. Accessed September 5, 2013.

11. Governor’s Press Office. Approved monthly premium rates: individual standard plans. www.governor.ny.gov/assets/documents/Approved2014HealthInsuranceRates. pdf. Accessed October 1, 2013.

12. Rabin RC, Abelson R. Health plan cost for New Yorkers set to fall 50%. New York Times. July 16, 2013. www.nytimes.com/2013/07/17/health/health-plan-costfor-new-yorkers-set-to-fall-50.html. Accessed September 5, 2013.

13. Antos J. The individual mandate won’t save Obamacare. RealClearMarkets.

April 11, 2012. www.realclearmarkets.com/articles/2012/04/11/the_individual_ mandate_wont_save_obamacare_99611.html. Accessed September 5, 2013.

14. Hart Research Associates/Public Opinion Strategies. NBC News/Wall Street Journal survey: study #13266. July 2013. http://online.wsj.com/public/resources/ documents/wsjnbcpoll_july2013.pdf. Accessed September 5, 2013.

15. Hart/McInturff. NBC News/Wall Street Journal survey: study #13200. May-June 2013. http://online.wsj.com/public/resources/documents/WSJpoll060513.pdf. Accessed September 5, 2013.

16. Morgan D; for Reuters. Senator gives administration ‘F’ on public education for health-care law. Press release. April 17, 2013. http://articles.washingtonpost.com/ 2013-04-17/local/38618904_1_affordable-care-act-max-baucus-senate-financecommittee. Accessed September 5, 2013.

17. DeNavas-Walt C, Proctor BD, Smith JC. Income, poverty, and health insurance coverage in the United States: 2012. United States Census Bureau. September 2013. www.census.gov/prod/2013pubs/p60-245.pdf.

18. The White House. Remarks by the president in health insurance reform town hall.

Transcript. August 11, 2009. www.whitehouse.gov/the-press-office/remarks-presidenttown-hall-health-insurance-reform-portsmouth-new-hampshire. Accessed September 5, 2013.

19. Abelson R. High-end health plans scale back to avoid ‘Cadillac Tax.’ New York Times. May 27, 2013. www.nytimes.com/2013/05/28/business/cadillac-tax-healthinsurance.html. Accessed October 1, 2013.

20. Hancock J. UPS won’t insure spouses of some employees. Kaiser Health News.

August 21, 2013. www.kaiserhealthnews.org/Stories/2013/August/21/Insurance-ForWorking-Spouses-At-UPS.aspx. Accessed September 5, 2013.

21. Towers Watson. Health care reform heightens employers’ strategic plans for health care benefits: over the short term, employers plan to retain active medical plans amid projected cost increase and excise tax concerns; greater change expected to retiree medical plans. Press release. August 21, 2013. www.towerswatson.com/en/ Press/2013/08/Health-Care-Reform-Heightens-Employers-Strategic-Plans-forHealth-Care-Benefits. Accessed September 5, 2013.

22. Pelosi remarks at the 2010 Legislative Conference for National Association of Counties. Democratic Leader Nancy Pelosi. March 9, 2010. www.democraticleader. gov/news/speeches/pelosi-remarks-2010-legislative-conference-national-associationcounties. Accessed October 1, 2013.

23. Adler JH, Cannon MF. Taxation without representation: the illegal IRS rule to expand tax credits under the PPACA. Health Matrix. 2013;23:119-195.

24. Pear R. States will be given extra time to set up health insurance exchanges. New York Times. January 14, 2013. www.nytimes.com/2013/01/15/us/states-will-be-givenextra-time-to-set-up-health-insurance-exchanges.html. Accessed September 5, 2013.

25. Walberg T; for the US House Education and the Workforce Committee. Committee statement. Presented at the hearing on “The Employer Mandate: Examining the Delay and its Effect on Workplaces”; July 23, 2013; Washington, DC. http:// edworkforce.house.gov/news/documentsingle.aspx?DocumentID=343487. Accessed September 5, 2013.

26. Roy A. White House considers awarding Obamacare subsidies, intended for the uninsured, to labor unions. The Apothecary, with Avik Roy. August 30, 2013. www. forbes.com/sites/theapothecary/2013/08/30/white-house-considers-awardingobamacare-subsidies-intended-for-the-uninsured-to-labor-unions/. Accessed September 5, 2013.

27. Humer C. Aetna pulls out of another Obamacare health exchange. Reuters.

August 29, 2013. www.reuters.com/article/2013/08/29/us-aetna-exchanges-idUS BRE97S18520130829. Accessed September 5, 2013.

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Utilizing a Personalized Diagnostic in a Class of Hodgkin Lymphoma Patients: An Interview With Lawrence M. Weiss, MD, of Clarient Diagnostic Services, Inc.

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larient Diagnostic Services, Inc, a GE Healthcare Company, combines innovative diagnostic technologies with pathology expertise to assess and characterize cancer. Their stated mission is to “become the leader in cancer diagnostics by dedicating ourselves to collaborative relationships with the healthcare community to translate cancer discovery and research into better patient care.”

The rise of individualized medicine as the new direction in oncology has created the need for innovative diagnostic technologies. Clarient is meeting this need by commercializing new lab-developed tests and companion diagnostic markers for therapeutics in breast, prostate, lung, and colon cancers and leukemia/lymphoma. Most recently, they have introduced the Hodgkin Lymphoma Profile by MultiOmyx™, an aid to a pathologist’s diagnosis of CD30-positive lymphoma

cases with difficult morphology or otherwise insufficient tissue to adequately evaluate the case. This test utilizes a new pathology platform that uses proprietary methodology to assess multiple proteins from a single tissue section at a single-cell level. If you have a small amount of tissue, you do not have to sacrifice or choose between important markLawrence M. ers. You can assess them all.

Weiss, MD Personalized Medicine in Oncology (PMO) had the pleasure of meeting with Dr Lawrence Weiss in his Aliso Viejo, California, office to talk about his definition of personalized medicine, the implications of costs to a burdened healthcare system, and the venues in which MultiOmyx is best used. To view the interview in its entirety, please go to www.PersonalizedMedOnc. com/videolibrary.

PMO Thank you so much for speaking with us, Dr Weiss. As a hematopathologist, how do you define personalized medicine in oncology?

Dr Weiss Personalized medicine is different things to different people. As a hematopathologist, I think it’s matching the person’s cancer to the best diagnosis and the best treatment modalities.

PMO Personalized medicine remains sporadic and occurs mainly at well-funded academic medical centers or prompted by physicians who really understand the genetic principles behind molecular biomarkers and how

to assess them appropriately. How can this situation change so that personalized medicine in oncology can be made available broadly to patients managed by the community caregivers?

Dr Weiss Clarient’s objective has always been to deliver reliable information to the community cancer caregivers, to help keep cancer care local. Bringing personalized medicine to the community and individual patients is a difficult issues – the biggest driver is cost. We’re talking about expensive diagnostic and treatment procedures. We not only have to provide innovative diagnosis and treatment, but we have to do it at a cost that is affordable to our healthcare system. Juggling the two is a difficult proposition.

PMO What are the barriers and opportunities for this to actually occur, bringing these types of molecular biomarkers and genetic principles into the community?

Dr Weiss The basic barrier is cost. The medical profession needs to convince the payers – government and private payers – that the diagnostic modalities and the treatment modalities that we want to bring to individual patients will have benefit to those patients. But just by virtue of it being individualized therapy, it may be hard

Lawrence M. Weiss, MD, is Medical Director of Clarient Diagnostic Services. He is Chairman Emeritus of the Department of Pathology at the City of Hope National Medical Center. He received his BS summa cum laude and his MD summa cum laude from the University of Maryland. He completed a residency in anatomic pathology at the Brigham & Women’s Hospital in Boston and a fellowship in surgical pathology at Stanford University Medical Center. He was previously an Assistant Professor at Stanford and Director of Surgical Pathology at the City of Hope. Dr Weiss’ interests lie in surgical pathology, hematopathology, and immunohistochemistry.

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Multiplexed fluorescence microscopy and image acquisition (MultiOmyxTM) was performed using the 9 stains in the Hodgkin Lymphoma Profile. The hallmark Reed-Sternberg cell (center of image) shows expression patterns of both CD30 and CD45. The antigen illustrated can be changed by moving the vertical divider left or right. to prove in clinical studies, at least in clinical studies as we provide them today. As a result, we have to invest in resources to prove to payers that our innovative therapies and treatments are going to be effective, and try to do it at a reasonable cost so that when it translates to reimbursable procedures and treatments, it’s still within the bounds of the healthcare budget.

PMO The Hodgkin Lymphoma Profile by MultiOmyx is being launched as a Clarient-validated lab-developed test which uses a new proprietary methodology to aid pathologists and oncologists in delivering a genomic profile they can use as a guide in the treatment of difficult lymphoma cases. Please explain the differentiating factors of this test as opposed to other laboratory-developed tests.

Dr Weiss When we speak of personalized medicine, we usually talk about the therapy side being personalized. But in this particular case, MultiOmyx is a personalized diagnostic. It will be utilized in lymphoma – but not every case. It will be utilized in certain types of biopsies showing particular findings as a way of making a more precise and accurate diagnosis of Hodgkin lymphoma so people can get the correct therapies that they deserve.

PMO Issues raised regarding genomic profiling include the accuracy, sensitivity, and reproducibility of results. If the right drug is to be delivered to the right patient at the right time, we have to have confidence in the results of molecular biomarker analyses. Can you please compare MultiOmyx’s tests versus genomic tests and also as opposed to proteomic tests?

Dr Weiss As of this time, genomic tests are really not helpful in the accurate diagnosis of Hodgkin lymphoma.

Currently, Hodgkin lymphoma is diagnosed by having a pathologist look down a microscope, supplemented by protein studies – immunohistochemical analyses – performed in sections taken from paraffin-embedded blocks.

MultiOmyx offers a superior way of looking at multiple antigens in tissue.

First, in immunohistochemistry it’s 1 antibody, 1 section; with MultiOmyx you can get numerous proteins looked at in 1 section. Therefore, if you have small biopsies, you will never run out of tissue. In fact, you’ll preserve the tissue that’s there for additional studies if they’re needed, whereas with immunohistochemistry you’re very limited.

Second, immunohistochemistry has the limitation that proteins are being examined on different tissue sections; you never quite look at the same cell. Hodg­ kin lymphoma has a unique morphologic appearance in which the neoplastic element is only about 1% of the infiltrate that you see. So when you look at antibody studies you’ll see, for example, some CD30-positive cells, you’ll see some CD15-positive cells. Both are characteristics of Hodgkin lymphoma, and when you see them on the same cell it helps you toward that diagnosis.

But when you look on the typical immunohistochemistry studies, you’re never quite sure whether it’s the same cell expressing both antigens or it’s 2 separate cell populations that express those antigens.

With MultiOmyx, you can look at your CD30 or other antigen stain and see how those positive cells are stained with other markers so you have a direct comparison, whereas with immunohistochemistry there’s a little bit of guesswork in indirect comparison.

