AHDB June 2014, Vol 7, No 4

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ June 2014

Volume 7, Number 4

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

2014: The Year of the Healthcare Consumer David B. Nash, MD, MBA BUSINESS

The Economic Burden of Ischemic Stroke and Major Hemorrhage in Medicare Beneficiaries with Nonvalvular Atrial Fibrillation: A Retrospective Claims Analysis ™

Kathryn Fitch, RN, MEd; Jonah Broulette, ASA, MAAA; Winghan Jacqueline Kwong, PharmD, PhD Stakeholder Perspective: The Clinical Toll of Nonvalvular Atrial Fibrillation Poses Significant Economic Burden

By Raymond L. Singer, MD, MMM, CPE

The Health and Economic Effects of Counterfeit Drugs Erwin A. Blackstone, PhD; Joseph P. Fuhr, Jr, PhD; Steve Pociask, MA Stakeholder Perspective: The Hidden Market of Counterfeit Drugs a Concern for All Stakeholders

By James T. Kenney, Jr, RPh, MBA CLINICAL

Salsalate, an Old, Inexpensive Drug with Potential New Indications: A Review of the Evidence from 3 Recent Studies Kenneth Anderson, DO; Lance Wherle, DO; Min Park, DO; Kenneth Nelson, DO; Loida Nguyen, PharmD, BCPS Stakeholder Perspective: Considering Salsalate Use in Patients at Risk for Diabetes

By Quang Nguyen, DO, FACP, FACE

AMCP 2014 Highlights

©2014 Engage Healthcare Communications, LLC

www.AHDBonline.com

For your members with chronic obstructive pulmonary disease (COPD) who require maintenance bronchodilator treatment

Consider once-daily ANORO ELLIPTA for formulary inclusion

Indication • ANORO ELLIPTA is a combination anticholinergic/long-acting beta2-adrenergic agonist 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.

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

Important Safety Information for ANORO ELLIPTA WARNING: ASTHMA-RELATED DEATH • Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in ANORO 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 LABA, including vilanterol.

• The safety and efficacy of ANORO ELLIPTA in patients with asthma have not been established.

ANORO ELLIPTA is not indicated for the treatment of asthma.

CONTRAINDICATIONS • The use of ANORO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

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

• ANORO 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 ANORO ELLIPTA should not use another medicine containing a LABA (eg, salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

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

• If paradoxical bronchospasm occurs, discontinue ANORO 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, or symptoms. If such effects occur, ANORO ELLIPTA may need to be discontinued. ANORO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

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

The first and only FDA-approved product for patients with COPD combining 2 long-acting bronchodilators in 1 inhaler Contact your GSK Account Manager to schedule a presentation

Important Safety Information for ANORO ELLIPTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Use with caution in patients with narrow-angle glaucoma. Instruct patients to contact a physician immediately if signs or symptoms of acute narrow-angle glaucoma develop.

• Use with caution in patients with urinary retention, especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to contact a physician immediately if signs or symptoms of urinary retention develop.

• Be alert to hypokalemia and hyperglycemia.

ADVERSE REACTIONS • The most common adverse reactions (≥1% and more common than placebo) reported in four 6-month clinical trials with ANORO ELLIPTA (and placebo) were: pharyngitis, 2% (<1%); sinusitis, 1% (<1%); lower respiratory tract infection, 1% (<1%); constipation, 1% (<1%); diarrhea, 2% (1%); pain in extremity, 2% (1%); muscle spasms, 1% (<1%); neck pain, 1% (<1%); and chest pain, 1% (<1%).

• In addition to the 6-month efficacy trials with ANORO ELLIPTA, a 12-month trial evaluated the safety of umeclidinium/vilanterol 125 mcg/25 mcg in subjects with COPD. Adverse reactions (incidence ≥1% and more common than placebo) in subjects receiving umeclidinium/vilanterol 125 mcg/25 mcg were: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, viral respiratory tract infection, toothache, and diabetes mellitus.

DRUG INTERACTIONS • Caution should be exercised when considering the coadministration of ANORO ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (eg, ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic exposure to vilanterol and cardiovascular adverse effects may occur.

• ANORO 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 COPD. • 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.

• Avoid coadministration of ANORO ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects.

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

ANORO ELLIPTA was developed in collaboration with

BRIEF SUMMARY ANOROTM ELLIPTATM (umeclidinium 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 all LABA, including vilanterol, one of the active ingredients in ANORO ELLIPTA [see Warnings and Precautions (5.1)].

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

1 INDICATIONS AND USAGE ANORO ELLIPTA is a combination anticholinergic/long-acting beta2-adrenergic agonist (anticholinergic/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.

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

4 CONTRAINDICATIONS The use of ANORO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients [see Warnings and Precautions (5.6), 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 asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in ANORO ELLIPTA. • No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with ANORO ELLIPTA has been conducted. The safety and efficacy of ANORO ELLIPTA in patients with asthma have not been established. ANORO ELLIPTA is not indicated for the treatment of asthma.

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

ANORO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. ANORO 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 ANORO 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 ANORO ELLIPTA, the healthcare provider should also prescribe an inhaled, shortacting 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 ANORO ELLIPTA no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, 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 ANORO ELLIPTA beyond the recommended dose is not appropriate in this situation.

5.3 Excessive Use of ANORO ELLIPTA and Use With Other Long-Acting Beta2-Agonists ANORO 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 ANORO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

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

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

5.6 Hypersensitivity Reactions Hypersensitivity reactions may occur after administration of ANORO 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 use ANORO ELLIPTA [see Contraindications (4)].

5.7 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, or symptoms [see Clinical Pharmacology (12.2) of full Prescribing Information]. If such effects occur, ANORO 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.

Therefore, ANORO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.8 Coexisting Conditions ANORO 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.

5.9 Worsening of Narrow-Angle Glaucoma ANORO ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.10 Worsening of Urinary Retention ANORO ELLIPTA should be used with caution in patients with urinary retention.

Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.11 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 medicines may produce transient hyperglycemia in some patients. In 4 clinical trials of 6-month duration evaluating ANORO 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 ANORO ELLIPTA, increase the risk of asthma-related death. ANORO ELLIPTA is not indicated for the treatment of asthma. [See Boxed Warning and Warnings and Precautions (5.1).]

The following adverse reactions are described in greater detail in other sections: • Paradoxical bronchospasm [see Warnings and Precautions (5.5)] • Cardiovascular effects [see Warnings and Precautions (5.7)]

• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.9)] • Worsening of urinary retention [see Warnings and Precautions (5.10)] 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 ANORO ELLIPTA included 8,138 subjects with COPD in four 6-month lung function trials, one 12-month long-term safety study, and 9 other trials of shorter duration. A total of 1,124 subjects have received at least 1 dose of ANORO ELLIPTA (umeclidinium/vilanterol 62.5 mcg/25 mcg), and 1,330 subjects have received a higher dose of umeclidinium/vilanterol (125 mcg/25 mcg).

The safety data described below are based on the four 6-month and the one 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 ANORO ELLIPTA in Table 1 is based on four 6-month trials: 2 placebo-controlled trials (Trials 1 and 2; n = 1,532 and n = 1,489, respectively) and 2 active-controlled trials (Trials 3 and 4; n = 843 and n = 869, respectively). Of the 4,733 subjects, 68% were male and 84% were Caucasian. They had a mean age of 63 years and an average smoking history of 45 pack-years, with 50% identified as current smokers. At screening, the mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV1) was 48% (range: 13% to 76%), the mean post-bronchodilator FEV1/forced vital capacity (FVC) ratio was 0.47 (range: 0.13 to 0.78), and the mean percent reversibility was 14% (range: -45% to 109%).

Subjects received 1 dose once daily of the following: ANORO ELLIPTA, umeclidinium/ vilanterol 125 mcg/25 mcg, umeclidinium 62.5 mcg, umeclidinium 125 mcg, vilanterol 25 mcg, active control, or placebo.

Table 1. Adverse Reactions With ANORO ELLIPTA With ≥1% Incidence and More Common Than With Placebo in Subjects With Chronic Obstructive Pulmonary Disease Placebo (n = 555) %

ANORO ELLIPTA (n = 842) %

<1 <1

2 1

1 <1

2 1

<1

1

<1

<1

Gastrointestinal disorders Constipation Diarrhea

<1 1

1 2

<1 <1

<1 2

Musculoskeletal and connective tissue disorders Pain in extremity Muscle spasms Neck pain

1 <1 <1

2 1 1

<1 <1 <1

2 <1 <1

General disorders and administration site conditions Chest pain

<1

1

<1

<1

S:9.5”

T:10.5”

B:11.25”

Adverse Reaction Infections and infestations Pharyngitis Sinusitis Lower respiratory tract infection

Umeclidinium Vilanterol 62.5 mcg 25 mcg (n = 418) (n = 1,034) % %

Other adverse reactions with ANORO ELLIPTA observed with an incidence less than 1% but more common than with placebo included the following: productive cough, dry mouth, dyspepsia, abdominal pain, gastroesophageal reflux disease, vomiting, musculoskeletal chest pain, chest discomfort, asthenia, atrial fibrillation, ventricular extrasystoles, supraventricular extrasystoles, myocardial infarction, pruritus, rash, and conjunctivitis.

12-Month Trial: In a long-term safety trial, 335 subjects were treated for up to 12 months with umeclidinium/vilanterol 125 mcg/25 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled efficacy trials described above. Adverse reactions that occurred with a frequency of greater than or equal to 1% in the group receiving umeclidinium/vilanterol 125 mcg/25 mcg that exceeded that in placebo in this trial were: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, viral respiratory tract infection, toothache, and diabetes mellitus.

7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Vilanterol, a component of ANORO ELLIPTA, is a substrate of CYP3A4. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to vilanterol. Caution should be exercised when considering the coadministration of ANORO ELLIPTA with 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 (5.4), 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 ANORO ELLIPTA, but may produce severe bronchospasm in patients with COPD. 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 beta-agonists, such as vilanterol, a component of ANORO ELLIPTA, 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 ANORO ELLIPTA with non– potassium-sparing diuretics.

7.5 Anticholinergics There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of ANORO ELLIPTA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.9, 5.10), Adverse Reactions (6)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials of ANORO ELLIPTA or its individual components, umeclidinium and vilanterol, in pregnant women. Because animal reproduction studies are not always predictive of human response, ANORO 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 ANORO ELLIPTA. Umeclidinium: There was no evidence of teratogenic effects in rats and rabbits at approximately 50 and 200 times, respectively, the MRHDID (maximum recommended human daily inhaled dose) in adults (on an AUC basis at maternal inhaled doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).

Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 70 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 450 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.

Nonteratogenic Effects: Umeclidinium: There were no effects on perinatal and postnatal developments in rats at approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).

Vilanterol: There were no effects on perinatal and postnatal developments 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).

8.2 Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of ANORO ELLIPTA during labor and delivery.

Because beta-agonists may potentially interfere with uterine contractility, ANORO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk.

8.3 Nursing Mothers ANORO ELLIPTA: It is not known whether ANORO ELLIPTA is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be

exercised when ANORO ELLIPTA is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of ANORO ELLIPTA by nursing mothers, based on the data for the individual components, a decision should be made whether to discontinue nursing or to discontinue ANORO ELLIPTA, taking into account the importance of ANORO ELLIPTA to the mother.

Umeclidinium: It is not known whether umeclidinium is excreted in human breast milk. However, administration to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium in 2 pups, which may indicate transfer of umeclidinium in milk.

Vilanterol: It is not known whether vilanterol is excreted in human breast milk.

However, other beta2-agonists have been detected in human milk.

8.4 Pediatric Use ANORO ELLIPTA is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.

8.5 Geriatric Use Based on available data, no adjustment of the dosage of ANORO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Clinical trials of ANORO ELLIPTA for COPD included 2,143 subjects aged 65 and older and, of those, 478 subjects were 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 Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed [see Clinical Pharmacology (12.3) of full Prescribing Information].

8.7 Renal Impairment There were no significant increases in either umeclidinium 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 case of overdose has been reported with ANORO ELLIPTA. ANORO ELLIPTA contains both umeclidinium and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to ANORO ELLIPTA. Treatment of overdosage consists of discontinuation of ANORO 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.

10.1 Umeclidinium High doses of umeclidinium may lead to anticholinergic signs and symptoms.

However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD. 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.

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

Umeclidinium: Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 mcg/kg/day and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively).

Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and inhaled doses up to 294 mcg/kg/ day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC 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 7,800 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 210 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 20 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 1 time the MRHDID in adults on an AUC basis).

These tumor findings in rodents are similar to those reported previously for other betaadrenergic 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 14,500 times, respectively, the MRHDID in adults on a mcg/m2 basis).

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Asthma-Related Death: Inform patients that LABA, such as vilanterol, one of the active ingredients in ANORO ELLIPTA, increase the risk of asthma-related death.

ANORO ELLIPTA is not indicated for the treatment of asthma.

Not for Acute Symptoms: Inform patients that ANORO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise them to treat acute symptoms with a rescue inhaler such as albuterol. Provide patients with such medicine and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience any of the following: • Symptoms get worse • Need for more inhalations than usual of their rescue inhaler Patients should not stop therapy with ANORO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta2-Agonists: Instruct patients to not use other medicines containing a LABA. Patients should not use more than the recommended once-daily dose of ANORO ELLIPTA. Instruct patients who have been taking inhaled, short-acting beta2-agonists on a regular basis to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.

Paradoxical Bronchospasm: As with other inhaled medicines, ANORO ELLIPTA can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue ANORO ELLIPTA. Risks Associated With Beta-Agonist Therapy: Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Worsening of Narrow-Angle Glaucoma: Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Worsening of Urinary Retention: Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination).

Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

ANORO and ELLIPTA are trademarks of GSK group of companies.

ANORO ELLIPTA was developed in collaboration with

.

GSK Research Triangle Park, NC 27709 ©2013, GSK group of companies. All rights reserved.

Revised 12/2013 ©2014 GSK group of companies.

All rights reserved. Printed in USA. MH3871R0 April 2014

ANR:1BRS

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Table of Contents EDITORIAL

198 2014: The Year of the Healthcare Consumer

David B. Nash, MD, MBA BUSINESS

200 The Economic Burden of Ischemic Stroke and Major Hemorrhage in Medicare Beneficiaries with Nonvalvular Atrial Fibrillation: A Retrospective Claims Analysis Kathryn Fitch, RN, MEd; Jonah Broulette, ASA, MAAA; Winghan Jacqueline Kwong, PharmD, PhD 208 Stakeholder Perspective: The Clinical Toll of Nonvalvular Atrial Fibrillation Poses Significant Economic Burden

By Raymond L. Singer, MD, MMM, CPE 216 The Health and Economic Effects of Counterfeit Drugs

Erwin A. Blackstone, PhD; Joseph P. Fuhr, Jr, PhD; Steve Pociask, MA 224 Stakeholder Perspective: The Hidden Market of Counterfeit Drugs a Concern for All Stakeholders

By James T. Kenney, Jr, RPh, MBA Continued on page 193

Now Indexed in PubMed Central

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editorial board Editor-in-Chief

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

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

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

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

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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

GOVERNMENT

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

Jeffrey A. Bourret, PharmD, MS, BCPS, 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

Kelly Huang, PhD Operating Partner, Spindletop Capital 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

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA 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

192

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Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy Univ. of Cincinnati Medical Center, OH 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 Director, Pharmacy Services SelectHealth, Murray, 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

Bruce Pyenson, FSA, MAAA Principal & Consulting Actuary Milliman, Inc New York, NY

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA

Personalized medicine

SPECIALTY PHARMACY

PAYER-PROVIDER FINANCES

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

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(Continued) American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512.

Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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231 Salsalate, an Old, Inexpensive Drug with Potential New Indications: A Review of the Evidence from 3 Recent Studies Kenneth Anderson, DO; Lance Wherle, DO; Min Park, DO; Kenneth Nelson, DO; Loida Nguyen, PharmD, BCPS 235 Stakeholder Perspective: Considering Salsalate Use in Patients at Risk for Diabetes

By Quang Nguyen, DO, FACP, FACE DEPARTMENT

237 AMCP 2014 Highlights

By Kate O’Rourke, Medical Writer

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Now FDA Approved For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed after prior fluoropyrimidine- or platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1.

Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled.

Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe

events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event.

Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with ChildPugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly improved progression-free survival (PFS)1

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)

OS PROBABILITY

1.0

CYRAMZA

Placebo

0.8

months

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.6

• Median PFS with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1

MAJOR OUTCOME MEASURE

1

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

1

2

3

4

238 117

6

7

8

9

10 11 12 13

14 15 16 17 18 19

20

26

27

28

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

5

154 66

92 34

49 20

17 7

7 4

3 2

0 1

37%

0 0

The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

Major efficacy outcome measure was overall survival.

Supportive efficacy outcome measure was progressionfree survival. All patients were ECOG PS 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy.

Patients were randomized 2:1 to CYRAMZA 8 mg/kg q2w + BSC (n=238) or placebo + BSC (n=117).1 CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; PS=performance status; BSC=best supportive care.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%).

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

• The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%).

Red blood cell transfusions were given to 11% of CYRAMZAtreated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of CYRAMZAtreated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria.

The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

• As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZAtreated patients with post-baseline serum samples tested positive for anti-ramucirumab antibodies using an enzymelinked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined.

Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

• Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page.

RB HCP ISI 21APR2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

RB89003 05/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. CYRAMZA™ is a trademark of Eli Lilly and Company.

Visit CYRAMZANowApproved.com

CYRAMZATM (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

INDICATIONS AND USAGE CYRAMZA as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single-agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

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

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea.

The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

CYRAMZATM (ramucirumab) injection PA000IPAM00-BS 7x10

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 (MedDRA)a All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria.

The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZA-treated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal drug interaction studies have been conducted.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac.

In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single-agent.

Geriatric Use Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of CYRAMZATM (ramucirumab) injection PA000IPAM00-BS 7x10

the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over.

Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab.

Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab.

Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility.

Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Of increased risk of an arterial thromboembolic event.

• To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

Additional information can be found at www.CYRAMZAhcp.com.

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2014, Eli Lilly and Company. All rights reserved.

RB HCP BS 21APR2014 CYRAMZATM (ramucirumab) injection

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editorial

2014: The Year of the Healthcare Consumer David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits Jefferson School of Population Health, Philadelphia, PA

U

ndoubtedly, 2014 will be characterized by the ascendency of a new type of healthcare consumer. “Consumers are no longer passive patients, but rather engaged—and more discerning—customers wielding new tools and better information to comparison shop. The year ahead will be marked by how well the healthcare industry responds to this shift. Organizations that fail to adapt will risk declining revenues as consumers turn elsewhere to have their health needs met.”1 Now that we are at the midpoint of 2014, it is interesting to take a look at how expert predictions are playing out in the marketplace. With a little help from my friends at PricewaterhouseCoopers (PwC) and their report from the Health Research Institute entitled “Top Health Industry Issues of 2014: A New Health Economy Takes Shape,”1 let us take a look at the scorecard of predictions for 2014 as they relate to healthcare consumerism: the rise of the retail marketplace, the new role for employer private exchanges, price transparency, and how new technology may help put all of this together.

I am no stranger to the retail healthcare marketplace, having been a board member of the iTrax Corporation, which was eventually sold to Walgreens. And Walgreens combined iTrax with other resources to develop what is now known as Take Care Health Systems—the pharmacy giant’s retail healthcare arm.

According to our colleagues at PwC and their detailed consumer survey, nearly 1 in 4 persons indicated that either they or someone in their household had sought healthcare treatment in a retail clinic in 2013.1 Of those who sought care, a whopping 73% said they would go back to a retail clinic again in the future.1 Clearly, the predicted “retailization” of healthcare is progressing, as Walgreens and CVS Caremark continue to expand their product and service offerings inside their stores to deliver medical management of chronic conditions.

“Walgreens, the country’s largest drugstore chain, announced last week that its 330-plus Take Care Clinics, will be the first retail store clinics to both diagnose and manage chronic conditions like asthma, diabetes, high blood pressure, and high cholesterol.”2 Not to be outdone, CVS Caremark is now accepting Medicaid in its 28 South Carolina retail clinics. The

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company reportedly has more than 800 clinic locations across the United States,3 and continues to rapidly expand this aspect of its business. Consumers want care when they want it—and it better be convenient, and at an appropriate price point.

After a rocky rollout of the exchanges, there are many more insured Americans now that the federal and state exchanges have completed their initial open enrollment.

The implementation of the Affordable Care Act (ACA) has led to corresponding changes in the insurance market. As PwC predicted, there has been rapid growth in private exchanges, which are “reshaping the employer benefits landscape, drawing high profile converts, such as IBM and Sears.”1 These private exchanges offer a similar platform as those created by the ACA. Because more than 156 million Americans receive health insurance through the workplace, private exchanges have a bright future. “At its core, a private exchange is an online marketplace for employers to send active or retired employees who shop for medical and other benefits with an employer contribution.”1 Think of these private exchanges as very narrow networks, with high-quality providers linked via digital communication and personalized information for the employee. “While employers are pushing private exchanges, a large number of diverse organizations, including brokerage firms, consulting companies, managed care insurers and high technology companies are also in the mix.”1 While the move toward retail clinics and private exchanges is certainly important, none of this would be possible without price transparency. I completely agree with PwC that this time it’s a different story. “As families pay more for their care, the demand for transparency— and lower costs—has risen.”1 There are key implications of greater price transparency. As employers look to reduce costs, they will play “hardball” with provider organizations. Businesses will make price transparency a primary factor in negotiating with insurers and provider organizations. Perhaps the private exchanges will fuel this push toward price transparency.

Citing a report from the Los Angeles Times, the PwC report discusses a very interesting development in California. “When the health benefits plan for California’s

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retirees [CalPERS] said it would pay no more than $30,000 for hip or knee replacements, its members changed how they selected providers and medical treatment….Providers responded by dropping their prices to compete. CalPERS saved $5.5 million in the program’s first two years and the price of the procedure dropped 26% or about $9,000.”4 Price transparency drove providers to change in a dramatic way.

Can we put retail clinics, private exchanges, and price transparency together on our mobile devices? As we move through 2014, I envision a future in which providers integrate patient data visible in their electronic health records with the information that patients share with them via social media. I also see patients having complete and unfettered access to their own medical rec­ ords online. “Social mobile analytics and cloud technologies are the underpinnings for completing new business models in which organizations will be paid based on value rather than volume.”1 It only makes sense that providers, who will be under increasing pressure to keep costs down, would promote technology that helps patients manage health outside of the hospital setting. In other words, “today just 27% of physicians encourage patients to use mobile health applications, even though 59% of physicians and insurers believe that the widespread adoption of mobile health is inevitable in the near future.”1 Finally, as consumers assume more financial risks for their own healthcare, especially via high-deductible health plans, they may be more willing to pay for those social mobile analytics and cloud technologies that will enable them to manage their own health. This is the best example of a digital marketplace coming to healthcare,

fueled by price transparency and consumer engagement.

So far, 2014 is most certainly playing out to be the year of the healthcare consumer. What are your predic-

Can we put retail clinics, private exchanges, and price transparency together on our mobile devices? As we move through 2014, I envision a future in which providers integrate patient data visible in their electronic health records with the information that patients share with them via social media. tions for the year ahead? I am confident and excited that as we move forward, our work, and all the articles published in American Health & Drug Benefits, will continue to reflect new developments in our nearly $3-trillion-ayear healthcare economy.

As always, I am interested in your views, and you can reach me at david.nash@jefferson.edu.

References

1. PricewaterhouseCoopers Health Research Institute. Top health industry issues of 2014: a new health economy takes shape. December 2013. http://pwchealth.com/ cgi-local/hregister.cgi/reg/pwc-hri-top-healthcare-issues.pdf. Accessed May 1, 2014.

2. Ganguli I. Chronic care at Walgreens? Why not? Boston Globe. April 22, 2013. www.bostonglobe.com/lifestyle/health-wellness/2013/04/21/chronic-care-walgreenswhy-not/WVB3YqhyDIPqvI5APVuodM/story.html?event=event12. Accessed May 1, 2014.

3. CVS Caremark. MinuteClinic. 2014. http://info.cvscaremark.com/better-healthcare/minuteclinic. Accessed May 23, 2014.

4. Terhune C. Hospitals cut some surgery prices after CalPERS caps reimbursements.

Los Angeles Times. June 23, 2013. http://articles.latimes.com/2013/jun/23/business/ la-fi-mo-calpers-hospital-surgery-prices-20130623. Accessed May 1, 2014.

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Original Research

The Economic Burden of Ischemic Stroke and Major Hemorrhage in Medicare Beneficiaries with Nonvalvular Atrial Fibrillation: A Retrospective Claims Analysis Kathryn Fitch, RN, MEd; Jonah Broulette, ASA, MAAA; Winghan Jacqueline Kwong, PharmD, PhD

Kathryn Fitch

Stakeholder Perspective, page 208 Am Health Drug Benefits.

2014;7(4):200-209 www.AHDBonline.com Disclosures are at end of text

Background: Understanding the economic implications of oral anticoagulation therapy requires careful consideration of the risks and costs of stroke and major hemorrhage. The majority of patients with atrial fibrillation (AF) are aged ≥65 years, so focusing on the Medicare population is reasonable when discussing the risk for stroke.

Objective: To examine the relative economic burden associated with stroke and major hemorrhage among Medicare beneficiaries who are newly diagnosed with nonvalvular atrial fibrillation (NVAF).

Methods: This study was a retrospective analysis of a 5% sample of Medicare claims data for patients with NVAF from 2006 to 2008. Patients with NVAF without any claims of AF during the 12 months before the first (index) claim for AF in 2007 (baseline period) were identified and were classified into 4 cohorts during a 12month follow-up period after the index date. These cohorts included (1) no claims for ischemic stroke or major hemorrhage (without stroke or hemorrhage); (2) no claims for ischemic stroke and ≥1 claims for major hemorrhage (hemorrhage only); (3) ≥1 claims for ischemic stroke and no major hemorrhage claims (stroke only); and (4) ≥1 claims each for ischemic stroke and for major hemorrhage (stroke and hemorrhage). The 1-year mean postindex total all-cause healthcare costs adjusted by the Centers for Medicare & Medicaid Services Hierarchical Condition Categories (HCC) score were compared among the study cohorts.

Results: Of the 9455 eligible patients included in this study, 3% (N = 261) of the patients had ischemic stroke claims only, 3% (N = 276) had hemorrhage claims only, and <1% (N = 13) had both during the follow-up period. The unadjusted follow-up healthcare costs were $63,781 and $64,596 per patient for the ischemic stroke only and the hemorrhage only cohorts, respectively, compared with $35,474 per patient for those without hemorrhage or stroke claims. After adjustment for HCC risk score, the mean incremental costs for patients with stroke claims only and hemorrhage claims only, relative to those without stroke or hemorrhage claims, were $26,776 (95% confidence interval [CI], $20,785-$32,767; P <.001) and $26,168 (95% CI, $20,375-$31,961; P <.001), respectively.

Conclusion: The economic burden of managing patients with NVAF who experience ischemic stroke and hemorrhage were similarly significant during the first year after a diagnosis of NVAF. The burden of major bleeding complications on patients, clinicians, and payers should not be overlooked, and these complications should be considered in conjunction with the cost-savings associated with ischemic stroke risk reduction in future cost-benefit evaluations of oral anticoagulation therapy.

A

trial fibrillation (AF) is the most common form of sustained cardiac arrhythmia.1,2 The most recent estimates (published in 2013) of the prevalence of AF in the United States are for 2010 and range from 2.7 million to 6.1 million.3,4 The prevalence of AF doubles with each decade of life after the age of 60 years and occurs in approximately 10% of the US population aged ≥80 Ms Fitch is Principal and Healthcare Consultant, Milliman, Inc; Mr Broulette is a former Associate Actuary, Milliman, Inc, New York, NY; Dr Kwong is Senior Director, Health Economics and Outcomes Research, Daiichi Sankyo, Inc, Parsippany, NJ.

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years.5-7 A recent study estimates that the number of patients with AF in the United States could potentially reach 12.1 million by 20303; other estimates range from 5.6 million to 12 million patients with AF by 2050.4 Patients with AF have an approximate 5-fold increased risk for stroke compared with patients in normal sinus rhythm.4 Furthermore, the percentage of strokes that can be attributed to AF increases steeply with age, with rates of 1.5% in patients aged 50 to 59 years and 23.5% in those aged 80 to 89 years.4 The term “nonvalvular atrial fibrillation” (NVAF) is used to describe cases of AF that occur in the absence of rheumatic mitral valve disease, mitral valve

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repair, or a prosthetic heart valve.8 NVAF affects approximately 85% of the overall population with AF and is a substantial medical burden for Medicare beneficiaries (aged ≥65 years) in the United States.9,10 The current evidence-based clinical guidelines recommend the use of oral anticoagulation in patients with NVAF who are at an intermediate to high risk for stroke.8,11 Although the efficacy of oral anticoagulation therapy to prevent stroke in patients with NVAF is well-established, it is also associated with a risk of bleeding.12-15 Understanding the relative economic burdens of stroke and major hemorrhage is important when considering the costs and benefits of anticoagulation therapy.

Several studies have reported the incremental costs associated with stroke alone or with hemorrhage alone using different NVAF payer populations (ie, commercial or Medicare), and a few recent studies have provided incremental cost data for stroke and hemorrhage for the Medicare population, reporting significant incremental costs in the year after the stroke or hemorrhage index dates.7,16-20 Other studies have analyzed the incremental costs associated with stroke alone or with hemorrhage alone, or have analyzed these costs for a commercial population with NVAF.21-24 Most of these studies were done in separate patient populations and different time periods, making assessment of the relative economic burden of stroke versus bleeding difficult. By contrast, our study provides the cost estimates for these 2 conditions simultaneously based on the same patient population, which allows a more appropriate comparison of the economic implication of these 2 major consequences of oral anticoagulation therapy for the prevention of stroke among patients with NVAF. The prespecified objective in our study was to assess the relative economic burden (including Medicare Part D costs) associated with ischemic stroke and with major hemorrhagic events (ie, intracranial and gastrointestinal [GI] bleeding) among Medicare beneficiaries with newly diagnosed NVAF in the 12 months after the NVAF index diagnosis.

Methods Data Source This study was a retrospective analysis of claims data between 2006 and 2008 from the Medicare 5% sample research identifiable file (RIF) provided by the Research Data Assistance Center, a Centers for Medicare & Medicaid Services (CMS) contractor that assists researchers in obtaining CMS data. Requests for RIF data files, which contain beneficiary-level protected health information, are reviewed by the CMS Privacy Board to ensure that beneficiary privacy is appropriately protected and that the need for such data is justified. The RIF data

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Key Points The prevalence of atrial fibrillation is high among patients aged ≥65 years and continues to grow. ➤ Nonvalvular atrial fibrillation (NVAF) increases the risk for ischemic stroke or bleeding, which carry a substantial economic burden. ➤ Based on this new analysis of Medicate data, the costs associated with stroke and major hemorrhage in patients with newly diagnosed NVAF are almost doubled that of Medicare beneficiaries without NVAF. ➤ The healthcare costs were $63,781 per patient with ischemic stroke only and $64,596 with hemorrhage only versus $35,474 for those without these conditions. ➤ A large contributor to the incremental cost differences was inpatient utilization for stroke and bleeding. ➤ The median number of hospital admissions was tripled in patients with ischemic stroke or major hemorrhage. ➤ From an economic perspective, minimizing the risk for major bleeding is as important as reducing the risk for stroke. ➤ Bleeding complications should be considered in conjunction with cost-savings associated with ischemic stroke risk reduction in the context of oral anticoagulation therapy management. ➤

used in our study included de-identified enrollment data and Medicare Part A, Part B, and Part D claims from Medicare beneficiaries who were identified to have chronic AF by the CMS Chronic Conditions Data Warehouse in 2006 or 2007.