PMO Incorporating a molecular biomarker profile in the management plan for all cancer patients is an extremely expensive undertaking. How should patients be selected for biomarker analysis?

Dr Weiss There are 2 ways to select patients for biomarker analysis. First, there has to be effective therapy. If there’s no effective therapy, you can do all the analysis that you want, and it really won’t help the individual patient. There has to be something on the treatment end that one could be offered. It could be 1% of patients, it could be 70% of patients, it could be 0.1% of patients,

but there has to be some benefit should a certain profile be obtained.

But I look at it another way as well. I look at it from the standpoint of whether there is something in the patient’s cancer that will benefit in diagnosis as well from a particular modality.

Hodgkin lymphoma is generally a difficult diagnosis.

First of all, it’s not a very common lymphoma, and many pathologists have limited experience with the diagnosis, so that makes it hard right from the start.

Second, quite often the differential diagnosis of Hodg­kin versus something else, even benign conditions, can be quite difficult even for a very experienced hemato­pathologist. So if you have a treatment modality for those small subsets of hard cases, I think that’s personalized medicine as well.

PMO Should the Hodgkin Lymphoma Profile by MultiOmyx be added to the management plan for all patients with Hodgkin lymphoma and, if so, how can the added cost be justified?

Dr Weiss At this point in time I don’t think that MultiOmyx should be included in the diagnostic regimen for all patients with Hodgkin lymphoma. I think it should be included when the pathologist thinks there is a chance it may help the diagnosis.

So where may it help? Currently excisional biopsies represent the most common diagnostic medium because Hodgkin or any lymphoma diagnosis is a difficult one, and an important one, and you do not want to skimp on tissue. But sometimes you have to do needle biopsies; for example, a biopsy of a large mediastinal mass. Cracking the chest would be an awful lot of money as well as morbidity for the patient. If MultiOmyx can help you by more frequently obtaining diagnoses on small pieces of tissue, this actually is going to be very cost-effective.

I had a case the other day where the diagnosis in the referring pathologist’s mind, and in my mind as well, was Hodgkin versus non-Hodgkin lymphoma. We threw this on MultiOmyx and were able to get a definitive diagnosis. That’s going to save a lot of money for the system by preventing a second excisional biopsy.

Where will MultiOmyx be in the future? I think we may go away from more excisional biopsies for possible patients with lymphoma and go more to core needle biopsies to make the diagnosis, and I think MultiOmyx is going to help with that. It may be more expensive than routine immunohistochemistry, but when you factor in the cost of an excisional biopsy versus the cost of an easy outpatient needle biopsy, you may find that going the latter route is going to be the more cost-effective, and from a quality standpoint, the better way.

PMO How will MultiOmyx help cancer patients who

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Here the very same Reed-Sternberg cell as pictured on the previous page is evaluated for expression patterns of CD15 and CD79a. The antigen illustrated can be changed by moving the vertical divider left or right. either do not respond to therapy or acquire resistance to standard therapy?

Dr Weiss Currently for Hodgkin lymphoma, patients with favorable low-stage disease have about a 90% cure rate. For those with a higher stage or more unfavorable features, the cure rate is still relatively high, but on the order of 75% to 80%.

Hodgkin lymphoma is generally a difficult diagnosis....MultiOmyx can help you by more frequently obtaining diagnoses on small pieces of tissue.

Typically at some point during the treatment of a patient with Hodgkin lymphoma, some radiologic studies are performed, perhaps a PET-CT scan to see if the patient is responding. In a small percentage of the cases, the patient may not respond to therapy. Is it because the patient had the correct diagnosis of Hodgkin lymphoma and is just not responding to therapy, or is there a possibility that it was an incorrect diagnosis?

Hodgkin is a tough diagnosis. We’ve made a lot of progress in terms of pathology and diagnoses, but I’d still estimate that perhaps 5% of diagnoses may be incorrect,

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even by expert hematopathologists who don’t always agree with each other.

So it could be that if a patient is found not to respond, or have an unusual occurrence, that this is a mandate to implement this better technology and either definitively confirm that the original diagnosis is right or that this is 1 of the 5% of cases in which you are treating the wrong disease.

PMO Education of providers, pharmacists, payers, and patients is vital in achieving personalized medicine in oncology. How is GE Healthcare positioning itself in personalizing medicine and oncology as a whole?

Dr Weiss I think GE Healthcare is very interested in personalized medicine and wants to be part of the solution. They want to bring innovative diagnostic modalities that will help guide individualized therapies.

PMO What do you foresee as the future clinical application of personalized medicine when sequencing the entire human genome will hopefully cost less than $1000

within the next several years, and how is GE Healthcare positioned for next-generation sequencing?

Dr Weiss I think there’s an unlimited potential for next-generation sequencing, particularly when the costs do come down to a reasonable point. Clarient recently acquired SeqWright Genomic Services, a DNA sequencing service organization that is well poised to be part of this revolution.

PMO What could be offered to patients without a biomarker that directs a targeted therapy, especially if this impacts a significant percentage of patients?

Dr Weiss I don’t think we ought to be giving individualized treatments without detecting the biomarkers, because we could be overtreating a segment of the population and giving them morbidity, mortality, without any benefits. I’m a big believer that for any personalized medicine therapy there ought to be a corresponding diagnostic that will give some probability whether patients will or will not respond to that therapy. I see the two as a yin-yang going together. The diagnostic has to come with the individualized therapy, otherwise it’s not individualized therapy.

PMO Do you foresee a future in which pharmaceutical and biotech companies will not develop new therapeutic agents for oncology if the agent isn’t linked to a biomarker that identifies the patient population most likely to benefit?

Dr Weiss I agree, I don’t see pharmaceutical companies or other biotech companies developing therapies without accompanying biomarkers. I think patients want it, I think payers want it, and it’ll bring cost down, and it’ll prevent morbidity in patients who don’t need that therapy. So I think the two go hand in hand, the diagnostic and the therapeutic.

PMO Thank you so much for your time and insights today.

Dr Weiss My pleasure. u

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Original research

The Incidence Rate and Economic Burden of Community-Acquired Pneumonia in a Working-Age Population Jonah Broulette, ASA, MAAA; Holly Yu, MSPH; Bruce Pyenson, FSA, MAAA; Kosuke Iwasaki, FIAJ, MAAA; Reiko Sato, PhD

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2013;6(8):494-503 www.AHDBonline.com Disclosures are at end of text

Background: Community-acquired pneumonia (CAP) is frequently associated with the very young and the elderly but is a largely underrecognized burden among working-age adults.

Although the burden of CAP among the elderly has been established, there are limited data on the economic burden of CAP in the employed population.

Objective: To assess the economic impact of CAP in US working-age adults from an employer perspective by estimating the incidence rate and costs of healthcare, sick time, and short-term disability for this patient population.

Methods: This retrospective cohort study is based on data from 2 Truven Health Analytics databases. The study population consisted of commercially insured active employees aged 18 to 64 years, early retirees aged <65 years, and adult dependents of both cohorts. CAP was identified using medical claims with pneumonia diagnosis codes during the 2009 calendar year. Incidence rate, episode level, and annual costs were stratified by age and by risk based on the presence of comorbidities. Descriptive statistics were used to compare healthcare (ie, medical and pharmacy) costs, sick time, and short-term disability costs between the cohorts with and without CAP. Linear regression was used to estimate the average annual incremental healthcare cost in employed patients with inpatient or outpatient CAP versus individuals without CAP. Results: Study eligibility was met by 12,502,017 employed individuals, including 123,920 with CAP and 12,378,097 without CAP; the overall incidence rate of CAP was 10.6 per 1000 person-years. Among individuals with and without CAP, the costs of healthcare, sick time, and short-term disability increased with advancing age and with higher risk status. The mean annual healthcare costs were $20,961 for patients with CAP and $3783 for individuals without CAP. Overall, the mean costs of sick time and short-term disability were $1129 and $1016, respectively, in active employees with CAP, and $853 and $322, respectively, in their counterparts without CAP. Compared with individuals without CAP, the average annual incremental healthcare cost ranged from $39,889 to $113,837 for inpatient management of patients with CAP and from $4170 to $31,524 for outpatient management of patients with CAP, depending on the risk level.

Conclusions: CAP is a common and costly infection among working-age individuals, especially in patients with comorbidities. Prevention strategies, such as influenza and pneumococcal vaccination, that target working-age adults with underlying medical conditions may be the most valuable in reducing the morbidity and costs associated with CAP.

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ommunity-acquired pneumonia (CAP) is most often defined as a lower respiratory tract infection characterized by cough, fever, chills, fatigue, dyspnea, rigors, and pleuritic chest painâ&#x20AC;&#x201D;with or without

new infiltrate on chest radiographyâ&#x20AC;&#x201D;acquired outside of a hospital or long-term care setting.1,2 Despite progress in the prevention and diagnosis of CAP, the development and use of antibiotic therapies, and in intensive care

Mr Broulette is Actuarial Analyst, Milliman, New York, NY; Ms Yu is Director, Market Access, Pfizer Specialty Care Business Unit, Pfizer Inc, Collegeville, PA; Mr Pyenson is Principal and Consulting Actuary, Milliman, New York, NY; Mr Iwasaki is Consulting Actuary, Milliman, New York, NY; and Dr Sato is Director, Market Access, Pfizer Specialty Care Business Unit, Pfizer Inc, Collegeville, PA.

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Burden of CAP in a Working-Age Population

management, CAP remains a leading cause of morbidity, mortality, and economic burden worldwide.2-8 In the United States, CAP affects approximately 5.6 million patients annually, and is the sixth leading cause of death in people aged ≥65 years.3,9 Notably, in 2011, influenza and pneumonia were the eighth leading cause of US deaths across all age-groups.10 Pneumonia, which is widely recognized as a disease of the elderly (age ≥65 years) and the very young (age <5 years), is also common in nonelderly adults.5 According to data from the 2010 National Hospital Discharge Survey, 257,000 adults aged 45 to 64 years and 621,000 adults aged ≥65 years had pneumonia as their primary diagnosis at hospital discharge.11 Although the number of pneumonia hospitalizations was more than twice greater in elderly adults than in nonelderly adults, the mean lengths of hospital stay—5.6 and 5.5 days, respectively—were remarkably similar.11 Unlike in elderly adults, however, the presence of pneumonia in younger individuals (ages 18-64 years) who are still actively employed has an impact on employers—most notably, lost productivity costs associated with workplace sick time and short-term disability.12-16 Several studies have evaluated the economic burden of CAP on elderly populations,17-19 but data are scarce on the working-age population.12,13 Three studies conducted in the late 1990s examined the direct and indirect costs of pneumonia from an employer perspective; however, the findings had several limitations, including the use of a single large national employer.13-15 Two recent studies complement the findings of our study and are of particular interest.12,16 Both studies show that CAP is a common and costly infection in the working-age population, especially in adults with comorbidities, with estimated national direct and indirect costs of $8.5 billion and $2.1 billion, respectively.12,16 Despite the data, CAP remains an underrecognized burden among employers, payers, healthcare providers, and the nonelderly adult population.