Patient Inclusion and Exclusion Criteria Patients included in the analysis had to have at least 2 inpatient, emergency department/observation, or physician evaluation and management claims associated with an International Classification of Diseases, Ninth Revision (ICD-9) code of AF (ie, 427.31) during 2007 to confirm the presence of AF. The 2 claims had to occur at least 30 days apart, and 1 of the claims had to be for care in an outpatient setting to confirm that the patients included in this study had chronic AF. Patients were excluded from the analysis if they were (1) aged ≤18 years; (2) without 12 months of Medicare Parts A and B eligibility before the index date; (3) without 12 months of Medicare Part A, B, and D eligibility after the index date for reasons other than death; (4) identified as having mitral and/or aortic valvular disease (repair or replacement), transient preoperative AF, or hyperthyroidism in the 12 months before the index date;

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Figure Population Attrition

Medicare beneficiaries with an AF chronic condition flag in 2007 N = 178,414

Beneficiaries with AF and at least 2 claims in 2007 with an ICD-9 diagnosis code of 427.31 that occurred ≥30 days apart, with 1 of the claims occurring in an outpatient setting N = 132,716

Patients with AF meeting study requirementsa N = 40,193

Eligible patients with newly diagnosed AF N = 9705

Patients with no stroke or bleeding on or 1 day after the AF index N = 9455

Cohort 1 No inpatient claims for stroke or bleeding in 12 mo after the AF index N = 8905

Cohort 2 No inpatient claims for stroke and ≥1 inpatient claims for bleeding in 12 mo after AF index N = 276

Cohort 3 ≥1 inpatient claims for stroke and no inpatient claims for bleeding in 12 mo after AF index N = 261

Cohort 4 ≥1 inpatient claims for stroke and ≥1 inpatient claims for bleeding in 12 mo after AF index N = 13

Study requirements: Having Medicare Part A and Part B coverage 12 months before and after index month and age ≥18 years; having Medicare Part D coverage 12 months after AF index month; not having valvular disease, hyperthyroidism, or transient AF in 12 months before AF index date; not having a stroke in 12 months before index date; not having an intracranial hemorrhage in 12 months before index date; not having a gastrointestinal hemorrhage in 12 months before index date.

AF indicates atrial fibrillation; ICD-9, International Classification of Diseases, Ninth Revision.

rhage claims during the 12 months after the AF index date. Cohort 1 included patients with no claims for ischemic stroke, intracranial hemorrhage, or GI hemorrhage (without stroke or hemorrhage); cohort 2 included patients with no claims for ischemic stroke and ≥1 claims for intracranial hemorrhage or GI hemorrhage (hemorrhage only); cohort 3 included patients with ≥1 claims for ischemic stroke and no claims for intracranial hemorrhage or GI hemorrhage (stroke only); and cohort 4 included patients with ≥1 claims for ischemic stroke and ≥1 claims for intracranial hemorrhage or GI hemorrhage (stroke and hemorrhage).

Ischemic stroke was identified by the presence of an inpatient or emergency department claim associated with an ICD-9 code for a primary diagnosis of ischemic stroke, and major hemorrhage was identified by an inpatient claim associated with a primary diagnosis of major hemorrhage (Appendix).

For 50% of patients with a stroke in the 12 months after their AF index date, their first stroke occurred on or 1 day after the AF index date. By contrast, only 25% of patients with major hemorrhage in the 12 months after the AF index date had their first major hemorrhage on or 1 day after their AF index date. To eliminate a bias toward a longer cost follow-up opportunity for stroke events, all patients who had an ischemic stroke or a major hemorrhage on or 1 day after their index date were excluded from the analysis to ensure there is sufficient length of a follow-up period for the cost assessment.

After excluding such patients, the distributions of time to first event (ie, first ischemic stroke or major hemorrhage) were similar across the cohorts.

a

or (5) identified as having a major hemorrhage or ischemic stroke in the 12 months before the AF diagnosis index date. The analysis was further limited to patients with newly diagnosed NVAF, which included those who had no claims with an ICD-9 diagnosis code of 427.31 in any position of the claim in the 12 months before the AF index date.

Patient Cohorts Patients with NVAF were assigned to 1 of 4 cohorts based on the presence of ischemic stroke and hemor-

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Patient Cohort Analysis Descriptive statistics were used to assess the differences in baseline characteristics among the study cohorts.

Healthcare resource use, including inpatient admissions, emergency department visits, and outpatient visits during the 12 months after the AF index date, was assessed in each cohort. The mean total all-cause healthcare costs during the 12-month follow-up period were compared among the study cohorts using ordinary least squares, adjusting for CMS Hierarchical Condition Categories (HCCs). All costs represent the Medicare allowed costs.

The CMS-HCC model, developed in 2004 to adjust Medicare capitation payments to private healthcare plans for the health expenditure risk of their enrollees, generates a risk score for each Medicare patient based on age, sex, original reason for Medicare entitlement, dual-­ eligibility status, and comorbidities during a 12-month baseline period. The risk score is designed and has been validated to be a credible predictor for healthcare costs incurred during the following 12-month period.25 We

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Table 1 Descriptive Summary of the 4 Study Cohorts Study sample Patient characteristic (N = 9455) Mean age, yrs (SD) Age range, yrs (median) Males, % â&#x2030;Ľ1 warfarin prescriptions in 90 days after AF index, %a Mean all-cause allowed costs in 12 months before AF index, $ (SD) Mean HCC score (SD)

Cohort 1 (N = 8905)

Cohort 2 (N = 276)

Cohort 3 (N = 261)

Cohort 4 (N = 13)

79 (9.5)

78.8 (9.5)

80.9 (9.1)

83.5 (8)

78.6 (9.5)

27-106 (80)

27-106 (79)

36-102 (81)

55-99 (84)

60-91 (77)

35

35

28.3

26.4

38.5

49.3

49.3

45.7

30.3

46.2

13,073 (21,020) 12,949 (20,548) 15,773 (25,491) 14,605 (29,880) 9920 (17,847) 1.84 (1.55)

1.83 (1.54)

2.17 (1.72)

2.00 (1.70)

1.91 (1.72)

Excluded patients who received warfarin after having a stroke.

AF indicates atrial fibrillation; HCC, Hierarchical Condition Categories; SD, standard deviation.

a

used the 2012 HCC definitions and weights to calculate a prospective risk score for each patient using claims from the 12 months before the AF index date.

Linear regression was used to determine the predictive relationship between the HCC score and the healthcare costs in the 12 months after the index date within each of the patient cohorts. The incremental cost difference between the cohorts was calculated after controlling for the differences in expected healthcare costs in the 12 months after the index date as predicted by HCC score. P values were also calculated using a 1-sided t-test to statistically compare the difference in mean incremental cost between the patients in the cohort without stroke or hemorrhage and the patients in each of the other 3 cohorts.

Results Study Population Data from 178,414 Medicare beneficiaries with chronic AF that were flagged in 2007 were available for analysis (Figure). Of these, 132,716 (74.4%) beneficiaries had at least 2 claims with an ICD-9 diagnosis code of 427.31 that occurred â&#x2030;Ľ30 days apart, with 1 of the claims occurring in an outpatient setting in 2007. After applying the additional exclusion criteria and including only patients with newly diagnosed NVAF, a total of 9705 patients were eligible to be included in the analysis. The newly diagnosed NVAF population was further reduced to 9455 patients, to include only those who did not have a stroke or a major hemorrhage on or 1 day after the NVAF index date.

Cohort Distribution The study sample (mean age, 79 years; 35% male) was divided into 4 cohorts based on the occurrence of a stroke or a major hemorrhage during the 12 months after the NVAF index date (Figure). Table 1 provides demographics and baseline characteristics of the patients in the 4 cohorts. The mean age of the cohorts ranged from

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78.6 years among patients with ischemic stroke and major hemorrhage claims to 83.5 years among patients with an ischemic stroke claim and no major hemorrhage claims. Patients with either a major hemorrhage claim or an ischemic stroke claim, but not both, were less likely to be male (28.3% and 26.4%, respectively) than patients without ischemic stroke or major hemorrhage claims.

Overall, approximately 49% of patients had â&#x2030;Ľ1 prescriptions for warfarin filled within the 90 days after the index date; the proportion of patients filling warfarin prescriptions was highest among patients who did not have an ischemic stroke or hemorrhage claim (49.3%) and was lowest among patients with an ischemic stroke claim but no hemorrhage claim (30.3%).

The healthcare costs in the 12 months before the AF index ranged from $9920 among patients with ischemic stroke and major hemorrhage claims to $15,773 in patients with a major hemorrhage claim but no ischemic stroke claim. The overall mean HCC score was 1.84, ranging from 1.83 in patients without ischemic stroke or major hemorrhage claims to 2.17 in patients with a major hemorrhage claim but no ischemic stroke claim.

Events in the 12 Months after the Index Date Claim The average incidence of ischemic stroke and of major hemorrhage in the overall study cohort of patients with AF was 3.3% and 3.4%, respectively. Among patients with major hemorrhage and no ischemic stroke, the mean number of major hemorrhagic events per member in the 12 months after the index NVAF date was 1.09 (standard deviation [SD], 0.36), with 15% associated with an intracranial major hemorrhage ICD-9 diagnosis. The median allowed cost per major hemorrhage event was $6328 (interquartile range [IQR], $3400).

Among patients with ischemic stroke and no major hemorrhage claims, the mean number of strokes per

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Table 2 Healthcare Costs and Utilization in the 12 Months after the AF Index Study sample Cohort 1 Cohort 2 Cost component (N = 9455) (N = 8905) (N = 276)

Cohort 3 (N = 261)

Cohort 4 (N = 13)

Mean (SD) healthcare cost per member in the 12 mo after the AF index Total cost, $ Inpatient facility, $ Skilled nursing facility, $

37,157 (42,920)

35,474 (41,875)

64,596 (51,594)

63,781 (48,422)

72,984 (46,418)

18,592 (30,159)

17,628 (29,742)

34,919 (31,291)

33,242 (33,908)

38,152 (31,217)

5269 (11,659)

4806 (11,014)

10,791 (16,800)

14,621 (18,141)

17,796 (23,515)

2 (44)

2 (44)

0 (0)

4 (42)

35 (92)

Home health, $ Emergency department, $

402 (539)

385 (527)

676 (716)

683 (554)

692 (499)

Outpatient facility, $

2782 (6096)

2765 (6068)

2840 (5878)

3292 (7274)

2927 (3908)

Professional services, $

7031 (8487)

6819 (8311)

11,647 (12,440)

9215 (7678)

10,451 (6110)

Pharmaceutical, $

3080 (3450)

3070 (3378)

3723 (5734)

2724 (2459)

2931 (3163)

Mean inpatient admissions per member, N (SD)

1.7 (1.8)

1.6 (1.7)

3.7 (2.4)

3.4 (2.3)

4.5 (2.5)

Median inpatient admissions per member, N

1

1

3

3

5

Mean emergency department visits per member, N (SD)

0.8 (1.4)

0.8 (1.4)

1.1 (1.8)

1.1 (1.4)

1.4 (2.1)

Median emergency department visits per member, N

0

0

1

1

1

Mean office visits per member, N (SD)

12.7 (10.7)

12.8 (10.8)

12.8 (10.8)

10 (9.2)

9.3 (8)

Median office visits per member, N

11

11

11

8

8

Site-of-care utilization

AF indicates atrial fibrillation; SD, standard deviation.

member was 1.14 (SD, 0.38), with a median allowed cost per event of $7242 (IQR, $3550). Among patients with both ischemic stroke and major hemorrhage, the mean number of strokes and major hemorrhagic events were 1.15 (SD, 0.38) and 1.31 (SD, 0.63), respectively, with 47% of major hemorrhage claims associated with a diagnosis of intracranial bleeding. The median allowed costs were $6211 (IQR, $6959) per stroke event and $7077 (IQR, $8628) per major hemorrhage event.

Total Healthcare Costs in the 12 Months after the Index Date Claim The total allowed healthcare costs per member in each cohort in the 12 months after the index NVAF date were calculated and were grouped into 7 cost categories: inpatient facility, skilled nursing facility, home health, emergency department, outpatient facility, professional services, and pharmaceutical (Table 2). The mean numbers of inpatient admissions and emergency department/office visits per member are also shown in Table 2. Overall, the mean total allowed healthcare cost per member was $37,157, with approximately 50% of the cost attributed to inpatient care.

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The mean total allowed healthcare costs per patient by cohort were $35,474 in the patients without stroke or major hemorrhage; $64,596 with major hemorrhage only; $63,781 with stroke only; and $72,984 in patients with stroke and major hemorrhage (Table 2).

Incremental Cost of the Cohorts The unadjusted mean postindex total all-cause healthcare costs in the 12 months after the index date were lowest among patients without stroke or major hemorrhage and highest among patients with both stroke and major hemorrhage (Table 3). After adjusting for the HCC risk score, the adjusted mean cost for patients with major hemorrhage and no ischemic stroke was $26,168 higher (P <.001) than the adjusted mean cost for patients with no major hemorrhage or ischemic stroke.

Patients with ischemic stroke and no major hemorrhage had an adjusted mean cost that was $26,776 higher (P <.001) than patients with no major hemorrhage or ischemic stroke. Patients with both ischemic stroke and major hemorrhage had an adjusted mean cost that was $36,723 higher (P = .005) than patients with no major hemorrhage or ischemic stroke.

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Table 3 Incremental Cost of the 4 Study Cohorts Total allowed costs per member in the 12 months after AF index Difference in mean cost vs patients with no stroke or bleeding claims after adjusting for HCC Unadjusted total Mean 95% CI, 95% CI, Probability that Members, Average all-cause postindex estimate, lower bound, upper bound, cohort 1 is more Cohort N HCC score mean cost, $ $ $ $ expensive 1

8905

1.83

35,474

2

276

2.17

64,596

26,168

20,375

31,961

<.001

3

261

2.00

63,781

26,776

20,785

32,767

<.001

4

13

1.91

72,984

36,723

10,715

62,731

.005

AF indicates atrial fibrillation; CI, confidence interval; HCC, Hierarchical Condition Categories.

Discussion A large contributor to the incremental cost difference between patients with stroke and/or bleeding and the cohort without stroke or bleeding was primarily driven by inpatient utilization. The median number of hospital admissions was 3 times higher in patients experiencing ischemic stroke or major hemorrhage than in patients who experienced neither adverse event, whereas the utilization of emergency department services was similar.

The use of a skilled nursing facility was significantly higher for patients with stroke and/or bleeding as were professional claims.

Furthermore, the incremental costs of ischemic stroke and major hemorrhage during the 1-year follow-up period were similar, suggesting that minimizing the risk for major hemorrhage is no less important than reducing the risk for stroke, from an economic perspective. By considering the relative economic burdens of ischemic stroke and major hemorrhage, these data provide important information for future cost-effectiveness evaluations of alternative oral anticoagulant medications with different efficacy and safety profiles.

Although the 12-month incidence rate of ischemic stroke observed in this study was 2.9%, which is within the range of 2.2% to 6% noted for patients with AF receiving warfarin or placebo in previous clinical trials,12 the incidence rate of major hemorrhage in our study sample was higher (3.06%) than the rates observed in clinical trials of patients receiving warfarin versus placebo (0.69%-1.27%)12 or in a more recent retrospective claims study of patients with AF who received warfarin (1.5%).26 This difference may be attributed to limiting the current study to Medicare beneficiaries, because it is believed that older age is a major risk factor for bleeding while receiving oral anticoagulation therapy.27,28 A scatterplot was constructed for each cohort using member HCC scores (x-axis) and allowed costs in the 12

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months after the NVAF index date (y-axis) after which linear regression was performed to obtain a best-fit line.