The purpose of the current study was to assess the direct and indirect economic impacts of CAP in working-age adults by estimating the incidence rates and the associated healthcare, sick time, and short-term disability costs in the United States from an employer perspective of active employees aged 18 to 64 years, early retirees aged <65 years, and adult dependents in both cohorts.

Methods This retrospective cohort study is based on data from the Truven Health Analytics MarketScan Commercial Claims and Encounters Database (hereafter, “MarketScan database”) and the Truven Health Analytics Health and Productivity Management (HPM) database between January 1, 2008, and March 31, 2010. The MarketScan

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Key Points Community-acquired pneumonia (CAP) is traditionally considered a disease of the elderly and is underrecognized among working-age adults. ➤ CAP remains a leading cause of morbidity and mortality, with a substantial economic burden. ➤ Using a large database, this new study shows that in 2009, the overall incidence of CAP in active employees was 10.6 per 1000 person-years and 6-fold greater in high-risk patients than in low-risk patients. ➤ Lost productivity costs associated with sick time and short-term disability of employees with CAP have a significant impact on US employers. ➤ During a 12-months period, the mean sick time cost was $1129 for an employee with CAP compared with $853 for an employee without CAP. ➤ Similarly, the mean short-term disability cost was $1016 for an employee with CAP compared with $322 for an employee without CAP. ➤ Implementing effective preventive services for working-age adults with underlying medical conditions may reduce morbidity and the associated costs. ➤

database captures healthcare administrative claims data (ie, medical and pharmacy) from employer-sponsored private health insurance plans for several million individuals annually, encompassing employees, early retirees, and the dependents of both cohorts. The claims data were derived from approximately 100 different insurance companies representing more than 30 million lives who were covered under a variety of health plans during the study period. The HPM database contains employee-level workplace information collected by employers, including employment status, sick leave and short-term disability benefit eligibility, reported sick leave time, and shortterm disability and workers’ compensation paid by employers. The HPM database is a subset of approximately 1.4 million individuals in the MarketScan database.

The study population was derived from the MarketScan database. The population consisted of active employees or early retirees aged 18 to 64 years and their adult dependents who were actively enrolled in employer health plans (with medical and pharmacy benefits) on January 1, 2009, and continued with the plans until the loss of health coverage as a result of death or a change of employment. Active employees and adult dependents aged ≥65 years or adults who were eligible for Medicare were excluded from the study. Eligible individuals also had to have continuous medical and pharmacy coverage between January 1, 2008, and December 31, 2008. The

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incidence of CAP, all-cause costs associated with CAP episodes, and overall healthcare costs (medical and pharmacy) were estimated in 2009 using the same data source. To assess the sick time and short-term disability costs associated with CAP, eligible active employees from the MarketScan database were merged with employees in the HPM database. Eligible active employees who were not in both databases were dropped from the sick time and/or the short-term disability cost analyses.

Identification of the Cohorts with and without CAP The presence of CAP was identified by pneumonia claims between January 1, 2009, and December 31, 2009. Patients who were hospitalized in a skilled nursing facility or other institutional facility within 2 weeks before a pneumonia diagnosis were excluded. Inpatient CAP diagnosis was identified by (1) a primary inpatient diagnosis for pneumonia (International Classification of Diseases Clinical Modification, Ninth Edition, [ICD-9CM] 480.xx or 487.0); or (2) a secondary inpatient diagnosis for pneumonia but with a primary inpatient diagnosis for sepsis (ICD-9-CM 515.8), respiratory failure (ICD-9-CM 038.x), bacteremia (ICD-9-CM 790.7), or empyema (ICD-9-CM 510, 510.0, or 510.9); or (3) a secondary inpatient diagnosis for pneumonia with an outpatient or emergency department diagnosis for pneumonia or a chest x-ray claim (Current Procedural Terminology code between 71010 and 71035) less than 90 days before hospitalization.

Outpatient CAP was defined as a primary or a secondary diagnosis of pneumonia in the outpatient or emergency department setting, with a chest x-ray claim within 14 days of the first pneumonia diagnosis and no inpatient pneumonia claim.

An episode of CAP was defined as the period between the date of the first and last pneumonia claims or the last date of an antibiotic medication, based on prescription fill data. A 90-day period free of pneumonia claims was applied to distinguish one episode of CAP from another.

Using these criteria, an individual could have ≥1 episodes of CAP during 2009. Eligible patients with any episodes of CAP were designated as part of the cohort with CAP. Individuals with no pneumonia claims between January 1, 2009, and December 31, 2009 were designated as part of the cohort without CAP. For the cost analysis of the CAP episode level, follow-up until March 2010 was allowed to capture all resource use for episodes of CAP that started late in 2009.

Stratification by Risk Level Because the risk of developing pneumonia, healthcare resource use, and costs differ by the presence of underlying comorbidities,20,21 each individual was as-

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signed to a risk category (high, moderate, or low) based on claims data from January 1, 2008, through December 31, 2009. The risk category assignment was based on the presence of immunocompromising and/or chronic conditions on either 1 inpatient claim, 1 emergency department claim, or 2 outpatient claims on different dates, or 2 pharmacy claims for the same immunocompromising or chronic conditions.

Patients were considered to be high risk if they had an immunocompromising condition (eg, HIV, neoplasm, nephritic syndrome, chronic renal failure, organ transplant). Moderate risk was assigned to patients who had no indication of an immunocompromising condition but had ≥1 chronic conditions (eg, congestive heart failure [CHF], cardiomyopathy, diabetes, chronic obstructive pulmonary disease [COPD], liver disease, asplenia, sickle-cell disease, alcoholism, asthma, or coronary artery disease [CAD]). Patients who did not belong to either the high- or moderate-risk categories were assigned to the low-risk category.

Statistical Analysis Demographic characteristics, including 5 common comorbidities of interest—diabetes, CHF, CAD, COPD, and asthma—were described in the cohorts with and without CAP. The incidence rate of CAP was analyzed as the number of episodes per 1000 person-years in 2009.

All-cause healthcare (ie, medical and pharmacy) costs were compiled for inpatient and outpatient episodes of CAP. The annual all-cause healthcare costs, sick leave, and short-term disability costs were descriptively compared between the cohorts with and without CAP during 2009. Amounts paid by the health plan and the individual were used to estimate the costs for all services that were rendered.

Monetized values of sick leave were derived by multiplying recorded sick days by the national average wage according to age and sex. The costs of short-term disability were estimated based on actual amounts paid to the employee for the incident.

To further assess the impact of CAP, multivariate linear regression was used to estimate the incremental overall healthcare costs between patients with inpatient or outpatient CAP and individuals without CAP during 2009. Factors adjusted in the models included age, sex, and risk category. Based on published literature, as well as on our current study, age and underlying medical conditions are major risk factors for developing pneumonia and are determinants of cost to treat pneumonia.1,16,22 Therefore, these variables were included in the regression analysis. Employment is not a main factor for the development of pneumonia or for the associated high cost of the disease.

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Table 1 Demographic Characteristics by Members with and without CAP: 2009 MarketScan Data

Characteristics Age, yrs 18-29 30-39 40-49 50-64 Sex Female Male Geographic distribution Northeast North central South West CAP risk level Low Moderate High Chronic medical conditionsb Diabetes Congestive heart failure Coronary artery disease Chronic obstructive pulmonary disease Asthma Employment category Active employees Adult dependents of active employees Early retirees and their adult dependents

All members, N (%)a

Members with CAP, N (%)a

Members without CAP, N (%)a

12,502,017

123,920

12,378,097

2,279,922 (18.2)

13,055 (10.5)

2,266,867 (18.3)

2,498,276 (20.0)

20,436 (16.5)

2,477,840 (20.0)

3,178,212 (25.4)

30,894 (24.9)

3,147,318 (25.4)

4,545,607 (36.4)

59, 535 (48.0)

4,486,072 (36.2)

6,534,732 (52.3)

67,412 (54.4)

6,467,320 (52.2)

5,967,285 (47.7)

56,508 (45.6)

5,910,777 (47.8)

1,143,089 (9.1)

10,667 (8.6)

1,132,422 (9.1)

3,420,281 (27.4)

34,238 (27.6)

3,386,043 (27.4)

5,703,475 (45.6)

58,393 (47.1)

5,645,082 (45.6)

2,235,172 (17.9)

20,622 (16.6)

2,214,550 (17.9)

11,201,501 (89.6)

83,107 (67.1)

11,118,394 (89.8)

1,053,299 (8.4)

30,122 (24.3)

1,023,177 (8.3)

247,217 (2.0)

10,691 (8.6)

236,526 (1.9)

709,694 (5.7)

16,330 (13.2)

693,364 (5.6)

44,893 (0.4)

4765 (3.8)

40,128 (0.3)

205,852 (1.6)

7546 (6.1)

198,306 (1.6)

78,174 (0.6)

9584 (7.7)

68,590 (0.6)

183,145 (1.5)

10,302 (8.3)

172,843 (1.4)

7,363,171 (58.9)

71,737 (57.9)

7,291,434 (58.9)

4,187,260 (33.5)

39,265 (31.7)

4,147,995 (33.5)

951,586 (7.6)

12,918 (10.4)

938,668 (7.6)

Percentages are rounded.

Comorbidities were not mutually exclusive.

CAP indicates community-acquired pneumonia. a

b

Results In total, 12,502,017 individuals in the MarketScan database met the studyâ&#x20AC;&#x2122;s eligibility criteria (Table 1). Of these, 58.9% (N = 7,363,171) were active employees, 33.5% (N = 4,187,260) were adult dependents of active employees, and 7.6% (N = 951,586) were early retirees and their adult dependents. The mean age of the active employees and their dependents was 41.9 years, and that of the early retirees and their dependents was 56.5 years.

In the database, the number of patients with CAP was 123,920 and the number of individuals without CAP was 12,378,097. In general, the CAP population was older and had higher risk levels for pneumonia and more co-

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morbidities than the population without CAP. Approximately 39% of the CAP population had underlying comorbidities (ie, moderate- or high-risk combined) compared with only 10% of the population without CAP. The prevalence of each of the 5 selected comorbidities (ie, diabetes, CHF, CAD, COPD, asthma) was at least 2-fold higher in the population with CAP than in the population without CAP. Overall, there was no obvious difference in the geographic distribution between the populations with and without CAP.