In patients without ischemic stroke or major hemorrhage, the modeled line fit the data points with a high R2 value (0.9265), thereby showing a clear and credible linear relationship between HCC score and cost. (Note: The linear relationship in this study is assessed by R2 rather than by t-test.) In patients with major hemorrhage and no ischemic stroke, there is evidence of a meaningful linear relationship between the HCC score and cost; however, the modeled line does not fit extremely well, as shown by a lower R2 value (0.4899), and its intercept is higher than that of the modeled line for patients without ischemic stroke or major hemorrhage.

These findings indicate that baseline costs are higher in patients with major hemorrhage and no ischemic stroke, regardless of risk. The modeled lines for patients with ischemic stroke and no major hemorrhage and patients with both ischemic stroke and major hemorrhage are poorly fitting with very low R2 values (0.0161 and 0.1638, respectively), suggesting the lack of a linear relationship between HCC score and cost. Among patients with ischemic stroke and no major hemorrhage, the findings indicate that stroke costs did not increase significantly in patients with higher HCC scores. The small sample sizes for patients with both ischemic stroke and major hemorrhage likely affect the findings for that cohort.

Although our study design compared costs for the 12 months after patients were newly diagnosed with NVAF, whereas other studies compared costs from the day of the adverse event (stroke or hemorrhage) for patients with newly diagnosed and those with existing NVAF, our incremental cost findings corroborate those of previous studies. In a retrospective observational cohort study investigating the costs (in 2004 US dollars) associated with the onset of chronic NVAF, the use of anticoagu-

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lants, and the presence of cerebrovascular events in a commercially insured population, Boccuzzi and colleagues reported that the total direct healthcare costs (per member per month [PMPM] before and after the onset of AF in 3891 patients with incidence chronic NVAF were $412 and $1235, respectively ($494 and $1480, respectively, in 2011 US dollars).19,20 Of the 448 patients (12%) who had a cerebrovascular event (ie, transient ischemic attack, ischemic stroke, or major bleeding), the PMPM costs ranged from $2235 to $3135 ($2679-$3758, respectively, in 2011 US dollars) based on stroke risk status and on exposure to anticoagulation.19,20 The total cohort PMPM costs before and after the event were $3446.91 and $4262.12, respectively ($4132 and $5109, respectively, in 2011 US dollars), which represents an increase of 24%.19,20 Data from a study conducted by Mercaldi and colleagues assessing the cost-effectiveness of anticoagulation therapy on medical costs in 119,764 Medicare beneficiaries with NVAF showed that the average annual total healthcare cost was $15,718 (in 2006 US dollars) in patients with no major events during follow-up compared with $43,937; $60,123; and $39,943 in patients who had an ischemic stroke, hemorrhagic stroke, or major bleeding, respectively, at any time during the study.7 The incremental cost relative to the average annual costs of patients with no events was $34,201 for ischemic stroke; $44,716 for hemorrhagic stroke; and $29,965 for major bleeding.7 Of note, these incremental costs are higher than the costs that we report, even though these authors’ calculations are based on 2006 US dollars.

Mercaldi and colleagues also recently conducted a retrospective cohort study to quantify long-term costs in 25,465 Medicare beneficiaries with newly diagnosed NVAF who subsequently developed ischemic stroke, major bleeding, or intracranial hemorrhage.16 Using Medicare medical and enrollment data (1999-2009), patients with NVAF and events were matched with patients with NVAF without events to separate the event-related costs from the general NVAF-related healthcare costs.16 The total incremental costs of events were calculated as the cost difference between patients with and without events for up to 3 years.16 The investigators reported that the average incremental costs in the first year after the event were $32,900; $23,414; and $47,640 for ischemic stroke, major bleeding, and intracranial hemorrhage, respectively, and that the costs remained higher, by $3156 to $5400 annually, at 3 years postevent.16

Limitations We acknowledge several potential study limitations.

First, although risk adjustment based on HCC was per-

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formed, unobserved confounding variables that could affect healthcare costs (eg, patient socioeconomic status and race) are not available in the database, and therefore were not included for adjustment. We acknowledge that, in general, risk adjustment is most effective in predicting costs across large populations and may not be as predictive with smaller cohorts.

Second, as a result of data limitations and study design, we are only able to observe 12 months of claims before a patient’s AF index date. As a result, our definition of “newly diagnosed” (ie, no claim with an ICD-9 diagnosis code of 427.31 in any position in the 12 months before the index date) could potentially have included some patients with AF who had infrequent contact with a healthcare provider. We are not able to adjust for major hemorrhage or ischemic stroke occurring more than 12 months before the AF index.

Third, all the major hemorrhagic events occurred after the NVAF index diagnosis in this study; however, we could not confirm if these bleeding events were caused by oral anticoagulant treatment.

Finally, our analysis was based on Medicare CMS Chronic Conditions Data Warehouse RIF data, which may not be generalizable to a commercial patient population.

Conclusion NVAF poses a substantial economic burden in Medicare beneficiaries as a result of an increased risk for ischemic stroke and hemorrhagic events. Although oral anticoagulation has been shown to reduce the risk of stroke in patients with NVAF, it remains underused in clinical practice, possibly because of concerns over the risk for bleeding.29-31 The economic burden of managing patients with AF experiencing ischemic stroke or major hemorrhage was similar during the first year after a diagnosis of AF. The burden of bleeding complications to patients, clinicians, and payers should not be overlooked, and these complications should be considered in conjunction with cost-savings associated with ischemic stroke risk reduction in the future cost-benefit evaluation of oral anticoagulation therapy. Understanding the economic burden of clinical events is an important aspect of health economics and outcomes research that, in addition to providing a basis for decision-making, also provides the fundamental data input for a cost-benefit analysis. A future cost-benefit analysis of this topic is recommended as a future area of research to provide further information for decision makers. n Acknowledgments We would like to thank Lauren Lee for her contribution to the study design and data analysis, as well as Xin Ye for his assistance in the preparation of this manuscript.

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Appendix. ICD-9 Codes Used to Identify Strokes and Hemorrhages ICD-9 codes used to identify ischemic strokes; any inpatient or emergency department claim coded with any of the following diagnosis codes in the primary position of the claim: 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434.01, 434.11, 434.91

ICD-9 codes used to identify major gastrointestinal hemorrhage; any inpatient admission coded with the following diagnosis codes in the primary position of the claim: 455.2, 455.5, 455.8, 456.0, 456.20, 530.82, 531.0x, 531.2x, 531.4x, 532.0, 532.2, 532.4, 532.6, 531.6x, 533.0x, 533.2x, 533.4x, 533.6x, 534.0x, 534.2x, 534.4x, 534.6x, 535.x1, 537.83, 562.02, 562.03, 562.12, 562.13, 569.3, 578.xx

ICD-9 codes used to identify intracranial hemorrhage; any inpatient admission coded with the following diagnosis codes in the primary position of the claim: 430.x, 431.x, 432.xx

ICD-9 indicates International Classification of Diseases, Ninth Revision.

Funding Source This study was funded by Daiichi Sankyo, Inc. Author Disclosure Statement Ms Fitch is an employee of Milliman, Inc, and Mr Broulette was formerly an employee of Milliman, Inc, which consults with several pharmaceutical and medical device companies, including Daiichi Sankyo, Inc. Dr Kwong is an employee of Daiichi Sankyo, Inc.

References

1. Ali A, Bailey C, Abdelhafiz AH. Stroke prophylaxis with warfarin or dabigatran for patients with non-valvular atrial fibrillation—cost analysis. Age Ageing. 2012;41: 681-684.

2. Andrew NE, Thrift AG, Cadilhac DA. The prevalence, impact and economic implications of atrial fibrillation in stroke: what progress has been made? Neuroepi­ demiology. 2013;40:227-239.

3. Colilla S, Crow A, Petkun W, et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112: 1142-1147.

4. Go AS, Mozaffarian D, Roger VL, et al; for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation.

2013;127:e6-e245. Erratum in: Circulation. 2013;127:e841.

5. Ali A, Bailey C, Abdelhafiz AH. Stroke prevention with oral anticoagulation in older people with atrial fibrillation—a pragmatic approach. Aging Dis. 2012;3:339-351.

6. Kannel WB, Benjamin EJ. Status of the epidemiology of atrial fibrillation. Med Clin North Am. 2008;92:17-40.

7. Mercaldi CJ, Ciarametaro M, Hahn B, et al. Cost efficiency of anticoagulation with warfarin to prevent stroke in Medicare beneficiaries with nonvalvular atrial fibrillation. Stroke. 2011;42:112-118.

8. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57:e101-e198.

9. Lévy S, Maarek M, Coumel P, et al. Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. The College of French Cardiologists. Circulation. 1999;99:3028-3035.

10. Fitch K, Iwasaki K, Pyenson B. Non-valvular atrial fibrillation and anticoagulation therapy: an actuarial study of the Medicare population. August 2010. http:// publications.milliman.com/research/health-rr/pdfs/non-valvular-atrial-fibrillation. pdf. Accessed February 3, 2014.

11. You JJ, Singer DE, Howard PA, et al; for the American College of Chest Physicians. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e531S-e575S.

12. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.

13. Connolly SJ, Ezekowitz MD, Yusuf S, et al; for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation.

N Engl J Med. 2009;361:1139-1151. Erratum in: N Engl J Med. 2010;363:1877.

14. Patel MR, Mahaffey KW, Garg J, et al; for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365: 883-891.

15. Granger CB, Alexander JH, McMurray JJ, et al; for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation.

N Engl J Med. 2011;365:981-992.

16. Mercaldi CJ, Siu K, Sander SD, et al. Long-term costs of ischemic stroke and major bleeding events among Medicare patients with nonvalvular atrial fibrillation.

Cardiol Res Pract. 2012;2012:645469.

17. O’Brien CL, Gage BF. Costs and effectiveness of ximelagatran for stroke prophylaxis in chronic atrial fibrillation. JAMA. 2005;293:699-706.

18. Rose AJ, Berlowitz DR, Ash AS, et al. The business case for quality improvement: oral anticoagulation for atrial fibrillation. Circ Cardiovasc Qual Outcomes.

2011;4:416-424.

19. Boccuzzi SJ, Martin J, Stephenson J, et al. Retrospective study of total healthcare costs associated with chronic nonvalvular atrial fibrillation and the occurrence of a first transient ischemic attack, stroke or major bleed. Curr Med Res Opin. 2009;25: 2853-2864.

20. Singh SN. Costs and clinical consequences of suboptimal atrial fibrillation management. Clinicoecon Outcomes Res. 2012;4:79-90.

21. Kotowycz MA, Filion KB, Joza J, et al. In-hospital management of atrial fibrillation: the CHADS2 score predicts increased cost. Can J Cardiol. 2011;27:506-513.

22. Ghate SR, Biskupiak J, Ye X, et al. All-cause and bleeding-related health care costs in warfarin-treated patients with atrial fibrillation. J Manag Care Pharm. 2011;17: 672-684.

23. Lee WC, Lamas GA, Balu S, et al. Direct treatment cost of atrial fibrillation in the elderly American population: a Medicare perspective. J Med Econ. 2008;11:281-298.

24. Suh DC, Nelson WW, Choi JC, Choi I. Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fibrillation. Clin Ther. 2012;34:1569-1582.

25. Pope GC, Kautter J, Ellis RP, et al. Risk adjustment of Medicare capitation payments using the CMS-HCC model. Health Care Financ Rev. 2004;25:119-141.

26. Fang MC, Stafford RS, Ruskin JN, Singer DE. National trends in antiarrhythmic and antithrombotic medication use in atrial fibrillation. Arch Intern Med. 2004; 164:55-60.

27. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093-1100.

28. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151:713-719.

29. Ogilvie IM, Newton N, Welner SA, et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123:638-645.

30. Reynolds MR, Shah J, Essebag V, et al. Patterns and predictors of warfarin use in patients with new-onset atrial fibrillation from the FRACTAL Registry. Am J Cardiol. 2006;97:538-543.

31. Fitch K, Broulette J, Pyenson BS, et al. Utilization of anticoagulation therapy in Medicare patients with nonvalvular atrial fibrillation. Am Health Drug Benefits. 2012; 5(3):157-168.

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Stakeholder Perspective The Clinical Toll of Nonvalvular Atrial Fibrillation Poses Significant Economic Burden

By Raymond L. Singer, MD, MMM, CPE Chief, Division of Cardiothoracic Surgery, Vice Chair, Quality and Patient Safety, Department of Surgery, Lehigh Valley Health Network, Philadelphia, PA

PATIENTS: Atrial fibrillation (AF) is the most common arrhythmia in patients aged â&#x2030;Ľ65 years and is associated with a significant risk for thromboembolic stroke. Nonvalvular AF (NVAF) increases the risk for stroke by 5 times, whereas AF in the setting of valvular heart disease increases stroke risk by 20 times versus patients who have a normal sinus rhythm.1 Many patients with AF are completely asymptomatic, thus underscoring the importance of routine physical examinations for senior patients. Common presentations include palpitations and a fast, irregular heartbeat.

More serious presentations include congestive heart failure resulting from ischemia, valvular heart disease, or AF-arrhythmiaâ&#x20AC;&#x201C;induced cardiomyopathy.

Because of the ineffective contractions of the atria, blood stasis occurs, resulting in clot formation. Typically, clotting may be found in the left atrial appendage. The greatest risk for stroke occurs with paroxysmal AF (PAF). The clot forms in the atrial appendage during periods of PAF and may be ejected as an embolus during a subsequent normal sinus contraction. The appropriate use of antithrombotic medications substantially reduces the risk of stroke in patients with AF and PAF. Warfarin is the most frequently prescribed antithrombotic medication. Warfarin is inexpensive and is well-tolerated; however, its use is associated with an increased risk for bleeding complications. Moreover, patients taking warfarin must watch their diets, because many foods and medications interact with warfarin, either decreasing or even enhancing its anticoagulation potential.2 Patients also need monthly blood testing to ensure the appropriate anticoagulation level by measuring prothrombin time, which is reported as an international normalized ratio (INR). Unlike most medications that are administered as a fixed dose, warfarin dosing is adjusted according to the INR blood test results.2 Therefore, it is important that patients are compliant with their follow-up testing. A patient with an abnormally high INR level is at an increased risk for bleeding complications.

Conversely, if the INR is subtherapeutic, the patient is at an increased risk for thromboembolic events. Of note, if

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the patient needs urgent warfarin reversal (eg, as a result of trauma or to undergo an invasive test or surgery), the effect of warfarin can be reversed by administering vitamin K and/or fresh frozen plasma transfusions.2 Recently, safe and effective alternatives to warfarin have been introduced, including dabigatran, rivaroxaban, and apixaban. These drugs are direct thrombin and/or factor Xa inhibitors that do not require anticoagulation monitoring and are not associated with food or medication interactions.3 Early randomized, double-blind clinical trials suggest that these drugs may be more effective than warfarin for the prevention of stroke in patients with NVAF.4,5 In addition, apixaban may also be associated with a lower risk for bleeding complications compared with warfarin.6 However, these drugs are also substantially more expensive and may not be covered by insurance plans, which is a particular concern for patients with Medicare or Medicaid coverage. In addition, although the half-life of these drugs can be as little as 5 to 14 hours, patients need to understand that there are no antidotes for these drugs. Patients may be apprehensive about taking a drug that cannot be reversed even in an emergency setting.

Patients must weigh the benefits and risks of antithrombotic medication for the treatment of NVAF. In their retrospective claims analysis, Fitch and colleagues show that stroke and bleeding complications significantly increase the clinical and economic burdens on patients during the first year after a diagnosis of NVAF. To improve the safety of antithrombotic therapy, the associated risks for stroke (eg, hypertension and hypercholesterolemia) and for bleeding (eg, liver disease and alcohol intake) must be assessed before the initiation of the drug regimen. Patient compliance, along with consistent, timely, and accurate anticoagulation monitoring, is paramount.

PAYERS: As Fitch and colleagues have shown, NVAF, along with its associated complications, pose a significant economic burden. Even more concerning is that the incidence and prevalence of AF continue to increase as the population ages.7 It is expected that the incidence of AF will double from 1.2 million cases in

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2010 to 2.6 million cases in 2030. Given this increase in incidence, the prevalence of AF is projected to increase from 5.2 million in 2010 to 12.1 million cases in 2030.7 More outcomes research is needed to investigate the benefits and risks of antithrombotic medications for NVAF. Although the newer agents are easier to prescribe and to monitor, the costs of these drugs remain high (Table). Payers will need to balance the cost of these drugs with their safety profiles, efficacy, cost of monitoring, and most of all, the evidence (or lack thereof) of clinical superiority.