Incidence Rates of CAP During 2009, there were 114,063 episodes of CAP

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Table 2 CAP Incidence Rates for Active Employees, Early Retirees, and their Dependents: 2009 MarketScan Data Patients with CAP managed in the hospital

All patients with CAP Age and risk categories

Patients with CAP in outpatient setting

Incidence Incidence Person-years, Episodes, per 1000 Episodes, per 1000 Episodes, N N person-years N person-years N

Active employees and their adult dependents 7,267,964 65,045 Age, 18-49 yrs 6,847,855 51,503 Low risk 348,130 10,530 Moderate risk 71,978 3012 High risk 3,479,241 49,018 Age, 50-64 yrs 2,865,264 26,871 Low risk 492,878 15,981 Moderate risk 121,099 6166 High risk 10,747,205 114,063 Total: age, 18-64 yrs 9,713,119 78,374 Low risk 841,009 26,511 Moderate risk 193,077 9178 High risk Early retirees and their adult dependents 896,885 13,411 Total: age, 18-64 yrs 703,402 6314 Low risk 154,762 4967 Moderate risk 38,721 2130 High risk

Incidence per 1000 person-years

8.9

8936

1.2

56,109

7.7

7.5

3831

0.6

47,672

7.0

30.2

3536

10.2

6994

20.1

41.8

1569

21.8

1443

20.0

14.1

11,908

3.4

37,110

10.7

9.4

2655

0.9

24,216

8.5

32.4

5882

11.9

10,099

20.5

50.9

3371

27.8

2795

23.1

10.6

20,844

1.9

93,219

8.7

8.1

6486

0.7

71,888

7.4

31.5

9418

11.2

17,093

20.3

47.5

4940

25.6

4238

21.9

15.0

4067

4.5

9344

10.4

9.0

821

1.2

5493

7.8

32.1

2026

13.1

2941

19.0

55.0

1220

31.5

910

23.5

CAP indicates community-acquired pneumonia.

among active employees and their adult dependents (inpatient, N = 20,844 [18.3%]; outpatient, N = 93,219 [81.7%]) and 13,411 CAP episodes among early retirees and their adult dependents (inpatient, N = 4067 [30.3%]; outpatient, N = 9344 [69.7%]; Table 2). Overall, approximately 19.5% of CAP episodes were inpatient.

The overall incidence rate of CAP in active employees and their adult dependents was 10.6 per 1000 person-years; the rate was almost 6 times greater in high-risk patients than in low-risk patients (47.5 vs 8.1 per 1000 person-years, respectively). The incidence rates of inpatient and outpatient CAP in this population were 1.9 and 8.7 per 1000 person-years, respectively. The overall incidence rate of CAP in early retirees and their adult dependents was somewhat higher, at 15.0 per 1000 person-years (ie, 4.5 and 10.4 per 1000 person-years for inpatient and outpatient CAP, respectively). There was a clear trend in both groups: the incidence of CAP was greater with increasing age and risk.

Costs for a CAP Episode Overall, the mean cost for an inpatient CAP episode among active employees and their adult dependents was

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$36,139 compared with $1091 for an outpatient CAP episode (Table 3). The mean cost for an episode rose dramatically with increased risk for inpatient and outpatient episodes of CAP, with more than a doubling noted between low-risk and high-risk patients; in contrast, the increase in mean episode costs was more modest across age-groups. The overall mean episode costs for early retirees and their adult dependents (inpatient CAP, $32,133; outpatient CAP, $1462) were close to those of active employees, and a similar pattern of cost increase was observed across risk categories.

Total Healthcare Costs The annual healthcare costs were higher with increasing age and increased risk in the 2 cohorts with and without CAP. Among active employees and their adult dependents, the mean annual healthcare costs were found to be more than 5 times higher in patients with CAP than in individuals without CAP ($20,961 vs $3783, respectively; Table 4). Such costs in patients with CAP versus those without CAP were consistently 3-fold higher across all risk strata. A similar pattern was observed among early retirees and their adult dependents.

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As with the descriptive results, the adjusted annual incremental healthcare costs between patients with inpatient and outpatient CAP versus individuals without CAP were significantly higher and rose with increasing risk (all P values <.01). Compared with individuals without CAP, the average annual incremental healthcare cost ranged from $39,889 to $113,837 for inpatient CAP and from $4170 to $31,524 for outpatient CAP, depending on the patientâ&#x20AC;&#x2122;s risk level (Table 5).

Sick Time and Short-Term Disability Costs Of the 12,502,017 eligible members in the MarketScan database, 1,254,974 employees were successfully merged with the HPM database. In total, 315,499 employees were eligible for sick time benefits and 1,031,231 employees were eligible for short-term disability benefits.

The mean sick time costs were calculated for 2911 employees with CAP and 312,588 employees without CAP (Table 6). Among employees with and without CAP, the mean sick time costs were higher in older individuals and in patients in the moderate- and high-risk categories. Overall, the mean sick time cost was $1129 for an employee with CAP and $853 for an employee without CAP. The mean recorded sick times for employees with and without CAP were 5.0 and 3.8 days, respectively (data not shown). In general, the number of days of sick time increased with age and with higher risk status in employees with and without CAP. Overall, 31.4% of employees with CAP versus 41.6% of employees without CAP had no sick time reported.

The mean short-term disability costs were calculated in 9118 employees with CAP and in 1,022,113 employees without CAP (Table 6). Overall, the mean shortterm disability cost was $1016 for employees with CAP and $322 for their counterparts without CAP. The mean recorded short-term disability times for employees with and without CAP were 16.1 and 4.9 days, respectively.

As with sick time, the number of days of short-term disability increased with age and with higher risk status in employees with and without CAP. Overall, 75% of employees with CAP versus 92.8% of those without CAP had no short-term disability to report.

Discussion The current study estimated the incidence rate and the healthcare, sick time, and short-term disability costs of CAP from an employer perspective in active employees aged 18 to 64 years, in early retirees aged <65 years, and in the adult dependents of both cohorts. The results of our study confirm the results of previous studies: the direct and indirect costs of CAP are substantial in working-age adults. It is well established that older adults

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Mean Costs for an Episode of CAP for Active Employees, Table 3 Early Retirees, and Their Dependents: 2009 MarketScan Data

Active employees and their adult dependents Age, 18-49 yrs Low risk Moderate risk High risk Age, 50-64 yrs Low risk Moderate risk High risk Total: age, 18-64 yrs Low risk Moderate risk High risk Early retirees and their adult dependents Total: age, 18-64 yrs Low risk Moderate risk High risk

Inpatient CAP Mean (SD), $ N = 20,844

Outpatient CAP Mean (SD), $ N = 93,219

32,844 (81,395)

894 (7890)

24,293 (57,365)

714 (7586)

27,994 (67,542)

1604 (8155)

64,650 (134,854)

3369 (13,710)

38,612 (82,437)

1391 (8097)

30,311 (83,962)

792 (3812)

31,393 (62,900)

1908 (9042)

57,745 (105,088)

4712 (20,838)

36,139 (82,039)

1091 (7977)

26,757 (69,551)

740 (6562)

30,117 (64,699)

1784 (8691)

59,938 (115,408)

4255 (18,727)

N = 4067

N = 9344

32,133 (73,073)

1462 (8041)

23,730 (52,276)

760 (2746)

28,029 (59,548)

2090 (10,141)

44,602 (99,251)

3665 (16,650)

CAP indicates community-acquired pneumonia; SD, standard deviation.

carry a disproportionately higher epidemiologic burden of CAP than their younger counterparts, with higher incidence, hospitalization, and mortality rates with advancing age.18,19,22,23 Given the strong correlation between older age and the presence of CAP, it is perhaps not surprising that the bulk of epidemiologic data focuses on older adults, and that there is a widely acknowledged lack of contemporary data in the nonelderly adult population.12,24 Nonetheless, some limited information is available on working-age adults in the United States, and it warrants mention here.

Using MarketScan data from 2003 through 2007, Bonafede and colleagues reported an annual incidence rate of CAP of 4.89 cases per 1000 person-years in working-age adults aged 18 years to 64 years.12 This incidence rate is much lower than that obtained in our study (ie, 10.6 cases per 1000 person-years), which used 2009 MarketScan data from a similar population. The higher rate observed in our study may be explained by population differencesâ&#x20AC;&#x201D;most notably, an older study population and a greater proportion of adults with comorbidities in the current cohort with CAP. For exam-

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Table 4 Mean Annual Healthcare Costs for Active Employees, Early Retirees, and Their Dependents: 2009 MarketScan Data Mean (SD), $ With CAP

P value Without CAP of t-test

N = 111,002

N = 11,439,429

Age, 18-49 yrs

15,012 (55,239)

2937 (12,185)

<.001

Low risk

7310 (27,194)

2332 (8674)

<.001

26,648 (64,813)

8843 (21,025)

<.001

Active employees and their adult dependents

Moderate risk High risk

110,855 (171,476) 34,899 (69,589)

<.001

Age, 50-64 yrs

28,942 (73,034)

5598 (18,307)

<.001

Low risk

10,657 (38,074)

3493 (9510)

<.001

Moderate risk

31,364 (59,447)

10,657 (22,824)

<.001

105,179 (142,409) 36,007 (66,173)

<.001

High risk Total: age, 18-64 yrs Low risk Moderate risk High risk

20,961 (63,825)

3783 (14,468)

<.001

8453 (31,378)

2668 (8940)

<.001

29,491 (61,676)

9904 (22,113)

<.001

107,044 (152,586) 35,595 (67,466)

<.001

Early retirees and their adult dependents

N = 12,918

N = 938,668

Total: age, 18-64 yrs

30,932 (67,794)

6038 (18,578)

<.001

Low risk

11,536 (30,919)

3647 (9855)

<.001

Moderate risk

31,232 (58,410)

10,631 (22,099)

<.001

High risk

89,173 (117,917)

32,653 (59,491)

<.001

CAP indicates community-acquired pneumonia; SD, standard deviation.

Regression Analysis of the Annual Incremental Healthcare Table 5 Costs for Inpatient and Outpatient CAP Management versus Members without CAP: 2009 MarketScan Data CAP management setting Inpatient management of patients with CAP vs members without CAP

Risk

Annual incremental healthcare costs, $ P value

High

113,837

<.001

Moderate

45,315

<.001

Low

39,889

<.001

31,524

<.001

8780

<.001

4170

.003

High Outpatient management of patients with CAP vs Moderate members without CAP Low

CAP indicates community-acquired pneumonia.

ple, in our study, 13.2% and 7.7% of the cohort with CAP had diabetes and COPD, respectively, compared with 8.1% and 4.1%, respectively, in the study by Bonafede and colleagues.12 In addition, unlike Bonafede and colleagues,12 we did not specifically exclude healthcare-associated pneumonia (HCAP), because of the

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substantial overlap between individuals with CAP and HCAP, as is recognized in guidelines from the American Thoracic Society and the Infectious Diseases Society of America.1,25 This disparity in the incidence of CAP between the 2 studies can perhaps also be explained by methodologic differences.