PROVIDERS: Providers must also balance the benefits and risks of selecting an antithrombotic regimen for patients with NVAF. Risk stratification schemes (eg, CHADS2, CHA2DS2-VASc, and HAS-BLED) are beyond the scope of this perspective, but they represent scoring guidelines that have been validated in multiple cohorts with NVAF. Based on this score, a patient can be stratified as low, intermediate, or high risk for a thromboembolic event, and therefore be properly evaluated for the initiation of antithrombotic medication. In patients aged ≥65 years, it would be rare to have a CHADS2 or CHA2DS2-VASc of zero, and therefore the majority of patients will be treated. Furthermore, studies indicate that all women aged ≥65 years with NVAF should be treated, even with a score of zero, because of their observed increased risk for stroke.1,8 To reduce the risk for bleeding, providers must offer proper education and timely, consistent, and accurate monitoring to patients who are receiving antithrombotic medications. The education should include the importance of drug compliance, dietary restrictions, medication interactions, and lifestyle changes. There must be a defined process in place for prothrombin/INR testing.

Equally important is to establish a defined process for communicating the testing results to the patient and for any adjusted medication dosing. Many thromboembolic and bleeding complications occur as a result of inconsistent monitoring and poor communication. In addition to the quality and safety concerns discussed herein, the mismanagement of warfarin is a common source of medical malpractice litigation.

Because of the simplicity of monitoring, many providers prefer to use the newer antithrombotic agents as firstline therapy for patients with nonvalvular AF. However,

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onthly Costs of Select Antithrombotic Table M Medications Antithrombotic Cost of monthly medication supply, $ Warfarin 5 mg

17.25

Dabigatran

349

Rivaroxaban

343.62

Apixaban

349.99

Source: Health Spectrum Pharmacy, Lehigh Valley Health Network, Allentown, PA.

as previously noted here, the cost of these newer agents can be ≥5 times as expensive as warfarin and may not be covered by the patient’s insurance plan. The lack of an antidote, again, may be a concern for the patient, but should also give some caution to the provider.

Although many patients have few symptoms from NVAF, providers should nonetheless make every effort to convert the patient back to a normal sinus rhythm. Many antiarrhythmic medications are available today. If the patient cannot be converted to a sinus rhythm using medications alone, transesophageal echocardiography cardioversion and ablation procedures should be considered. Surgical options using radiofrequency ablation and left atrial appendage occlusion are also showing great promise. n I wish to thank Courtney E. Bennett, DO, for her assistance in preparing this perspective.

1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 Mar 28.

[Epub ahead of print].

2. Fiumara K, Goldhaber SZ. A patient’s guide to taking coumadin/warfarin. Circulation. 2009;119:e220-e222.

3. Spinler SA, Shafir V. New oral anticoagulants for atrial fibrillation. Circulation.

2012;126:133-137.

4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

6. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

7. Colilla S, Crow A, Petkun W, et al. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013;112: 1142-1147.

8. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients wih non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013;34:2094-2106.

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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.

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• 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

Call for Papers Cardiometabolic Health Theme Issue American Health & Drug Benefits will be publishing a theme issue on Cardiometabolic Health in 2014 Readers are invited to submit articles for publication in this theme issue on topics relevant to the clinical, business, and policy aspects of cardiometabolic health and wellness. Original research, comparative effectiveness analyses, cost-effective analyses, evidence-based systematic reviews, and case studies are of particular interest. All articles will undergo the journal’s rigorous peer-review process and acceptance is contingent on that review.

Topics of high interest include:

• Insulin resistance and type 2 diabetes

• Benefit designs to improve cardiometabolic outcomes

• Lifestyle strategies and cardiometabolic health and wellness

• Best practices in insulin control, lipid management, blood pressure control

• Lipid management in patients with diabetes

• Comparative effectiveness analyses of best therapies for cardiovascular health

• Medication adherence

• Cost-effective analyses of current therapies for diabetes • Current recommendations for optimizing A1c target outcomes • Diabetes management and prevention

• New biomarkers for assessing cardiometabolic risk • New therapies for diabetes, cardiovascular disease, or obesity • Optimal therapies for cardiovascular disease, diabetes, and/or obesity • Pharmacoeconomic analyses

• Emerging therapies for diabetes, heart disease, obesity

• Prevention strategies for diabetes risk reduction

• Employers’ strategies to enhance employees’ cardiometabolic wellness • Health plan initiatives for cardiometabolic health and prevention

• Wellness programs for patients with heart disease, diabetes, obesity

• Hot topics in diabetes management

Submission deadline: August 15, 2014 Articles must follow Manuscript Instructions for Authors at www.AHDBonline.com Submit articles to editorial@engagehc.com or online Vol 7, No 4

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Review Article

The Health and Economic Effects of Counterfeit Drugs Erwin A. Blackstone, PhD; Joseph P. Fuhr, Jr, PhD; Steve Pociask, MA

Stakeholder Perspective, page 224 Am Health Drug Benefits.

2014;7(4):216-224 www.AHDBonline.com Disclosures are at end of text

Background: Counterfeit drugs comprise an increasing percentage of the US drug market and even a larger percentage in less developed countries. Counterfeit drugs involve both lifesaving and lifestyle drugs.

Objective: To review the health and economic consequences of counterfeit drugs on the US public and on the healthcare system as a whole.

Method: This comprehensive review of the literature encompassed a search of MEDLINE/PubMed, Google Scholar, and ProQuest using the keywords “counterfeit drugs,” “counterfeit medicines,” “fake drugs,” and “fake medicines.” A search of the various FiercePharma daily newsletter series on the healthcare market was also conducted. In addition, the US Food and Drug Administration and the World Health Organization websites were reviewed for additional information.

Discussion: The issue of counterfeit drugs has been growing in importance in the United States, with the supply of these counterfeit drugs coming from all over the world. Innovation is important to economic growth and US competitiveness in the global marketplace, and intellectual property protections provide the ability for society to prosper from innovation. Especially important in terms of innovation in healthcare are the pharmaceutical and biopharmaceutical industries. In addition to taking income from consumers and drug companies, counterfeit drugs also pose health hazards to patients, including death. The case of bevacizumab (Avastin) is presented as one recent example. Internet pharmacies, which are often the source of counterfeit drugs, often falsely portray themselves as Canadian, to enhance their consumer acceptance. Adding to the problems are drug shortages, which facilitate access for counterfeits. A long and convoluted supply chain also facilitates counterfeits. In addition, the wholesale market involving numerous firms is a convenient target for counterfeit drugs. Trafficking in counterfeits can be extremely profitable; detection of counterfeits is difficult, and the penalties are modest.

Conclusion: Counterfeit drugs pose a public health hazard, waste consumer income, and reduce the incentive to engage in research and development and innovation. Stronger state licensure supervision of drug suppliers would be helpful. Technological approaches, such as the Radio Frequency Identification devices, should also be considered. Finally, counterfeit drugs may raise concerns among consumers about safety and reduce patient medication adherence.

I

ntellectual property represents original, creative works and innovations who belonging to inventors, artists, musicians, and authors who, and businesses that, create something or acquire rights to a creation.

The exclusive rights and legal protections of intellectual property come in the form of copyrights, trademarks, and patents. These protections encourage innovation and creativity, but the rewards for innovation and creativity can be undermined by widespread theft associated with counterfeiting and trafficking of pirated goods. The Internet has become an important and convenient means for consumers to shop and save money. However, websites that traffic counterfeit goods have flourished on the Dr Blackstone is Professor of Economics, Temple University, Philadelphia, PA; Dr Fuhr is Professor of Economics, Widener University, Philadelphia, PA; Mr Pociask is President, The American Consumer Institute, Washington, DC.

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Internet, creating confusion between which sites sell authentic goods and which do not.

When reflecting on counterfeit and pirated goods, knockoff luxury handbags, fake watches, and free music and videos may come to mind. The counterfeiting and pirating of goods may seem to be a victimless crime, where no one is harmed by imitation goods sold at much lower prices than brand-name products. However, the world of counterfeiting and piracy stretches to nearly every product on the market and has often led to considerable harm to consumers, including death. The consequences are well-known, as the Department of Homeland Security states, “counterfeit and pirated goods pose a serious threat to America’s economic vitality, the health and safety of American consumers, and our critical infrastructure and national security.”1 Piracy and counterfeiting are not victimless crimes; they cost US businesses more than $200 billion annually and account

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for the loss of more than 750,000 jobs.2 This is also a worldwide problem.

Medicines have often been counterfeited, sometimes with dire consequences to patients.3 Counterfeit drugs are a public health issue in the United States and worldwide. The issue of counterfeit drugs has been growing in the United States with the supply of these counterfeit drugs coming from all over the world. Counterfeit drugs not only take income from consumers, by having them pay for products that have little or no medical value, but they can also lead to unresolved health problems, and even death.3 There are various issues involved with counterfeit drugs and reducing their availability. Especially significant, counterfeit drugs may raise concerns among consumers about safety, and may therefore reduce patient adherence.

In this review, we examine how the legitimate supply chain has been infiltrated by counterfeits, as well as the role of the Internet in facilitating the distribution of counterfeit drugs, and the impact on patients, drug innovation, and the pharmaceutical industry.

Counterfeit Medicines Counterfeit medication is a problem in the United States, and even more so worldwide. Counterfeit medications are a waste of income of patients, and they often endanger the public’s health and safety. One case that illustrates this problem is that of a patient who was treated with injections for anemia, after a liver transplant. After 8 weeks of injections, the patient was still not responding to treatment. The treating physicians discovered that the medicine the patient used was counterfeit.4 In such cases, the consequences of counterfeits can be serious.4 A particularly serious case involved counterfeit versions of bevacizumab (Avastin), a cancer-fighting medication. Avastin’s manufacturer, Roche, notified physicians in February 2012 of a counterfeit version of bevacizumab that contained salt and starch, but not the active component of the drug.5 Another example of the dangers of counterfeit medications in the United States is the 2008 counterfeit case of the blood thinner heparin.

In this case, the active ingredient was replaced with a cheaper substance that caused patients to have adverse reactions and resulted in a nationwide recall of heparin.6 The medication, whose counterfeit active ingredient came from China (a major source of counterfeiting), was suspected to be the cause of as many as 81 deaths.6 The implications for patients are clear: counterfeits can kill.

The US company that sold heparin was subject to 740 lawsuits and eventually sold the division that produced the medicine.6 Preventing counterfeit medicines from entering the United States is especially difficult, in part because near-

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Key Points Counterfeit drugs comprise a growing percentage of the US drug market. ➤ Drug shortages, a long and convoluted supply chain, and Internet pharmacies are contributing factors. ➤ US consumers are largely unaware of the dangers of purchasing counterfeit drugs from Internet pharmacies: an estimated 36 million Americans have bought drugs online without a valid prescription. ➤ This review of the literature investigates the implications of how the legitimate supply chain has been infiltrated by counterfeits. ➤ Real-world evidence from several cases, including the case of bevacizumab (Avastin), are presented as recent examples of the serious harm drug counterfeiting can cause patients and the cost to manufacturers and drug innovation. ➤ Controlling the availability of counterfeit drugs is not simple, but necessary, given the serious public health issues they pose. ➤ The threat to the safety of American patients and drug innovation merit strong sanctions regarding counterfeit drugs. ➤

ly 40% of drugs are made overseas and approximately 80% of the active medicinal components of drugs are imported.7 Because many of these medicines are expensive, buyers are attracted by lower prices. The rise of Internet pharmacies makes regulation of drug safety more difficult. Detecting counterfeits is often difficult, because many of these goods pass through a long and complicated distribution network, thereby creating opportunities for counterfeits to enter the legitimate supply chain.

Counterfeit medications are also a worldwide problem. The World Health Organization (WHO) estimates that as much as 30% of the medicines sold in parts of Asia, Africa, and Latin America are counterfeit.8 In 2011, 64% of antimalarial drugs in Nigeria were found to be counterfeit.9 Worldwide, an estimated 10% of all medicines are counterfeit.10

Method This comprehensive review of the literature is based on a search of online databases, including MEDLINE/ PubMed, Google Scholar, and ProQuest using the keywords “counterfeit drugs,” “counterfeit medicines,” “fake drugs,” and “fake medicines.” A search of the various FiercePharma daily newsletter series related to the healthcare industry was also conducted. In addition, the US Food and Drug Administration (FDA) and the WHO websites were reviewed for additional information.

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Consumer Issues: Harmful Effects Patients can experience a variety of problems from the use of counterfeit drugs. The various scenarios depend on the ingredients that make up the counterfeit drug. The first scenario is a counterfeit drug that contains no active ingredient or no harmful ingredients.11 In the case of the counterfeit drug that has no active ingredient, the drug fails to help the patient get better, which can ultimately harm the patient. In the case of antibiotics, for example, this can promote antibiotic resistance and the use of stronger antibiotics, because physicians would believe that the first-line drug was not working, not knowing that the patient had been taking a counterfeit drug.11 A second scenario is that the counterfeit drug has no active ingredient and may have any number of harmful ingredients, including bacteria-laced water, toxic yellow paint, floor wax, colored dye, powdered cement, boric acid, and antifreeze.11 More than 500 children around the world died from counterfeit cough syrup that was tainted with ethylene glycol (ie, antifreeze).11 In another case, counterfeit inhalers for the treatment of pediatric cystic fibrosis were found to contain contaminated bacteria that went directly into the lungs of unsuspecting children.12 Another case involved patients with cancer who used erythropoietin, in which the counterfeit intravenous drug was diluted with bacterially contaminated water and injected directly into the patients.12 Another scenario is that of a wrong drug used in the counterfeit agent. Counterfeit versions of GlaxoSmithKline’s over-the-counter weight-loss medication orlistat (Alli) have been distributed in the United States. The counterfeit contained the controlled substance sibutramine instead of orlistat.13 The FDA reported that this counterfeit version could be dangerous for certain patient populations who unknowingly take it, and could potentially produce harmful interactions with other medications that patients may be taking.13 One other scenario involves a counterfeit drug that contains the wrong concentration or wrong dose of the drug. One example of this is the case of a physician who was supplied with a research version of onabotulinumtoxinA (Botox) that was much more concentrated than the real medicine, and is not intended for human use.11 This resulted in respiratory paralysis and near death for several patients, including the physician who was using it himself.11 In general, counterfeit drugs create uncertainty, confusion, and doubts about the value of the real drug and may lead to the use of alternative, less-desirable drugs or therapies.

Supply Issues Indicative of the concern over supply chain issues, on February 27, 2014, the House Energy & Commerce Sub-

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committee on Oversight and Investigations conducted a hearing entitled, “Counterfeit Drugs: Fighting Illegal Supply Chains.”14 Counterfeit drugs are available through the legitimate supply chain, which also includes a small percentage of online pharmacies. The legitimate supply chain has many stages in which counterfeits can enter, starting with providing ingredients for manufacturing of the drug. Subsequent stages for infiltration include storage, transportation, and finally distribution. Approximately 90% of drugs are distributed in the United States by national wholesalers directly to end suppliers that generally include pharmacies, physicians, hospitals, and clinics.15 However, the remaining 10% can often follow a circuitous route, which increases the risk for counterfeits entering the market.15 In one instance, counterfeit epoetin alfa (Epogen), which was purchased from a pharmacy, had at least 13 chains of owners and caused considerable health issues for a young patient who had undergone a liver transplant in the United States. In addition to the manufacturer and the major distributor, this drug was handled by 3 different wholesalers, 2 pharmacies, 4 unlicensed go-betweens, and 1 suspected counterfeiter.15 This case and many others illustrate why decreasing the number of links in the supply chain, in an effort to reduce the counterfeit drug supply, is desirable for the health and safety of patients.