Several early studies using data from the late 1990s have examined the direct and indirect costs of CAP from an employer perspective; however, their findings were limited by the use of the same large employer in those studies, a lack of incremental cost burden of CAP, and the imputation of sick leave time and costs.13-15 In addition to investigating the incidence of CAP, Bonafede and colleagues also used MarketScan data (2003 through 2007) to assess the excess direct medical and productivity (short-term disability and absence) costs (in 2008 dollars) of CAP in US adults aged 18 to 64 years.15 The authors, who used generalized linear models to compare the cohorts with and without CAP, reported crude annual incremental healthcare costs that were lower than those in our study ($11,443 vs $17,178, respectively), but indirect costs that were higher ($2391 vs $970, respectively).12 A follow-on study examining the annual excess cost of CAP in patients with asthma, diabetes, COPD, and CHF reported mean healthcare costs of $10,158 to $31,593, which were similar to our findings.16 Further assessment of healthcare costs by risk and care setting showed that the burden of CAP is very high in certain risk groups, even in adults with CAP who are not hospitalized for the treatment of CAP. The annual incremental healthcare cost burden in working-age adults with an outpatient episode of CAP compared with adults without CAP was surprisingly highâ&#x20AC;&#x201D;$4170, $8780, and $31,524 in the low-, moderate-, and high-risk groups, respectively. Several reports cite hospitalization the key driver of the treatment costs of CAP, but the cost burden of outpatient CAP is rarely highlighted.14,17,18 Our results suggest that outpatient CAP should not be dismissed as being inconsequential. Approximately 80% of all episodes of CAP in our study were outpatient, and the annual incremental healthcare costs associated with outpatient CAP was at least several thousand dollars more than that of an adult without CAP. The notable increase in cost in the higher-risk groups, regardless of whether CAP is treated in the hospital or in an outpatient setting, also points to the significance of chronic comorbidities in determining costs. As one would expect, the annual cost per patient with CAP managed in the inpatient setting was much higher than the annual cost per patient with CAP managed in the outpatient setting.

In the current study, the proportion of episodes of CAP that resulted in hospitalization was high (19.5%), considering that patients who were hospitalized were of

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Table 6 Mean Annual Sick Time and Short-Term Disability Costs for Active Employees: MarketScan and HPM Data in 2009 Sick time cost, $ With CAP (N = 2911)

Short-term disability cost, $

Without CAP With CAP vs (N = 312,588) without CAP

Mean No sick Mean No sick (SD), $ time, % (SD), $ time, %

P value of t-test of means

With CAP (N = 9118)

Without CAP (N = 1,022,113)

No shortNo shortMean term Mean term (SD), $ disability, % (SD), $ disability, %

With CAP vs without CAP P value of t-test of means

Age, 18-49 yrs

949 (1747)

35.0

762 (1313)

43.3

<.001

826 (3266)

78.2

288 (2020)

93.0

<.001

Low risk

888 (1605)

35.8

742 (1239)

43.7

<.001

689 (3033)

81.6

252 (1833)

93.6

<.001

Moderate risk

1172 (2209)

31.9

1034 (1902)

35.9

.185

1097 (3545)

63.2

692 (3121)

84.0

.001

High risk

1642 (2797)

26.5

1557 (3450)

34.8

.418

3136 (5847)

52.0

2150 (7019)

72.5

.010

Age, 50-64 yrs

1372 (2310)

27.1

1008 (1918)

38.7

<.001

1320 (4172)

70.2

396 (2617)

92.4

<.001

Low risk

1185 (1525)

27.2

927 (1672)

39.7

<.001

801 (2998)

79.3

279 (2114)

94.0

<.001

Moderate risk

1673 (3544)

25.6

1358 (2602)

33.2

.058

1767 (5135)

59.0

752 (3591)

86.1

<.001

High risk

1948 (2763)

29.8

1976 (3953)

32.2

.543

3464 (6417)

43.0

2,283 (6819)

72.6

<.001

Total: age, 18-64 yrs

1129 (2001)

31.4

853 (1553)

41.6

<.001

1016 (3644)

75.0

322 (2226)

92.8

<.001

Low risk

1002 (1583)

32.3

808 (1399)

42.3

<.001

725 (3027)

80.8

260 (1919)

93.7

<.001

Moderate risk

1441 (2990)

28.1

1208 (2299)

34.3

.038

1462 (4480)

60.7

726 (3397)

85.2

<.001

High risk

1811 (2697)

28.9

1789 (3701)

33.1

.459

3359 (6194)

46.2

2230 (6899)

72.6

<.001

CAP indicates community-acquired pneumonia; HPM, Health and Productivity Management; SD, standard deviation.

working age and that approximately 33% of them did not seem to have underlying comorbidities (ie, they were low risk). Coincidently, the proportion of hospitalized individuals was nearly identical to a nearly decade-old employer study that reported a 19.6% hospitalization rate.13 This lack of change over time is noteworthy, given the trend in the past decade toward outpatient treatment and the establishment of society guidelines that serve to better identify patients with CAP who can be treated in an outpatient setting.1 The incremental indirect costs resulting from sick time and short-term disability in our study were approximately 33% to 50% that of previous reports using the same data source.12,16 The magnitude of the difference was small in the context of overall costs, and could potentially be explained by methodologic differences. Previous studies have applied wage constants to employer-recorded sick days and to short-term disability days,

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whereas we used wage constants by age, sex, and shortterm disability costs that were based on short-term disability payments made to the employee. As a result of the smaller indirect costs, the contribution of indirect cost within the total cost was only 5%, much lower than the 20% contribution that was previously reported by Bonafede and colleagues.12 Because our study relied on employer-recorded sick days, it is also possible that sick time tracking was incomplete, or that some workers took personal time off instead of reporting it as sick time. The latter scenario is likely, because almost 33% of employees with CAP who were eligible for sick time benefits did not have any sick days recorded during the 1 year period of this study.

Limitations The limitations of a burden of disease study using administrative claims databases are well known; however,

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we also acknowledge other limitations that are specific to our study. Although we applied ICD-9 codes for pneumonia that were used in previous published studies, as well as additional criteria to identify adults with CAP, we might have misclassified some patients as having CAP when, in fact, they had another respiratory condition.

There is also the potential of misclassification of patients to certain risk strata, because we relied only on claims codes, despite applying the risk classification used in other similar studies.18,26,27 The area of greatest uncertainty, however, lies in estimating the indirect costs in this patient population.

Specifically, we did not have wage information for the employees, nor could we explore the absence benefit structure to assess how it could potentially have impacted sick time leave and the recording of sick time. It is quite possible that the lack of such information might have led to an underestimation of indirect costs. In addition, reduced work performance during the pneumonia recovery period (after returning to work) was not considered. Furthermore, our results are largely descriptive, which may be viewed by some readers as limiting; yet, such descriptions may be very relevant to employers, who are more likely to compile crude cost values and differences than to calculate extensive multivariate-adjusted costs.

Despite these limitations, our study draws from a diverse commercially insured working-age population with a variety of health and employer plans, which has enabled a realistic estimate of the burden of CAP from an employer perspective. Our stratification of results by age, risk group, and care setting further provides a transparent view of how costs differ among subgroups.

Conclusions CAP is a common respiratory infection in the commercially insured working-age population and one that poses a substantial financial burden to employers. The current analysis documents higher annual direct costs for working-age adults with CAP than for their counterparts without CAP, regardless of age or risk group.

Given these findings, a call for renewed interest in the efforts to prevent CAP is clearly warranted. At present, society guidelines recommend annual influenza vaccination in all adults, pneumococcal vaccination in adults aged ≥65 years and in adults aged <65 years who have clinical risk factors (ie, underlying medical conditions), and smoking cessation.1 Despite its recommendation, influenza vaccination rates in adults aged 18 years to 49 years and 50 years to 64 years were 28.6% and 42.7%, respectively, and even lower (20.1%) for working-age adults with indicated risk factors for pneumococcal vaccination.28,29 The economic burden of CAP on employ-

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ers and on health plans highlights the need to encourage and implement more effective preventive health services, including the prevention of CAP. The implementation of such preventive measures in working-age adults with comorbidities could be particularly meaningful, because such individuals face an increased risk of CAP and higher CAP-related costs, even if the treatment of CAP does not require hospitalization. Given the substantial medical, social, and economic ramifications of CAP for working-age adults and their employers, the following question is not unreasonable: should CAP be considered primarily a disease of the elderly or one with notable consequences that warrants attention in adults of all ages? n Funding Source This study was funded by Pfizer Inc. Author Disclosure Statement Mr Broulette, Mr Pyenson, and Mr Iwasaki have received funding from Pfizer; Ms Yu is an employee of Pfizer; and Dr Sato is an employee and stockholder of Pfizer.

References

1. Mandell LA, Wunderink RG, Anzueto A, et al; for the Infectious Diseases Society of American, and the American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72.

2. Nair GB, Niederman MS. Community-acquired pneumonia: an unfinished battle.

Med Clin North Am. 2011;95:1143-1161.

3. Brar NK, Niederman MS. Management of community-acquired pneumonia: a review and update. Ther Adv Respir Dis. 2011;5:61-78.

4. Mertz D, Johnstone J. Modern management of community-acquired pneumonia: is it cost-effective and are outcomes acceptable? Curr Infect Dis Rep. 2011;13:269-277.

5. Polverino E, Torres Marti A. Community-acquired pneumonia. Minerva Anestesiol.

2011;77:196-211.

6. Carbonara S, Monno L, Longo B, Angarano G. Community-acquired pneumonia.

Curr Opin Pulm Med. 2009;15:261-273.

7. Niederman MS, Luna CM. Community-acquired pneumonia guidelines: a global perspective. Semin Respir Crit Care Med. 2012;33:298-310.

8. Ramirez JA, Anzueto AR. Changing needs of community-acquired pneumonia.

J Antimicrob Chemother. 2011;66(suppl 3):iii3-iii9.

9. Niederman MS. Community-acquired pneumonia: the U.S. perspective. Semin Respir Crit Care Med. 2009;30:179-188.

10. Hoyert DL, Xu J. Deaths: preliminary data for 2011. Natl Vital Stat Rep. 2012;61:1-51.

11. Centers for Disease Control and Prevention. National Hospital Discharge Survey.

Number of discharges from short-stay hospitals, by first-listed diagnosis and age: United States, 2010. Updates August 22, 2013. www.cdc.gov/nchs/data/nhds/3firstlisted/2010first3_numberage.pdf. Accessed February 4, 2013.

12. Bonafede MM, Suaya JA, Wilson KL, et al. Incidence and cost of CAP in a large working-age population. Am J Manag Care. 2012;18:380-387.

13. Colice GL, Morley MA, Asche C, Birnbaum HG. Treatment costs of community-acquired pneumonia in an employed population. Chest. 2004;125:2140-2145.

14. Birnbaum HG, Morley M, Greenberg PE, et al. Economic burden of pneumonia in an employed population. Arch Intern Med. 2001;161:2725-2731.

15. Birnbaum HG, Morley M, Greenberg PE, Colice GL. Economic burden of respiratory infections in an employed population. Chest. 2002;122:603-611.

16. Polsky D, Bonafede M, Suaya JA. Comorbidities as a driver of the excess costs of community-acquired pneumonia in U.S. commercially-insured working age adults.

BMC Health Serv Res. 2012;12:379.

17. Niederman MS, McCombs JS, Unger AN, et al. The cost of treating community-­ acquired pneumonia. Clin Ther. 1998;20:820-837.

18. Yu H, Rubin J, Dunning S, et al. Clinical and economic burden of community-­ acquired pneumonia in the Medicare fee-for-service population. J Am Geriatr Soc. 2012;60:2137-2143.

19. Thomas CP, Ryan M, Chapman JD, et al. Incidence and cost of pneumonia in Medicare beneficiaries. Chest. 2012;142:973-981.

20. Centers for Disease Control and Prevention, Advisory Committee on Immunization Practices. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep. 2010;59:1102-1106.

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21. Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP).

MMWR Recomm Rep. 1997;46(RR-8):1-24.

22. Jackson ML, Neuzil KM, Thompson WW, et al. The burden of community-acquired pneumonia in seniors: results of a population-based study. Clin Infect Dis. 2004;39:1642-1650.

23. Kaplan V, Angus DC, Griffin MF, et al. Hospitalized community-acquired pneumonia in the elderly: age- and sex-related patterns of care and outcome in the United States. Am J Respir Crit Care Med. 2002;165:766-772.

24. Cunha BA. Community-acquired pneumonia. Medscape. Updated July 1, 2013. http://emedicine.medscape.com/article/234240-overview#aw2aab6b4. Accessed February 4, 2013.

25. American Thoracic Society, Infectious Diseases Society of America. Guidelines

for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

26. Wasser T, Yu J, Singer J, et al. Long-term cost consequences of community-acquired pneumonia in adults. Am J Pharm Benefits. 2013;5:e66-e72.

27. Sato R, Gomez Rey G, Nelson S, Pinsky B. Community-acquired pneumonia episode costs by age and risk in commercially insured US adults aged ≥50 years. Appl Health Econ Health Policy. 2013;11:251-258.

28. Centers for Disease Control and Prevention. Flu vaccination coverage, United States, 2011-12 influenza season. Updated August 15, 2013. www.cdc.gov/flu/pdf/ professionals/vaccination/vax-coverage-1112estimates.pdf. Accessed August 12, 2013.

29. Centers for Disease Control and Prevention (CDC). Noninfluenza vaccination coverage among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2013; 62:66-72.

Stakeholder Perspective CAP Is a Burden for All Ages—Prevention Strategies Are Key

By F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare, Managing Principal, Bentelligence, Greenville, SC

PURCHASERS: As a respiratory disease that can lead to related chronic diseases, community-acquired pneumonia (CAP) has been typically seen as a health issue of retirees from the perspective of health benefits.

The study by Broulette and colleagues in this issue of American Health & Drug Benefits aptly points out the common nature of CAP in a commercial health insurance population in the United States that can be treated and managed in the outpatient settings.

Not surprisingly, treatment costs in this study were higher in patients with CAP than in employees without CAP, yet the cost of CAP treatments can result in lower overall healthcare costs through more effective preventive services as part of an improved care strategy. For the past 2 years, the National Employer Initiative on Specialty Pharmacy showed that costs alone are not the only important factor for human resource decision makers. In fact, according to an online tool kit (available at www. specialtyrxtoolkit.com), the performances of the health plan and its vendors are of equal or greater importance to human resource decision makers: CAP is one example of a condition for which overall health plan performance rather than a silo cost management is needed. As the present study by Broulette and colleagues illustrates for purchasers of healthcare, occupational health, wellness programs, and traditional prevention strategies (eg, vaccinations) can contribute to reducing the economic risks and the health risks of working-age individuals that contribute to the overall savings or the enterprise savings.

PAYERS: Over the past several years, CAP has become a difficult condition to manage from a managed care standpoint. Drugs used for the treatment of CAP are beginning to get more attention and are growing slowly in number. Some newer drug entries to the market for the treatment of CAP are projected to become among

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the largest cost contributors, as a result of their expected increased use. For these reasons, medications for the treatment of patients with CAP have become a prominent concern for payers, including health insurance companies. Fortunately, much is known about CAP in the young and in the elderly populations that can allow more effective healthcare strategies to be implemented in the working-age population.

Drug manufacturers will likely hesitate to conduct comparative effectiveness trials for their products, because safety and efficacy have already been well documented. This means greater reliance on retrospective analyses or real-world evidence to determine if enough data are available to recommend the coverage of one therapy over another for first-line treatment of patients with CAP; however, prevention strategies can make a difference if health plan designs are more clearly communicated and executed.

PATIENTS: The past decade has led research and development efforts to give working-age patients with CAP some novel drug options for this life-altering condition that progresses if left untreated. This study demonstrates the value of preventive strategies toward minimizing the health risks and improving clinical and economic outcomes in the employed population in the United States.

Hospitalizations or expensive emergency department visits for CAP can be avoided. Nonetheless, differences between the medical and pharmacy benefits, and a lack of coverage clarity, may also create challenges for patients who are trying to understand the optimal prevention strategy or treatment coverage. However, healthcare reform coverage changes will provide first-dollar coverage for vaccinations, including for CAP prevention, if these are not already in place.

www.AHDBonline.com

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American Health & Drug Benefits

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INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Iclusig (ponatinib) Unlocks efficacy for your resistant or intolerant CML or Ph+ ALL plan members ™

IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events.

• Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity.

Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusig-treated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events.

Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST,

or both. Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449).

The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse.

Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in

C H R O N I C P H A S E C M L (C P - C M L ) More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved major cytogenic response (MCyR).

54 % 44 %

MCyR

CCyR

Ponatinib is the only TKI recommended by the National Comprehensive Cancer Network® (NCCN®) for patients with any BCR-ABL mutation1

(144/267) 95% CI: 48-60

(118/267) 95% CI: 38-50

Most patients who achieved MCyR also achieved complete cytogenetic response (CCyR) • At baseline, 6% (16/267) of patients had received 1 prior TKI, 37% (98/267) had received 2 TKIs, and 57% (153/267) had received ≥3 TKIs2 • Median duration of follow-up was 10 months2

24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization.

Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Mutation

ponatinib

nilotinib

dasatinib

bosutinib

imatinib

T315I

+

—

—

—

—

V299L

+

+

—

—

—

T315A

+

+

—

+

+*

F317L/V/I/C

+

+

—

+

—

Y253H

+

—

+

+

—

E255K/V

+

—

+

+

—

F359V/C/I

+

—

+

+

—

Any other mutation

+

+

+

+

+†

*If mutation is detected following dasatinib. †High-dose imatinib.

Iclusig is a once-daily oral tablet that can be taken with or without food.

Tablet is not shown at actual size.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the full Prescribing Information for Iclusig (ponatinib), including the Boxed Warning.

References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myelogenous Leukemia V.4.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed June 7, 2013.

To view the most recent and complete version of the guideline, go online to www.nccn.org.

NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Data on file.

Note: Unless otherwise indicated, data presented are from Iclusig [package insert].

Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012.

For more information, please visit iclusig.com.

Iclusig is a trademark of ARIAD Pharmaceuticals, Inc. ©2013 ARIAD Pharmaceuticals, Inc. All rights reserved.

PB/0713/0065/US

BRIEF SUMMARY Iclusig (ponatinib) Rx only Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

INDICATIONS AND USAGE Iclusig™ (ponatinib) is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

This indication is based upon response rate [see Clinical Studies (14)].

There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Thrombosis and Thromboembolism Arterial Thrombosis Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients.

Serious arterial thrombosis occurred in 8% (34/449) of Iclusigtreated patients. Twenty-one patients required a revascularization procedure (16 patients with coronary revascularization, 4 patients with peripheral arterial revascularization, and 1 patient with cerebrovascular revascularization). Overall, fifty-one patients (11%) experienced an arterial thrombosis event of any grade.

Myocardial infarction or worsening coronary artery disease was the most common arterial thrombosis event and occurred in 21 patients (5%) of Iclusig-treated patients. Eleven of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.

Serious cerebrovascular events were reported in 2% (8/449) of Iclusig-treated patients. Two patients experienced hemorrhagic conversion of the initial ischemic event. Four patients developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery).

Serious peripheral arterial events were reported in 2% (7/449) of Iclusig-treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations.

5.2

1

5.3

5.4

5.5

Thirty of 34 Iclusig-treated patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].

Venous Thromboembolism Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

Hepatotoxicity Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred.

The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts.

The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Congestive Heart Failure Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities.

Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig.

Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

Hypertension Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.

Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations.

Pancreatitis Clinical pancreatitis occurred in 6% (28/449) of patients (5% grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%.

5.6

5.7

5.8

5.9

5.10

Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required.

In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)].

Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].

Fluid Retention Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Cardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients.

The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).

Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Myelosuppression Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ ALL than in patients with chronic phase CML (CP-CML). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

Tumor Lysis Syndrome Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

5.11 Compromised Wound Healing and Gastrointestinal Perforation No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing.

Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing.

5.12 Embryo-Fetal Toxicity Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. 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. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

6 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 clinical practice.

The following adverse reactions are discussed in greater detail in other sections of the prescribing information: • Thrombosis and Thromboembolism [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2) and Dosage and Administration (2.3)] • Congestive Heart Failure [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)] • Hemorrhage [see Warnings and Precautions (5.6)] • Fluid Retention [see Warnings and Precautions (5.7)] • Cardiac Arrhythmias [see Warnings and Precautions (5.8)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.9)] The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83%, of the expected 45 mg dose.

Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia.

The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%).

Dose modifications (dose delays or dose reduction) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions (â&#x2030;Ľ5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%).

Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) System Organ Class Any CTCAE Any CTCAE Any CTCAE Any CTCAE Grade Grade Grade Grade Grade Grade Grade Grade (%) 3/4 (%) 3/4 (%) 3/4 (%) 3/4 (%) (%) (%) (%) Cardiac or Vascular disorders Hypertension (a) 68 39 71 36 65 26 53 31 Arterial ischemia (b) 13 7 12 6 8 5 3 0 Cardiac Failure (c) 6 4 6 2 15 11 6 6 Gastrointestinal disorders Abdominal pain (d) 49 10 40 8 34 6 44 6 Constipation 37 2 24 2 26 0 47 3 Nausea 23 1 27 0 32 2 22 0 Diarrhea 16 1 26 0 18 3 13 3 Vomiting 13 2 24 0 23 2 22 0 Oral mucositis (e) 10 1 15 1 23 0 9 3 GI hemorrhage (f) 2 <1 8 1 11 5 9 6 Blood and lymphatic system disorders Febrile neutropenia 1 <1 4 4 11 11 25 25 Infections and infestations Sepsis 1 1 5 5 8 8 22 22 Pneumonia 3 2 11 9 13 11 9 3 Urinary tract infection 7 1 12 1 0 0 9 0 Upper respiratory tract infection 11 1 8 0 11 2 0 0 Nasopharyngitis 9 0 12 0 3 0 3 0 Cellulitis 2 1 4 2 11 3 0 0 Nervous system disorders Headache 39 3 28 0 31 3 25 0 Peripheral neuropathy (g) 13 2 8 0 8 0 6 0 Dizziness 11 0 5 0 5 0 3 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 3 1 11 2 13 0 19 3 Cough 12 0 17 0 18 0 6 0 Dyspnea 11 2 15 2 21 7 6 0 Skin and subcutaneous tissue disorders Rash and related conditions 54 5 48 8 39 5 34 6 Dry skin 39 2 27 1 24 2 25 0 Musculoskeletal and connective tissue disorders Arthralgia 26 2 31 1 19 0 13 0 Myalgia 22 1 20 0 16 0 6 0 Pain in extremity 17 2 17 0 13 0 9 0 Back pain 15 1 11 2 16 2 13 0 Muscle spasms 12 0 5 0 5 0 13 0 Bone pain 12 <1 12 1 11 3 9 3 General disorders and administration site conditions Fatigue or asthenia 39 3 36 6 35 5 31 3 Pyrexia 23 1 31 5 32 3 25 0 Edema, peripheral 13 <1 19 0 13 0 22 0 Pain 8 <1 7 0 16 3 6 3 Chills 7 0 11 0 13 2 9 0 Metabolism and nutrition disorders Decreased appetite 8 <1 12 1 8 0 31 0 Investigations Weight decreased 6 <1 7 0 5 0 13 0 Psychiatric disorders 0 Insomnia 7 0 12 0 8 0 9 Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity.