A problem area is the wholesale market, which comprises 3 types of wholesalers—primary wholesalers; several large, regional wholesalers; and many thousands of secondary wholesalers. The primary and large, regional wholesalers interact with the manufacturers, and they are usually not the avenue of entry for counterfeits. Conversely, secondary wholesalers do not deal directly with drug manufacturers, and they buy and sell drugs in response to market shortages and surpluses. In addition, they package and repackage the drugs, which provide an opportunity for counterfeits to enter the market.16 The issue related to decreasing the number of people and routes in the supply chain must be addressed. One suggestion from the House Energy & Commerce Subcommittee on Oversight and Investigations hearing on counterfeit drugs was to increase state licensure supervision of drug wholesalers: it was noted that state pharmacy boards should exercise more effective supervision of these wholesalers.16 Another approach is technology-­ based, which involves establishing a mandatory drug track-and-trace system. This type of tracking system was implemented in Turkey in 2011.16 On November 28, 2013, President Obama signed the Drug Quality and Security Act into law, which provides for a national track-and-trace system that would allow a specific drug to be followed from the manufacturer to the

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pharmacy.17 This should make it more difficult for counterfeit drugs to enter the legitimate US pharmaceutical supply chain. The law provides for a national system of electronic tracking of drugs and is expected to be implemented by 2015.17 The technology for the track-and-trace system most likely to be used is the Radio Frequency Identification (RFID) device, which uses information stored and remotely retrieved on transponders to provide automatic identification.18 An RFID tag is a chip that can be used to provide serial numbers to confirm the identity of a product.18 International harmonization should be considered to make tracking and tracing more effective.

Another factor exacerbating (or at least contributing to) the problem of counterfeit drugs is the recent shortages of several drugs in the United States.19 Many of the drugs in short supply are lifesaving anticancer drugs, and this promotes the development of counterfeits that can result in considerable suffering or death for the patient.

In the second quarter of 2012, there were 211 drugs associated with shortage issues in the United States.19 A 2009 case involving ineffective insulin illustrates the problem.20 Patients reported that their insulin was not controlling their blood sugar. The insulin used by these patients had been stolen and was not stored or handled properly, thus losing its potency.20 For drugs in short supply, hospitals and other providers search beyond normal sources to obtain the drugs, increasing the ability of inserting the counterfeits into the market. “Shortages of key medicines in the US and Europe have created new opportunities for illicit traders, while ever-longer manufacturer supply chains open the door to diversion and theft.”21 Drug shortages lead to increased prices for a legitimate drug and increase the opportunity and ability for unscrupulous people to make financial gains by introducing counterfeit drugs into the market.20 Counterfeiters are able to take advantage of the drug shortage and charge exorbitant prices. Cost markups (presumably compared with standard prices) on drugs associated with shortages during a 2-week period in the beginning of 2011 averaged 650%.20 Particularly high markups, 4533%, were reported for labetolol (cardiology); cytarabine (oncology), 3980%; dexamethasone (oncology, rheumatology), 3857%; and propofol (critical care sedation, surgery), 3161%.20 These shortages sometimes occur because of quality control problems that exist in manufacturing plants, which are then shut down by the FDA.

Internet Pharmacies Consumers (or patients) in the United States are largely unaware of the dangers of purchasing counterfeit drugs from Internet pharmacies.22 This lack of knowledge

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is contributing to what is becoming a major public health issue. In most cases, counterfeit drugs are neither safe nor effective. The use of these drugs can lead to greater sickness, or even to death.

According to a 2009 report, online pharmacy sales were an estimated $11 billion that year, up from an estimated $4 billion in 2007.23 Early on, counterfeit drugs involved primarily so-called lifestyle drugs, especially silden­ afil (Viagra), but the market has expanded to include all types of therapeutic medicines, including insulin, cancer medications, and cardiovascular drugs. Although counterfeit drugs sometimes end up in the pharmaceutical supply chain, the primary source of counterfeit drugs is online pharmacies.24 The National Association of Boards of Pharmacy found that 97% of the Internet pharmacies it examined were not compliant with either federal or state laws, or with industry standards.24 The FDA has the task of making sure that pharmaceuticals are safe and effective, but this task is becoming increasingly difficult, with patients bypassing traditional sources of medication and purchasing them from rogue Internet pharmacies that pose as legitimate businesses.22 Consumers are motivated by lower prices, and some are attracted by the ability to obtain prescription drugs without a prescription.22 The FDA notes that nearly 1 in 4 Internet users has bought from online pharmacies.25 To educate consumers about the dangers of purchasing prescription drugs online, the FDA has launched a campaign entitled “BeSafeRx: Know Your Online Pharmacy.”26 Some Internet pharmacies give the impression that they are located in Canada and are selling legitimate brand-name drugs that have been manufactured in Canada, but many of these legitimacy claims are blatantly false.22 In these cases, the drugs are not approved by the FDA and they are not safe or effective. They are often not even approved by the Canadian government.27 Medicines that are not used in Canada are not subject to the scrutiny of Canada’s safety laws.27 Therefore, drugs from Canadian Internet pharmacies can come from anywhere in the world. The fact is that many so-called Canadian Internet pharmacies are not Canadian at all, but are actually based in places such as Belize, Russia, and Vietnam, to name a few.22 A 2005 study found that only 214 of 11,000 online pharmacies claiming to be Canadian were actually registered in Canada.16 This has made “Canadian” Internet pharmacies the primary supplier of counterfeit drugs to the United States.27 One Canadian online pharmacy has been linked to counterfeit bevacizumab.28 This same online pharmacy blamed the US government for trying to stop its operations, stating on its website, “Washington wants to seize and destroy your safe, affordable imported drugs.”27 The

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truth is that these drugs are often neither safe nor affordable. As noted before, in most cases, these drugs can harm consumers, because they do not contain the active ingredients to resolve a health issue, and instead they can contain harmful ingredients, such as bacteria and toxins.

Of note, in the case of lifestyle drugs, such as sildenafil, the counterfeits often contain some of the active ingredient,29 because the effect of the drug is obvious.

Although Internet pharmacies often boast that they can save consumers up to 75% of the drug cost,30 patients often receive a medication that offers them zero benefits and may cause them more harm than good. Tap water or bacteria at a discount of 75% off the price of the legitimate drug is no bargain for anyone. Although it is possible to obtain legitimate drugs from overseas at considerable discounts,30 the Federal Food, Drug, and Cosmetic Act makes it technically illegal to import prescription drugs into the United States.31 Moreover, some of these Internet sites are linked to terrorist groups, such as Hezbollah and Al Qaeda, and others are linked to organized crime––posing a threat to national and international security.11 In an attempt by these sites to make even more profit, consumers may face other consequences of an online drug purchase, including credit card fraud, identity theft, and computer viruses.32 So, what is the real price of an online prescription?

Caveat emptor—let the buyer beware.

One hopeful sign is that of increased international cooperation. In June 2013, the United States, along with almost 100 other countries, collaborated in the Operation Pangea VI––a global action against online trading of counterfeit and illegal drugs. The FDA reported that the operation eliminated 1677 websites involved with the sale of illegal prescription drugs and seized $41 million worth of dangerous drugs.32

The Bevacizumab (Avastin) Case As noted before, the importation of non–FDA-approved drugs into the United States is illegal. Drugs that are not approved by the FDA or do not contain FDA-approved labeling are considered to be illegal for sale in the United States. Counterfeit cancer drugs first appeared in the United States in February 2012 and 2 subsequent cases were reported in June 2012 and February 2013.33 All 3 cases concern counterfeits of the cancer drug bevaciz­ umab and were supplied to patients in the United States.33 According to the FDA, there are only 4 approved suppliers of bevacizumab in the United States.

Physicians purchased the counterfeit bevacizumab from unapproved suppliers, at prices below the going price for bevacizumab.32 Although seeking lower-priced drugs is desirable, prices substantially below customary levels should raise

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questions. Thus, physicians need to perform due diligence to make sure that they are buying from legitimate suppliers to avoid putting their patients in harm’s way. In 1 case, counterfeit medicines should have been easily detected, because the writing on the box was in French.34 There have been other incidents of physicians supplying patients with drugs from unauthorized suppliers. In 1 case, 7 Ohio oncologists paid $2.6 million in fines and were sentenced to probation after pleading guilty to a misdemeanor of purchasing unapproved cancer drugs.35 This case also involved Medicare fraud: physicians bought the drugs at a price below the list price but billed Medicare at the list price.35

Incentives and Penalties According to an article published in the American Journal of Law & Medicine, “the success of prescription drugs and their extensive use has attracted unsavory characters interested in exploiting vulnerable patients and the markets for medicines.”11 Although pharmaceutical companies spend considerable amounts of money on the research and development (R&D) of new drugs that benefit society and are approved as safe and effective in the United States by the FDA, suppliers of counterfeit drugs bypass this process and supply these drugs at little cost to them; profit margins are often as high as 3000%.36 One expert estimates that a $1000 investment in counterfeit prescription drugs can result in a $30,000 return, which is 10 times the profit rate of trafficking heroin.37 For example, one source reported that selling counterfeit silden­afil “can be as much as 2000 times more profitable” than selling cocaine.38 Also, the risk of being caught is much lower because detection is much more difficult.38 Detection is difficult because medical personnel attrib­ ute the problem of drugs that produce poor clinical outcomes to patient variation.11 In most cases, patients are unlikely to suspect that they are using counterfeit drugs.

Often, drug packaging is thrown away, which makes it difficult to test for bad drugs, particularly because the drugs may be undetectable in the bloodstream after a few days. As was suggested by 1 case, “the evidence is destroyed the second it is ingested or injected.”15 Also, patients may not want to reveal that they have bought drugs without a prescription over the Internet. Therefore, the probability of a counterfeiter getting caught can be very low.

The criminal penalties for the sale of counterfeit medications can be far less than the criminal penalties for the sale of illegal narcotics, thus making it more profitable and less risky for criminals to sell counterfeits. It is estimated that counterfeit drugs provide approximately $75 billion in revenue annually to illegal operators and have caused more than 100,000 deaths worldwide.20 The pen-

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alties are obviously too low. The Federal Food, Drug, and Cosmetic Act penalizes drug counterfeiting with a maximum of $10,000 or 3 years in prison, or both.39 Representative Tim Murphy states, “The penalties for drug-­ counterfeiting under the Federal Food, Drug, and Cosmetic Act have not been updated since 1938. There is a steeper penalty for counterfeiting a designer purse under the Federal Criminal Code than a drug product under current FDA law.”40 By contrast, the penalties for selling narcotics can be life in prison and millions of dollars in fines. One person involved in the bevacizumab case received 6 months of house arrest and 5 years of probation.41 Clearly, more stringent penalties are needed to discourage counterfeit drug sales. A recent survey by the American Consumer Institute Center for Citizen Research showed that consumers strongly believe that the sale of counterfeit medicines can pose serious health risks to American consumers.42 The survey also showed that consumers overwhelmingly support criminal penalties for anyone who knowingly sells counterfeit medicines to Americans online.42

pharmaceutical industry. However, the attraction of counterfeits is their low prices, and the loss to the industry is presumably less than the estimated sales of the counterfeit drugs, because some consumers would likely not have purchased the drugs at the standard price. Nevertheless, the loss is significant and imposes a cost to society in the form of reduced incentives for innovation.

An example of the loss from counterfeit drugs comes from the experience of Pfizer. In 2010, authorities in 53 countries confiscated 8.4 million tablets, capsules, and vials of counterfeit Pfizer products.46 This part of the cost of fighting counterfeit drugs is borne by the companies.

Brian Donnelly, PhD, Director of Pfizer’s global security team (the unit that battles counterfeiters) is a pharmacologist who had worked as an FBI special agent for 21 years and is now leading the work on counterfeit drugs.46 Resources that could be used for more productive ventures are instead used to deal with the problem of counterfeit or adulterated goods. Such security officers investigate, and then seek cooperation, from public authorities to make arrests.

Economic Benefits of Intellectual Property Innovation is important to economic growth and US competitiveness in the global marketplace. Intellectual property protections provide the ability for society to prosper from innovation. As President Obama has stated, if we are to win the future and to be successful in an increasingly competitive international market, the United States must innovate.43 Innovations create jobs and provide products that enrich consumers’ lives.

In 2010, intellectual property-intensive industries accounted for 27.7% of all US employment.44 Such industries paid a 42%-wage premium compared with other industries, and they accounted for 60.7% of US merchandise exports in that year. As the US Department of Commerce puts it, “innovation protected by intellectual property rights is key to creating new jobs and growing exports.”43 Alternatively, intellectual property theft reduces incentives to create and innovate, and that, in turn, reduces economic output and employment.

Especially important in terms of innovation are the pharmaceutical and biopharmaceutical industries. These industries typically spend an average of 15% to 17% of their revenues on R&D, which is among the highest rates of R&D spending of any industry. For example, in 2006, the US pharmaceutical industry spent 22% of sales on R&D, whereas all manufacturing spent only 3.3% of their sales.45 Counterfeit drugs reduce the incentive to engage in R&D. Indeed, the National Association of Boards of Pharmacy estimated that counterfeit drugs generated $75 billion in revenues in 2010.46 This represents a substantial percentage of lost revenues to the

Implications Call for Action to Policymakers The prevalence of counterfeit drugs is increasing, especially with the expansion of the Internet. It is estimated that 36 million Americans have bought drugs online without a valid prescription.47 Counterfeit drugs pose a public health hazard, waste consumer income, and reduce the incentive to engage in R&D. The counterfeit problem is especially acute in less developed countries.

Counterfeiting involves both lifestyle and lifesaving drugs. Counterfeiting drugs is extremely profitable, and current penalties are insufficient to deter this practice.

A survey of US consumers showed that there is strong support for criminal penalties to combat counterfeit drugs.40 Internet pharmacies are a major source of counterfeits, as consumers search for lower-priced drugs or purchase prescription drugs without a prescription.

Shortages of drugs exacerbate the problem by increasing prices and enabling counterfeits to enter the market as providers seek to obtain drugs in short supply. The long supply chain, through which some drugs pass, facilitates the entry of counterfeits. Furthermore, the fact that most active ingredients for drugs come from foreign sources adds to this problem.

The loss of profit on an estimated $75 billion of counterfeit drug sales is significant.43 To illustrate the point, assuming that only 50% of the sales of drugs would occur at customary prices, and because counterfeits are most prevalent with the more profitable drugs, the annual lost commercial profit could be approximately $18 billion, which could be used for more productive uses or lower prices.

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Table Suggestions on How to Reduce Drug Counterfeiting • Increase public awareness, especially concerning Internet

pharmacies

• I mprove management of supply chain • Apply stiffer fines and jail sentences for convicted sellers of

counterfeit drugs

• Increase due diligence by physicians when purchasing drugs and

stiffer penalties for those who knowingly provide counterfeit drugs to their patients • Improve controls of secondary drug markets • Improve cooperation with foreign governments regarding counterfeiting drugs • Improve quality control by drug manufacturers to avoid drug shortages • Encourage more voluntary cooperation from companies along the Internet chain, such as credit card companies, domain registrars, Internet service providers, and couriers • Improve use of technology to track and trace counterfeiting drugs • Sell drug supplies only to licensed manufacturers • Construct Internet search algorithms so that legitimate online pharmacies appear first

Several public policy changes would help to improve the situation. Some of these are listed in the Table.

Overall, technological approaches should be utilized when appropriate and feasible to help ameliorate the counterfeit problem. Drug manufacturers need to improve the quality of the production process to decrease drug shortages. Higher fines, loss of medical license, and jail time should be implemented for physicians who knowingly give counterfeit drugs to their patients.

Penalties for counterfeiting should be increased. Given the difficulties and low probability of detection, penalties would have to be substantial to deter the practice. A 20year sentence and a life sentence for anyone selling drugs that lead to death is appropriate. More information concerning the hazards of purchasing from Internet pharmacies should be provided so that consumers can make more informed choices. Tracking of drugs is already being enhanced. Additional technological steps, including the possible insertion of radio chips, should also be considered as a way of tightening the supply chain.

The recently enacted drug security law (2013) is an important step in the right direction.48 More effective licensure control of drug wholesalers is also important.

Physicians should purchase drugs from only authorized distributors, which would reduce the ability of counterfeits to enter the market.

Greater international cooperation to confront counterfeiting in countries like China should also be considered.

Internet-access companies should be encouraged to make their algorithms list the approved online pharmacies first. These would be pharmacies that meet the

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standards of recognized industry organizations or licensing authorities. More voluntary cooperation from companies along the Internet chain, such as credit card companies, domain registrars, Internet service providers, and couriers would make counterfeiting less profitable.

Consumer Education Needed Consumers should be encouraged to know where the online pharmacy is actually located, and the actual source of their drug supply. In addition to scrutinizing the location of an online pharmacy, consumers should also be leery of any company that will distribute prescription drugs without a prescription. Consumers should also be informed about the extent of counterfeit drugs and the harm they cause. Finally, consumers should be encouraged not to buy prescription drugs without a valid prescription.

When it comes to buying drugs from online pharmacies, consumers should heed the old Latin phrase, caveat emptor—let the buyer beware.

Conclusion Solving the counterfeit drugs problem is important to ensure that patients do not lose faith in the benefits of pharmaceuticals and become nonadherent with their treatments. The expansion of the Internet, and the difficulty in controlling drug suppliers from the Internet, have greatly increased consumer purchases of counterfeit drugs. Controlling the availability of counterfeit drugs is not easy, but it is necessary, given the tremendous public health issues concerning counterfeit drugs, which can harm or kill people. Cooperation is necessary among all the stakeholders involved. n Author Disclosure Statement Dr Blackstone and Mr Pociask reported no conflicts of interest; Dr Fuhr was a member of the multistakeholder roundtable for NeoTract.

References

1. US Department of Homeland Security. Intellectual property rights: fiscal year 2012 seizure statistics. CBP publication # 0172-0113. www.cbp.gov/sites/default/files/ documents/FY2012%20IPR%20Seizure%20Statistics_0.pdf. Accessed May 3, 2014.

2. Office of the United States Intellectual Property Enforcement Coordinator. Intellectual property spotlight. March/April 2012. www.whitehouse.gov/sites/default/files/ omb/. Accessed May 3, 2014.

3. Liang BA, Mackey TK. Sexual medicine: online risks to health—the problem of counterfeit drugs. Nat Rev Urol. 2012;9:480-482.

4. Bennett CL. Government agencies and pharmaceutical industry must take action to thwart sales of counterfeit drug products. September 1, 2006. www.rheumatologynetwork.com/articles/government-agencies-and-pharmaceutical-industry-must-takeaction-thwart-sales-counterfeit-drug. Accessed May 3, 2014.

5. Palmer E. Feds nail key player in counterfeit Avastin probe: contract employer says he was aware Canada Drugs was breaking the law. FiercePharma. April 24, 2013. www.fiercepharma.com/story/feds-nail-key-player-counterfeit-avastin-probe/201304-24. Accessed April 26, 2013.

6. Toscano P. The dangerous world of counterfeit prescription drugs. CNBC. October 4, 2011. www.cnbc.com/id/44759526. Accessed May 23, 2014.

7. US House of Representatives, Committee on Energy and Commerce. Hearing on counterfeit drugs. Memorandum. February 25, 2014. http://docs.house.gov/meetings/IF/ IF02/20140227/101804/HHRG-113-IF02-20140227-SD002.pdf. Accessed May 3, 2014.

8. United Nations Office on Drugs and Crime. Counterfeit goods: a bargain or a costly

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mistake? www.unodc.org/toc/en/crimes/counterfeit-goods.html. Accessed May 3, 2014.

9. Fake pharmaceuticals: bad medicine: the world’s drug supply is global. Governments have failed to keep up. Economist. October 13, 2012. www.economist.com/node/ 21564546. Accessed May 3, 2014.

10. Berkrot B. Fake Avastin shows little protection of drug supply. Reuters. March 12, 2012. www.reuters.com/article/2012/03/12/us-avastin-drug-fake-idUSBRE82B0Y Y20120312. Accessed May 3, 2014.

11. Liang BA. Fade to black: importation and counterfeit drugs. Am J Law Med. 2006; 32:279-323.

12. Chachere V. Attorney General sues Tampa couple over fake cystic fibrosis drug.

Florida Times-Union. April 7, 2005. http://jacksonville.com/tu-online/apnews/stories/ 040705/D89APL0G0.shtml. Accessed May 3, 2014.

13. US Food and Drug Administration. FDA warns consumers about counterfeit Alli: the counterfeit products contain controlled substance sibutramine. Press release.

January 18, 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm 197857. Accessed May 3, 2014.

14. Subcommittee on Oversight and Investigations of the House Committee on Energy and Commerce. Hearing on “Counterfeit Drugs: Fighting Illegal Supply Chains.” February 27, 2014. http://democrats.energycommerce.house.gov/index.php ?q=hearing/hearing-on-counterfeit-drugs-fighting-illegal-supply-chains-subcommitteeon-oversight-and-in. Accessed May 3, 2014.

15. Brown EC. Pharmaceutical fakery: counterfeit drugs threaten patients’ health.

Long Island Press. June 9-15, 2005:24-26. http://twelvepointbold.com/pdf/Pharma ceutical_Fakery.pdf. Accessed May 3, 2014.

16. Prashant Yadav, PhD, MBA, director, Health Care Research Initiative, and senior research fellow, William Davidson Institute, University of Michigan. Statement before the Subcommittee on Oversight and Investigations of the House Committee on Energy and Commerce. Hearing on “Counterfeit Drugs: Fighting Illegal Supply Chains.” February 27, 2014. http://democrats.energycommerce.house.gov/sites/ default/files/documents/Testimony-Yadav-OI-Counterfeit-Drugs-Supply-Chain2014-2-27.pdf. Accessed May 3, 2014.

17. Gartner. New U.S. Drug Security Law Requires Review of Track-and-Trace Strategies. December 2, 2013. www.gartner.com/doc/2631239/new-drug-security-law-requires.

Accessed May 22, 2014.

18. Coustasse A, Arvidson C, Rutsohn P. Pharmaceutical counterfeiting and the RFID technology intervention. J Hosp Mark Public Relations. 2010;20:100-115.

19. Palmer E. Drug shortages ease but remain serious problem. FiercePharma. September 7, 2012. www.fiercepharma.com/story/drug-shortages-ease-remain-serious-problem/ 2012-09-07. Accessed May 3, 2014.

20. Cherici C, McGinnis P, Russell W; for Premier Healthcare Alliance. Buyer beware: drug shortages and the gray market. August 2011. www.premierinc.com/about/news/ 11-aug/Gray-Market/Gray-Market-Analysis-08152011.pdf. Accessed May 3, 2014.

21. Wechsler J. Campaign mounts to curb counterfeit drugs: manufacturers and regulators struggle to control phony versions of crucial medicines. BioPharm International.

September 1, 2012. www.biopharminternational.com/biopharm/Regulation+and+ Compliance/Campaign-Mounts-to-Curb-Counterfeit-Drugs/ArticleStandard/Article/ detail/787751. Accessed May 3, 2014.

22. US Government Accountability Office. Internet pharmacies: federal agencies and states face challenges combating rogue sites, particularly those abroad. GAO-13560. July 2013. www.gao.gov/assets/660/655751.pdf. Accessed May 3, 2014.

23. MarkMonitor. MarkMonitor finds online drug brand abuse is growing. September 28, 2009. www.markmonitor.com/pressreleases/2009/pr090928-bji.php. Accessed May 3, 2014.

24. National Association of Boards of Pharmacy. Internet Drug Outlet Identification program: progress report for state and federal regulators: April 2013. https://awarerx. s3.amazonaws.com/system/redactor_assets/documents/179/NABP_Internet_Drug_ Outlet_Report_Apr2013.pdf. Accessed May 3, 2014.

25. US Food and Drug Administration. FDA campaign aims to protect consumers from the risks of fake online pharmacies: survey data shows lack of confidence in purchasing drugs over the Internet. Press release. September 28, 2012. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm321470.htm. Accessed May 3, 2014.

26. US Food and Drug Administration. BeSafeRx: know your online pharmacy.

www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/buying medicinesovertheinternet/besaferxknowyouronlinepharmacy/default.htm. Accessed May 3, 2014.

27. Pociask S, Fuhr JP. Internet drugs can kill. Huffington Post. November 1, 2013. www.huffingtonpost.com/steve-pociask/internet-drugs-can-kill_b_4181418.html.

Accessed May 22, 2014.

28. Chasing CanadaDrugs.com. FiercePharma. October 10, 2012. www.fiercepharma. com/special-reports/6-chasing-canadadrugscom. Accessed May 3, 2014.

29. Moran B. Cracking down on counterfeit drugs. NOVA Next. August 20, 2013. www.pbs.org/wgbh/nova/next/body/uncovering-counterfeit-medicines/. Accessed May 3, 2014.

30. Jablow P. Ins, outs of getting meds from overseas. Philly.com. January 12, 2014. http://articles.philly.com/2014-01-12/news/46116373_1_prescription-drugs-buying-­ drugs-pharmaceutical-industry. Accessed May 3, 2014.

31. Federal Food, Drug, and Cosmetic Act, 21 USC §331 (2010).

32. US Food and Drug Administration. FDA takes action to protect consumers from dangerous medicines sold by illegal online pharmacies: international Operation Pangea VI combats online sale and distribution of unapproved prescription medicines. Press release. June 27, 2013. www.fda.gov/ICECI/CriminalInvestigations/ ucm358837.htm. Accessed May 3, 2014.

33. Imber S. Update on fake Avastin—FDA warnings in 28 states, six prosecutions.

Partnership for Safe Medicines. February 5, 2013. www.safemedicines.org/2013/01/ fda-warnings-in28-states-six-prosecutions-511.html. Accessed May 3, 2014.

34. Berkrot B. Doctors scour drug supplies after fake Avastin found. Reuters. February 15, 2012. www.reuters.com/article/2012/02/16/us-avastin-idUSTRE81F03220120216.

Accessed May 3, 2014.

35. US Department of Justice. Seven oncologists ordered to pay nearly $2.6 million for importing unapproved drugs. Press release. January 29, 2014. www.fda.gov/ICECI/ CriminalInvestigations/ucm384075.htm. Accessed May 3, 2014.

36. What’s in that pill? Bloomberg Businessweek. June 17, 2001. www.businessweek. com/stories/2001-06-17/whats-in-that-pill. Accessed May 3, 2014.

37. Ehrenberg R. Counterfeit crackdown. Science News. 2011;179:22-25.

38. Bingham J. Drug dealers ‘switching from cocaine to fake Viagra.’ Telegraph.

March 2, 2009. www.telegraph.co.uk/news/uknews/law-and-order/4925836/Drug-­ dealers-switching-from-cocaine-to-fake-Viagra.html. Accessed May 3, 2013.

39. Federal Food, Drug, and Cosmetic Act, 21 USC §333(a)(2) (2010).

40. Murphy T. Poison pills in your medicine cabinet: counterfeiters deliver deadly drugs. February 28, 2014. http://murphy.house.gov/latest-news/enews-from-congressmanmurphy97/#Poison. Accessed May 3, 2014.

41. Expert Briefings. Fake Avastin salesman ducks jail time. July 15, 2013. www.expert briefings.com/news/fake-avastin-salesman-ducks-jail-time/. Accessed May 22, 2014.

42. Blackstone EA, Fuhr JP Jr, Pociask S. Intellectual property: facts and consumer opinions on counterfeit and pirated goods. American Consumer Institute. July 25, 2013.

43. US Department of Commerce. Intellectual property and the U.S. economy: industries in focus. March 2012. www.uspto.gov/news/publications/IP_Report_March_ 2012.pdf. Accessed May 3, 2014.

44. US Department of Commerce. Intellectual property and the U.S. economy: industries in focus. April 10, 2012. www.esa.doc.gov/Reports/intellectual-property-andus-economy-industries-focus. Accessed May 3, 2014.

45. Levinson M. U.S. manufacturing in international perspective. Congressional Research Service. February 20, 2014. www.fas.org/sgp/crs/misc/R42135.pdf. Accessed May 23, 2014.

46. Gillette F. Inside Pfizer’s fight against counterfeit drugs. Bloomberg Businessweek.

January 17, 2013. www.businessweek.com/articles/2013-01-17/inside-pfizers-fightagainst-counterfeit-drugs. Accessed May 3, 2014.

47. Tim Murphy, chairman, Subcommittee on Oversight and Investigations. Opening statement before the Subcommittee on Oversight and Investigations of the House Committee on Energy and Commerce at the Hearing on “Counterfeit Drugs: Fighting Illegal Supply Chains.” February 27, 2014. https://energycommerce.house.gov/ sites/republicans.energycommerce.house.gov/files/Hearings/OI/20140227/HHRG113-IF02-MState-M001151-20140227.pdf. Accessed May 3, 2014.

48. Drug Supply Chain Security Act, S 957, 113th Cong, 1st Sess (2013).

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Stakeholder Perspective The Hidden Market of Counterfeit Drugs a Concern for All Stakeholders

By James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA

PAYERS: The issue of counterfeit drugs discussed by Blackstone and colleagues is largely unnoticed by the typical health plan in the United States. Health plans pay pharmacies for prescription drugs through pharmacy claims via a pharmacy benefit manager, and they pay physicians and other providers for drugs in the medical benefit through a variety of medical claims systems. In either case, the claim requires that a code that identifies a particular drug be submitted to the plan. The problem is, however, that the code would be the same for a legitimate or a counterfeit agent. The burden of determining whether a drug is counterfeit lies with the ultimate dispenser of the drug to a patient.

Health plans credential physicians before adding them to their networks, and they work with pharmacy benefit managers to ensure that the pharmacy network is of the highest quality, by denying access to or removing from the network pharmacies that have demonstrated fraudulent or unethical behavior in the dispensing of pharmaceuticals.

A bigger issue for health plans is the potential negative effects from patients obtaining and using counterfeit medications without getting the clinical benefit of the drugs. The risks for disease progression, side effects, or the need to change the treatment approach because of a poor response all present issues for the health plan, and can lead to poor patient outcomes and increased costs.

PATIENTS: An educational approach would be an effective way for health plans to communicate to patients regarding the risks of counterfeit medications. Patients need to be educated on the potential risks of using Internet pharmacies to obtain prescription drugs. Health plans usually have a preferred mail order pharmacy in their network, and ordering prescriptions on the Internet is generally allowed for that particular pharmacy. Patients can feel confident that the mail/Internet pharmacy has been chosen based on a number of key criteria, including that they are qualified to meet the needs of the

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health plan members, and that the patients need not be concerned about the legitimacy or safety of the medications obtained from this preferred provider.

PROVIDERS: When patients are concerned about the out-of-pocket costs of pharmaceuticals, providers and health plans need to be aware of the risk associated with the use of a secondary market to obtain their medications in an effort to save money. Providers can make patients aware of patient assistance programs or copay coupons that may defer some of the costs of prescription drugs. A majority of patients in a health plan have drug coverage, and physicians have many drugs to choose from with reasonable out-of-pocket costs for their patients. Physicians need to be aware of patients who do not have drug coverage and who may be looking for lower-cost pharmacy options.

POLICYMAKERS/OTHER STAKEHOLDERS: It is clear that the US Food and Drug Administration must work with drug purchasers to establish track and trace capabilities for the drugs in the distribution channels; however, if patients choose an Internet pharmacy, the track and trace system may not be of any benefit. Physicians and pharmacists need to apply common sense and sound business practices when purchasing medications and acknowledge that any discounts will usually come directly from the drug manufacturers and not from a secondary wholesaler, unless there is something potentially wrong with the medication.

At the end of the day, all healthcare providers need to help educate patients on the dangers of ordering medications over the Internet, and especially ordering drugs without a valid prescription. In particular, if drugs are in short supply, the potential for counterfeit drugs increases, and all purchasers and policymakers need to be aware of the risk of fraud when drug supply is a problem.