Treatment-emergent, all causality events (a) derived from blood pressure (BP) measurement recorded monthly while on trial (b) includes cardiac, central nervous system, and peripheral arterial ischemia (c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure (d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort (e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration (f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage (g) includes burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, polyneuropathy

Table 5: Serious Adverse Reactions (SAR) Cardiovascular disorders Arterial ischemic event Myocardial infarction or worsening coronary artery disease Stroke or TIA Peripheral arterial disease Hemorrhage CNS hemorrhage Gastrointestinal hemorrhage Cardiac failure Effusions* Atrial fibrillation Venous thromboembolism Hypertension Gastrointestinal disorders Pancreatitis Abdominal pain Blood and lymphatic system disorders Febrile neutropenia Thrombocytopenia Anemia Infections Pneumonia Sepsis General Pyrexia

N (%) 34 (8%) 21 (5%) 8 (2%) 7 (2%) 22 (4%) 10 (2%) 10 (2%) 20 (4%) 13 (3%) 11 (2%) 10 (2%) 8 (2%) 23 (5%) 17 (4%) 13 (3%) 13 (3%) 12 (2%) 24 (4%) 11 (2%) 14 (3%)

*includes pericardial effusion, pleural effusion, and ascites

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations.

The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 6).

Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) (%) (%) (%) (%) Hematology Thrombocytopenia 36 47 57 47 (platelet count decreased) Neutropenia (ANC decreased) 24 51 55 63 Leukopenia (WBC decreased) 14 35 53 63 Anemia (Hgb decreased) 9 26 55 34 Lymphopenia 10 26 37 22 ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any Grade* Grade 3/4 (%) (%) Liver function tests ALT increased 53 8 AST increased 41 4 Alkaline phosphatase increased 37 2 Albumin decreased 28 1 Bilirubin increased 19 1 Pancreatic enzymes Lipase increased 41 15 Amylase increased 3 <1 Chemistry Glucose increased 58 6 Phosphorus decreased 57 8 Calcium decreased 52 1 Sodium decreased 29 5 Glucose decreased 24 0 Potassium decreased 16 2 Potassium increased 15 2 Sodium increased 10 <1 Bicarbonate decreased 11 <1 Creatinine increased 7 <1 Calcium increased 5 0 Triglycerides increased 3 <1 ALT=alanine aminotransferase, AST=aspartate aminotransferase. *Graded using NCI-CTC-AE v 4.0

7

DRUG INTERACTIONS Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

7.1 Drugs That Are Strong Inhibitors of CYP3A Enzymes

7.2

7.3

7.4

8 8.1

In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)].

Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure.

Monitor patients for signs of reduced efficacy.

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. 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.

Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis.

At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3 Nursing Mothers

8.4

8.5

8.6

8.7

10

It is unknown whether ponatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%).

In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment.

As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

Renal Impairment Iclusig has not been studied in patients with renal impairment.

Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on cycle 1 day 2. The patient experienced fatigue and noncardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion.

In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment.

Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234 For information contact: 1-855-55-ARIAD (855-552-7423)

medinfo@ariad.com PB/0713/0065/US

industry trends

Technological Changes Can Transform Medicine by 2020: A Conversation with the Futurist Jim Carroll

By Rosemary Frei, MSc, Medical Writer

A

t the American Medical Group Association 2013 Institute for Quality Leadership annual conference, a session focused on transforming the US healthcare system was presented by Jim Carroll, author of Ready, Set, Done: How to Innovate When Faster is the New Fast,1 who discussed the ways in which the unprecedented technological changes in medicine can transform the system in a positive way, in a very short time.2 In a brief discussion after the meeting, Mr Carroll offered some food for thought for those involved in the “business” of medicine. He explained that he tells healthcare experts all across the country, “I know you are sick of the Affordable Care Act. But the future of medicine has nothing to do with government—it’s got everything to do with science, demographics, new forms of technological applications, such as genomics, new forms of equipment, and other innovations.”

Mr Carroll suggested that “by the year 2020, we absolutely can harness these to turn the healthcare system from one in which we wait until patients are sick and then we fix them, to understanding what things are going to go wrong in advance in order to avoid those problems.”

“Demographic changes mean healthcare administrators, providers, and patients are becoming more welcoming to technology-driven changes in the sector.

And that provides huge opportunities for improvement through innovation.”

The system that Mr Carroll says is well within reach will have characteristics such as being consumer-driven and retail-oriented for treatment that is not related to critical care, and encompassing many cost-saving technologies.

“One example is in the field of pharmacogenomics, involving pharmaceutical products targeted to particular genes for particular cancer treatments. The cost of sequencing machines has plummeted, and they could be-

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come low-cost items. Individuals could buy machines that tell them whether they have certain gene sequences that make them prone to cancer,” he said. Furthermore, “when this type of technology becomes ubiquitous and costs just pennies, it transforms everything in healthcare.”

Smartphone apps are also proliferating and becoming very inexpensive, and are increasingly being applied in medicine. More than 17,000 healthcare software apps are available for smartphones, according to Mr Carroll, and as many as 78% of consumers have expressed interest in such apps. For example, consumers are using medical apps to monitor their glucose levels and better understand their healthcare circumstances and options.

“The patient is changing; the consumer is changing.

And we all need to align ourselves to the changes that are occurring.” He also pointed to the virtualization of healthcare, with hospitals extending into the community.

“In the near future, a lot of non–critical care patients will be able to remain in their homes instead of being admitted to the hospital, and doctors will be able to monitor their vital signs remotely, using real-time analytics and location-intelligence technologies,” Mr Carroll predicted. He says that because medical knowledge doubles every 6 years, the pace of understanding new medical information is increasing as a result of the power of technology.

“I tell people in the healthcare system, ‘Don’t fixate on the negatives but on the positives. Think about how it’s good for your patients and their patients to embrace these changes,’ ” said Mr Carroll. “Demographic changes mean healthcare administrators, providers, and patients are becoming more welcoming to technology-driven changes in the sector. And that provides huge opportunities for improvement through innovation.” The future of US medicine, according to Mr Carroll, is bright. n

References

1. Carroll J. Ready, Set, Done: How to Innovate When Faster is the New Fast. Oblio Press: Canada; 2007.

2. Carroll J. Healthcare 2020: the transformative trends to define our future. Presented at the American Medical Group Association 2013 Institute for Quality Leadership; September 25-27, 2013; Phoenix, AZ.

www.AHDBonline.com

September/October 2013

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Vol 6, No 8

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:

T:10.5”

B:11.125”

S:9.875”

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 (%) Blood and lymphatic system disorders Neutropenia % 118 (33.4) 12 (3.4) Thrombocytopenia @ 43 (12.2) 22 (6.3) Anemia @ 35 (9.9) 20 (5.7) Leukopenia 14 (4.0) 1 (0.3) Lymphopenia 10 (2.8) 4 (1.1) Febrile Neutropenia % 8 (2.3) 0 (0.0) General disorders and administration site conditions Fatigue 23 (6.5) 17 (4.9) Vascular disorders Deep vein thrombosis % 29 (8.2) 12 (3.4) Infectionsb and infestations Pneumonia @ 30 (8.5) 19 (5.4) Urinary Tract Infection 5 (1.4) 1 (0.3) Metabolism and nutrition disorders Hypokalemia 17 (4.8) 5 (1.4) Hypocalcemia 13 (3.7) 6 (1.7) Hypophosphatemia 9 (2.5) 0 (0.0) Respiratory, thoracic and mediastinal disorders Pulmonary embolism@ 14 (4.0) 3 (0.9) Respiratory Distress @ 4 (1.1) 0 (0.0) Musculoskeletal and connective tissue disorders Muscle weakness 20 (5.7) 10 (2.9) Gastrointestinal disorders Diarrhea @ 11 (3.1) 4 (1.1) Constipation 7 (2.0) 1 (0.3) Nausea @ 6 (1.7) 2 (0.6) Cardiac disorders Atrial fibrillation @ 13 (3.7) 4 (1.1) Tachycardia 6 (1.7) 1 (0.3) Cardiac Failure Congestive @ 5 (1.4) 1 (0.3) Nervous System disorders Syncope 10 (2.8) 3 (0.9) Dizziness 7 (2.0) 3 (0.9) (continued)

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)

10

(6.8)

Anemia

9

(6.1)

Leukopenia

8

(5.4)

Fatigue

7

(4.7)

Dyspnea

7

(4.7)

Back Pain

7

(4.7)

Febrile Neutropenia

6

(4.1)

Nausea

6

(4.1)

Diarrhea

5

(3.4)

Pyrexia

5

(3.4)

Sepsis

4

(2.7)

Dizziness

4

(2.7)

Granulocytopenia

3

(2.0)

Chest Pain

3

(2.0)

Pulmonary Embolism

3

(2.0)

Respiratory Distress

3

(2.0)

Pruritus

3

(2.0)

Pancytopenia

3

(2.0)

Muscle Cramp

3

(2.0)

Respiratory Tract Infection

2

(1.4)

T:10.5”

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

2

(1.4)

Asthenia

2

(1.4)

Multi-organ Failure

2

(1.4)

Epistaxis

2

(1.4)

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

Hypoxia

2

(1.4)

22 17 16 12 8

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

Pleural Effusion

2

(1.4)

Pneumonitis

2

(1.4)

Pulmonary Hypertension

2

(1.4)

Vomiting

2

(1.4)

Sweating Increased

2

(1.4)

Arthralgia

2

(1.4)

Pain in Limb

2

(1.4)

Headache

2

(1.4)

Syncope

2

(1.4)

B:11.125”

S:9.875”

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

Metabolism and Nutrition Disorders Hypokalemia Anorexia Hypomagnesemia

16 15 9

(10.8) (10.1) (6.1)

Investigations Alanine Aminotransferase Increased

12

(8.1)

Psychiatric Disorders Insomnia Depression

15 8

(10.1) (5.4)

Renal and Urinary Disorders Dysuria

10

(6.8)

9

( 6.1)

10

(6.8)

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

79

(53.4)

Thrombocytopenia

74

(50.0)

Pneumonia

11

(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 (%)

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 (%)

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.

T:10.5”

B:11.125”

S:9.875”

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-∞ 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 ≤ 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

Call for Papers

Neurology Theme Issue American Health & Drug Benefits will be publishing a theme issue on neurology in 2014.

With the growing focus on the brain and other neurologic conditions by the National Institutes of Health and by researchers worldwide, and with the aging of the population and growing number of people with central nervous system conditions, a thorough examination of current and emerging trends in neurology is needed, focusing on diagnosis and treatment, benefit design, cost issues, current and emerging therapies, patient-reported outcomes, and health economics outcomes.

Readers are invited to submit manuscripts for this issue, including original research, costeffective analyses, comparative effectiveness analyses, new and emerging therapies, evidencebased systematic reviews, case studies, and industry surveys/trends.

All articles will undergo the journal’s rigorous peer-review process. Manuscripts must follow the Information for Authors guidelines available at www.AHDBonline.com.

Areas of particular interest include: • Aging and health disparities in neurology

• Headache management

• Alzheimer disease: diagnosis and/or treatment

• Pain Medicine

• Benefit design for multiple sclerosis

• Parkinson disease

• Best practices in neurology

• Patient-reported outcomes

• Cost considerations in multiple sclerosis

• Practice guidelines

• Developments in brain research/understanding • Sleep disorders • Emerging therapies in neurology

• Stroke management/cerebrovascular disease

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• Value-based issues in neurology

Submit articles to editorial@engagehc.com; for more information call 732-992-1536.

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Vol 6, No 8

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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American Health & Drug Benefits

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www.AHDBonline.com

September/October 2013

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Vol 6, No 8

Brief Summary of Full Prescribing Information

INJECTAFER® (ferric carboxymaltose injection)

Rx Only

INDICATIONS AND USAGE: Injectafer® (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients: • who have intolerance to oral iron or who have had unsatisfactory response to oral iron, • who have non-dialysis dependent chronic kidney disease.

DOSAGE AND ADMINISTRATION: For patients weighing 50 kg (110 lb) or more: Give Injectafer® in two doses separated by at least 7 days. Give each dose as 750 mg for a total cumulative dose not to exceed 1500 mg of iron per course.

For patients weighing less than 50 kg (110 lb): Give Injectafer® in two doses separated by at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not to exceed 1500 mg of iron per course.

Injectafer® treatment may be repeated if iron deficiency anemia reoccurs.

Administer Injectafer® intravenously, either as an undiluted slow intravenous push or by infusion. When administering as a slow intravenous push, give at the rate of approximately 100 mg (2 mL) per minute. When administered via infusion, dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is not less than 2 mg of iron per mL and administer over at least 15 minutes.

Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration. The product contains no preservatives. Injectafer® is a single-use vial. Discard unused portion.

Avoid extravasation of Injectafer® since brown discoloration of the extravasation site may be long lasting. Monitor for extravasation. If extravasation occurs, discontinue the Injectafer® administration at that site.

DOSAGE FORMS AND STRENGTHS: Single-use vials containing 50 mg elemental iron per mL in the following presentation: 750 mg iron/15 mL CONTRAINDICATIONS: Hypersensitivity to Injectafer® or any of its inactive components.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions:

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®.

Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.

Hypertension: In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects in these two clinical trials. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration.

Laboratory Test Alterations: In the 24 hours following administration of Injectafer®, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer®.

ADVERSE REACTIONS Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer® 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron.

Adverse reactions reported by  1% of treated patients are shown in the following table.

Table 1. Adverse reactions reported in  1% of Study Patients in Clinical Trials 1 and 2 Injectafer® Pooled Comparatorsa Oral iron Term (N=1775) (N=1783) (N=253) % % % 1.2 1.8 7.2 Nausea 0.4 1.9 3.8 Hypertension 0.0 0.2 3.6 Flushing/Hot Flush 0.0 0.1 2.1 Blood Phosphorus Decrease 0.0 1.2 2.0 Dizziness 0.4 0.5 1.7 Vomiting 0.0 0.3 1.4 Injection Site Discoloration 0.0 0.9 1.2 Headache 0.0 0.2 1.1 Alanine Aminotransferase Increase 0.0 2.1 1.1 Dysgeusia 0.0 1.9 1.0 Hypotension 3.2 0.9 0.5 Constipation Includes oral iron and all formulations of IV iron other than Injectafer® Transient decreases in laboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27% (440/1638) of patients in clinical trials.

Adverse Reactions from Post-marketing Experience: The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports with Injectafer®: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope. One case of hypophosphatemic osteomalacia was reported in a subject who received 500 mg of Injectafer® every 2 weeks for a total of 16 weeks. Partial recovery followed discontinuation of Injectafer®.

DRUG INTERACTIONS: Formal drug interaction studies have not been performed with Injectafer®.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Adequate and well controlled studies in pregnant women have not been conducted. Injectafer® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: A study to determine iron concentrations in breast milk after administration of Injectafer® (n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with postpartum iron deficiency anemia. Mean breast milk iron levels were higher in lactating women receiving Injectafer® than in lactating women receiving oral ferrous sulfate.

Pediatric Use: Safety and effectiveness has not been established in pediatric patients.

Geriatric Use: Of the 1775 subjects in clinical studies of Injectafer®, 50% were 65 years and over, while 25% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

OVERDOSAGE: Excessive dosages of Injectafer® may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. A patient who received Injectafer® 18,000 mg over 6 months developed hemosiderosis with multiple joint disorder, walking disability and asthenia. Hypophosphatemic osteomalacia was reported in a patient who received Injectafer® 4000 mg over 4 months. Partial recovery followed discontinuation of Injectafer®.

DESCRIPTION: Ferric carboxymaltose, an iron replacement product, is an iron carbohydrate complex with the chemical name of polynuclear iron (III) hydroxide 4(R)-(poly-(1→4)-O-α-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate.

It has a relative molecular weight of approximately 150,000 Da. Injectafer® (ferric carboxymaltose injection) is a dark brown, sterile, aqueous, isotonic colloidal solution for intravenous injection. Each mL contains 50 mg iron as ferric carboxymaltose in water for injection. Sodium hydroxide and/or hydrochloric acid may have been added to adjust the pH to 5.0-7.0. The vial closure is not made with natural rubber latex.

CLINICAL PHARMACOLOGY Mechanism of Action: Ferric carboxymaltose is a colloidal iron (III) hydroxide in complex with carboxymaltose, a carbohydrate polymer that releases iron.

Pharmacodynamics: Using positron emission tomography (PET) it was demonstrated that red cell uptake of 59Fe and 52Fe from Injectafer® ranged from 61% to 99%. In patients with iron deficiency, red cell uptake of radio-labeled iron ranged from 91% to 99% after 24 days Injectafer® dose. In patients with renal anemia red cell uptake of radio-labeled iron ranged from 61% to 84% after 24 days Injectafer® dose.

Pharmacokinetics: After administration of a single dose of Injectafer® of 100 to 1000 mg of iron in iron deficient patients, maximum iron levels of 37 µg/mL to 333 µg/mL were obtained respectively after 15 minutes to 1.21 hours post dose. The volume of distribution was estimated to be 3 L. The iron injected or infused was rapidly cleared from the plasma, the terminal half life ranged from 7 to 12 hours. Renal elimination of iron was negligible.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenicity studies have not been performed with ferric carboxymaltose.

Ferric carboxymaltose was not genotoxic in the following genetic toxicology studies: in vitro microbial mutagenesis (Ames) assay, in vitro chromosome aberration test in human lymphocytes, in vitro mammalian cell mutation assay in mouse lymphoma L5178Y/TK+/- cells, in vivo mouse micronucleus test at single intravenous doses up to 500 mg/kg.

In a combined male and female fertility study, ferric carboxymaltose was administered intravenously over one hour to male and female rats at iron doses of up to 30 mg/kg. Animals were dosed 3 times per week (on Days 0, 3, and 7). There was no effect on mating function, fertility or early embryonic development. The dose of 30 mg/kg in animals is approximately 40% of the human dose of 750 mg based on body surface area.

CLINICAL STUDIES: The safety and efficacy of Injectafer® for treatment of iron deficiency anemia were evaluated in two randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In these two trials, Injectafer® was administered at dose of 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1500 mg of iron.

PATIENT COUNSELING INFORMATION • Question patients regarding any prior history of reactions to parenteral iron products.

• Advise patients of the risks associated with Injectafer®.

• Advise patients to report any signs and symptoms of hypersensitivity that may develop during and following Injectafer® administration, such as rash, itching, dizziness, lightheadedness, swelling and breathing problems.

Injectafer® is manufactured under license from Vifor (International) Inc, Switzerland.

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IN0650BS Iss. 7/2013

NOW AVAILABLE

For adult patients with iron deficiency anemia (IDA) of various etiologies INDICATIONS Injectafer® (ferric carboxymaltose injection) is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients who have intolerance to oral iron or have had unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease. Injectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components.

IMPORTANT SAFETY INFORMATION Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Injectafer®. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. In clinical trials, serious anaphylactic/ anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer®. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.

In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration.

In two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by ≥2% of Injectafer®-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%).

The following serious adverse reactions have been most commonly reported from the postmarketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.

Please see Brief Summary of the Full Prescribing Information on the following page.

Injectafer® is an iron replacement product indicated for the treatment of IDA in adult patients1

• who have intolerance to oral iron or have had unsatisfactory response to oral iron

• who have non-dialysis dependent chronic kidney disease Up to 750 mg can be delivered in a single dose*1

• Give 2 doses separated by at least 7 days for a total cumulative dose of 1500 mg

• Administer intravenously by

†

– Infusion over at least 15 minutes – Slow push injection at the rate of approximately 100 mg (2 mL) per minute over at least 7.5 minutes

* For patients weighing 50 kg (110 lb) or more, give each dose as 750 mg. For patients weighing less than 50 kg (110 lb), give each dose as 15 mg/kg body weight. †

When administered via infusion, dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is not <2 mg of iron per mL and administer over at least 15 minutes. When administering as a slow intravenous push, give at the rate of approximately 100 mg (2 mL) per minute.

NDC 0517-0650-01 For more information, please call American Regent Customer Service at 800-645-1706 or visit Injectafer.com For reimbursement assistance, please call the Reimbursement Hotline at 877-4-IV-IRON REFERENCE: 1. Injectafer® [package insert]. Shirley, NY: American Regent, Inc.; 2013.

Injectafer® is manufactured under license from Vifor (International) Inc., Switzerland. ©2013 American Regent, Inc. Printed in USA FCM002 Iss. 08/2013