Blackstone and colleagues are absolutely correct in their warning to patients regarding the purchase of drugs online: caveat emptorâ&#x20AC;&#x201D;let the buyer beware. n

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NEW DATA AVAIL ABLE

WHAT

OUTCOMES

DO YOUR PATIENTS WANT FROM THEIR RA TREATMENT?

INDICATION â&#x20AC;˘ XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). â&#x20AC;˘ Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

IMPORTANT SAFETY INFORMATION Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Lymphoma and other malignancies have been observed in patients treated with XELJANZ.

Please see additional Important Safety Information and brief summary of full Prescribing Information, including boxed warning, on the following pages.

Indicated for adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX)

MEANINGFUL ONES XELJANZ DELIVERS POWERFUL EFFICACY

1,2

3,4

XELJANZ, AS MONOTHERAPY, REDUCED SIGNS AND SYMPTOMS OF RA3,4 — In ORAL Start, XELJANZ demonstrated statistically significantly superior ACR70 response rates vs MTX at 6 months, 25% vs 12%, respectively, and were sustained at 1 year, 29% vs 15%, respectively (p≤0.001)3,5 — In ORAL Solo, ACR20/50/70 response rates for XELJANZ at 3 months were 59%,*† 31%,* 15% ‡ vs placebo 26%, 12%, 6% (*p<0.001, ‡ p<0.01)4,6,7

XELJANZ REDUCED THE PROGRESSION OF JOINT DAMAGE4 ORAL START–STUDY VI

6 MONTHS

INHIBITION OF JOINT DAMAGE IN MTX-NAÏVE PATIENTS1,4 p<0.001 vs MTX

ORAL SCAN–STUDY IV

6 MONTHS

REDUCTION OF JOINT DAMAGE IN MTX-IR PATIENTS4,8 p= 0.0792 (Not statistically significant)

XELJANZ is not indicated in MTX-naïve patients.4 Mean change from baseline in mTSS was a primary end point at 6 months.4 MTX dose started at 10 mg/week, titrated by 5 mg every 4 weeks as tolerated to 20 mg/week by week 8.1

Mean change from baseline in mTSS was a primary end point at 6 months.4

— In ORAL Start, XELJANZ, as monotherapy, was statistically significantly superior to MTX, providing a greater inhibition of progression of joint damage out to 1 year (mean change from baseline in mTSS for XELJANZ was 0.4 vs MTX, 1.3) (p<0.001)3,4 — In ORAL Scan, XELJANZ reduced mean progression of joint damage as measured by mean change from baseline in mTSS compared to placebo at 6 months, but the result was not statistically significant4,8 Primary end point. mTSS=modified Total Sharp Score.

IR=inadequate responder.

†

IMPORTANT SAFETY INFORMATION (cont’d)

WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Please see additional Important Safety Information and brief summary of full Prescribing Information, including boxed warning, on following pages.

To schedule a presentation, contact your Pfizer Account Representative or e-mail payer1069@pfizer.com Study Designs (ORAL Start–Study VI) results of a 24-month, randomized, multicenter, double-blind, parallel-group trial (N=952) that compared XELJANZ to MTX in patients with active RA who were MTX-naïve, and received XELJANZ 5 mg BID or 10 mg BID or MTX. The co-primary end points at month 6 were mean change from baseline in van der Heijde-mTSS and ACR70 response rate.4 (ORAL Scan–Study IV) results of a 24-month, randomized, double-blind, placebo-controlled, multicenter trial in which 797 patients with moderately to severely active RA who had an inadequate response to MTX received XELJANZ 5 mg BID or 10 mg BID or placebo added to background MTX. The co-primary end points were ACR20 response, mean change from baseline in mTSS, and DAS28-4(ESR) <2.6 at month 6, and HAQ-DI improvement at month 3.4 (ORAL Solo–Study I) results of a 6-month, randomized, double-blind, controlled, multicenter monotherapy trial in which 610 patients with moderately to severely active RA who had an inadequate response to a biologic or nonbiologic DMARD received XELJANZ 5 mg twice daily or 10 mg twice daily or placebo.4

The recommended dose of XELJANZ is 5 mg twice daily.4 For full Prescribing Information, visit XeljanzPI.com.

IMPORTANT SAFETY INFORMATION (cont’d)

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus–associated posttransplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients: References: 1. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. In press.

2. Bruynesteyn K, van der Linden S, Landewé R, et al. Progression of rheumatoid arthritis on plain radiographs judged differently by expert radiologists and rheumatologists. J Rheumatol. 2004;31:1088-1094. 3. Supplement to: Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. In press. 4. XELJANZ® (tofacitinib) Prescribing Information. New York, NY: Pfizer Inc; 2014.

5. Data on file. Pfizer Inc, New York, NY. 6. Fleischmann R, Kremer J, Cush J, et al; for the ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507. 7. Supplement to: Fleischmann R, Kremer J, Cush J, et al; for the ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495-507. doi: 10.1056/NEJMoa1109071. 8. van der Heijde D, Tanaka Y, Fleischmann R, et al; and the ORAL Scan Investigators. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate. Arthritis Rheum. 2013;65(3):559-570.

• with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.

VISIT XELJANZOUTCOMES.COM

IMPORTANT SAFETY INFORMATION WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus–associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

SERIOUS INFECTIONS The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, and urinary tract infection. Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment before initiating XELJANZ in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis (TB); • with a history of a serious or an opportunistic infection; • who have lived or traveled in areas of endemic TB or mycoses; or • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.

Tuberculosis Evaluate and test patients for latent or active infection before administration of XELJANZ. Consider anti-TB therapy prior to administration of XELJANZ in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Treat patients with latent TB with standard therapy before administering XELJANZ. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (eg, herpes zoster), was observed in clinical studies with XELJANZ. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ. MALIGNANCY and LYMPHOPROLIFERATIVE DISORDERS Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy.

In the 7 controlled rheumatoid arthritis clinical studies, 11 solid cancers and 1 lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure.

Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids,

and mycophenolic acid products, Epstein Barr Virus–associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in rheumatoid arthritis clinical trials, although the role of JAK inhibition is not known. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (eg, patients with a history of diverticulitis).

LABORATORY ABNORMALITIES Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at 1 month of exposure followed by a gradual decrease in mean lymphocyte counts of approximately 10% during 12 months of therapy. Counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.

Lipid Elevations Treatment with XELJANZ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks.

Assess lipid parameters approximately 4-8 weeks following initiation of XELJANZ therapy, and manage patients according to clinical guidelines for the management of hyperlipidemia.

VACCINATIONS Avoid use of live vaccines concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

HEPATIC IMPAIRMENT Use of XELJANZ in patients with severe hepatic impairment is not recommended.

ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infections (4.5%, 3.3%), headache (4.3%, 2.1%), diarrhea (4.0%, 2.3%), and nasopharyngitis (3.8%, 2.8%).

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

Please see brief summary of full Prescribing Information, including boxed warning, on the following pages.

TRA644402-01

© 2014 Pfizer Inc.

May 2014

All rights reserved.

XELJANZ® (tofacitinib) BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. WARNING: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with XELJANZ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virusassociated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

INDICATIONS AND USAGE • XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).

• Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster and urinary tract infection. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.

Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis, coccidioidomycosis, and listeriosis).

Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients: •

with chronic or recurrent infection

•

who have been exposed to tuberculosis

•

with a history of a serious or an opportunistic infection

•

who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or

•

with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Tuberculosis Patients should be evaluated and tested for latent or active infection prior to administration of XELJANZ.

Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection.

Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Lipid Elevations Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Manage patients according to clinical guidelines [e.g., National Cholesterol Education Program (NCEP)] for the management of hyperlipidemia.

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ. Malignancy and Lymphoproliferative Disorders Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy.

Malignancies were observed in clinical studies of XELJANZ. In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure.

Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known.

XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Laboratory Abnormalities Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Avoid initiation of XELJANZ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3 treatment with XELJANZ is not recommended.

Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.

Avoid initiation of XELJANZ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended.

Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia Avoid initiation of XELJANZ treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.

Monitor hemoglobin at baseline and after 4–8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.

Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

Vaccinations No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. Avoid use of live vaccines concurrently with XELJANZ. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

ADVERSE REACTIONS Clinical Trial Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily.

The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections.

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.

Overall Infections In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.

Tuberculosis In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median

XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).

In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

Opportunistic Infections (excluding tuberculosis) In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.

In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

Malignancy In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.

Laboratory Abnormalities Lymphopenia In the controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm were associated with an increased incidence of treated and serious infections.

3

Neutropenia In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.

Liver Enzyme Elevations Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.

In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

• Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

• Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

Serum Creatinine Elevations In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the table below.

Adverse Reactions Occurring in at Least 2% or More of Patients on 5 or 10 mg Twice Daily XELJANZ With or Without DMARD (0-3 months) and at Least 1% Greater Than That Observed in Patients on Placebo XELJANZ 5 mg Twice Daily Preferred Term

XELJANZ 10 mg Twice Daily*

N = 1336 (%) N = 1349 (%)

Placebo N = 809 (%)

Diarrhea

4.0

2.9

2.3

Nasopharyngitis

3.8

2.8

2.8

Upper respiratory tract infection

4.5

3.8

3.3

Headache

4.3

3.4

2.1

Hypertension

1.6

2.3

1.1

N reflects randomized and treated patients from the seven clinical trials *The recommended dose of XELJANZ is 5 mg twice daily.

Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies I-V. DRUG INTERACTIONS Potent CYP3A4 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).

Moderate CYP3A4 and Potent CYP2C19 Inhibitors Tofacitinib exposure is increased when XELJANZ is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).

Potent CYP3A4 Inducers Tofacitinib exposure is decreased when XELJANZ is coadministered with potent CYP3A4 inducers (e.g., rifampin).

Immunosuppressive Drugs There is a risk of added immunosuppression when XELJANZ is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose XELJANZ with potent immunosuppressives has not been studied in rheumatoid arthritis. Use of XELJANZ in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic effects: Pregnancy Category C. There are no adequate and wellcontrolled studies in pregnant women. XELJANZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).

In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced.

No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects.

In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).

Nonteratogenic effects: In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).

Pregnancy Registry: To monitor the outcomes of pregnant women exposed to XELJANZ, a pregnancy registry has been established.

Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

Nursing Mothers Tofacitinib was secreted in milk of lactating rats.

It is not known whether tofacitinib 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 tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.

Pediatric Use The safety and effectiveness of XELJANZ in pediatric patients have not been established.

Geriatric Use Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Hepatic Impairment XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib levels than XELJANZ-treated patients with normal hepatic function. Higher blood levels may increase the risk of some adverse reactions; therefore, XELJANZ dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. XELJANZ has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ in patients with severe hepatic impairment is not recommended. No dose adjustment is required in patients with mild hepatic impairment. The safety and efficacy of XELJANZ have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

Renal Impairment XELJANZ-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than XELJANZ-treated patients with normal renal function; therefore, XELJANZ dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, XELJANZ was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the CockroftGault equation) less than 40 mL/min. No dose adjustment is required in patients with mild renal impairment.

OVERDOSAGE Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans There is no experience with overdose of XELJANZ. Treatment or Management of Overdose Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.

There is no specific antidote for overdose with XELJANZ. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.

This brief summary is based on XELJANZ® (tofacitinib) Prescribing Information LAB-0445-5.0 Issued: March 2014

© 2014 Pfizer Inc.

All rights reserved.

April 2014

clinical

Review Article

Salsalate, an Old, Inexpensive Drug with Potential New Indications: A Review of the Evidence from 3 Recent Studies Kenneth Anderson, DO; Lance Wherle, DO; Min Park, DO; Kenneth Nelson, DO; Loida Nguyen, PharmD, BCPS Background: Diabetes is a well-known growing epidemic, but prediabetes is increasing at an even greater rate. Lifestyle changes are effective tools to prevent the progression of prediabetes to diabetes, yet many people are unable to follow such changes. Salsalate has been suggested as a possible treatment for diabetes as early as 1876 and as recently as in a 2013 study.

Objective: To review the recently published evidence about the potential therapeutic benefits of the old drug salsalate for individuals who meet the criteria of having prediabetes.

Discussion: With the rising incidence of obesity and prediabetes, it has become prudent to look for more therapeutic options. Salsalate belongs to the salicylate drug class, which has been shown to inhibit I-κB kinase, thereby inhibiting the nuclear factor-κB (NF-κB) cascade and decreasing the production of inflammatory cytokines, as well as decreasing insulin resistance. Recent short-term clinical trials have shown that 3 g to 4.5 g of salicylate therapy daily has the ability to lower insulin resistance and to reduce the levels of glucose, triglycerides, and free fatty acid concentrations through regulation of the I-κB kinase beta/NF-κB pathway, with few if any side effects. However, the effectiveness of salsalate as a treatment option for prediabetes is largely unrecognized. This article summarizes the current evidence from 3 studies of salsalate therapy in the setting of the prediabetic population and presents the case for its use in this population.

Conclusion: As shown in this review, salsalate therapy at the dose of 3 g to 4.5 g daily can lower insulin resistance and reduce the levels of glucose, triglycerides, and free fatty acid concentrations with minimal side effects. This inexpensive medication could be a useful option in the treatment of prediabetes. Larger clinical trials are needed, but the data are encouraging and should lay the foundation for further investigation and grant funding.

O

besity and the metabolic syndrome are significant diseases that increase the risk for developing prediabetes and diabetes.1 Prediabetes is defined as blood glucose levels that are higher than normal but not high enough for a diagnosis of diabetes. Patients with prediabetes usually have impaired glucose tolerance, impaired fasting glucose, or both.2 According to the American Diabetes Association (ADA) criteria, impaired glucose tolerance is defined as a 2-hour glucose level of 140 mg/dL to 199 mg/dL on the 75-g oral glucose tolerance test. The

Dr Anderson is Chief Resident, Touro University-Nevada College of Osteopathic Medicine/Valley Hospital Medical Center; Dr Wherle is Senior Medical Resident, Touro University-Nevada College of Osteopathic Medicine/Valley Hospital Medical Center; Dr Park is Senior Medical Resident, Touro University-Nevada College of Osteopathic Medicine/Valley Hospital Medical Center; Dr Nelson is Senior Medical Resident, Ohio University, College of Osteopathic Medicine/Valley Hospital Medical Center; Dr Nguyen is Clinical Pharmacy Specialist, VA Southern Nevada Healthcare System; all in Las Vegas, NV.

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2014;7(4):231-235 www.AHDBonline.com Disclosures are at end of text

ADA defines impaired fasting glucose as a fasting blood glucose level ranging from 100 mg/dL to 125 mg/dL.2 Both impaired glucose tolerance and impaired fasting glucose are associated with altered insulin sensitivity and carry a risk for the progression to diabetes.2 The 3 disease states—obesity, metabolic syndrome, and prediabetes—exist in a state of chronic inflammation, leading to the production of inflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP), and others.

Nuclear factor-κB (NF-κB) is also known to be elevated in patients with 1 of these 3 conditions, thereby increasing the production of many of the same inflammatory cytokines.3 Increased cytokine production, in turn, interferes with the regulation of glucose and insulin and may promote the progression of prediabetes to diabetes.4 With the progression to diabetes comes increased mor­ bidity and mortality from other diseases, such as coronary artery disease, stroke, blindness, and kidney disease.1,5 It has been documented that patients with prediabetes have a 15% to 30% risk for developing type 2 diabetes within 5 years and a 50% risk for progressing to diabetes

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Key Points The prevalence of prediabetes is rising, and with it the need for novel options to prevent the progression to diabetes, especially for obese patients. ➤ Although lifestyle changes are effective for this purpose, many people cannot adhere to these changes and medications are often needed. ➤ Salsalate is an old and inexpensive medication that belongs to the salicylate drug class, which has been shown to lower insulin resistance and reduce glucose levels, triglycerides, and free fatty acid concentrations, with minimal adverse effects. ➤ Recent short-term trials have shown that 3 g to 4.5 g of salicylate therapy daily can be effective for patients with prediabetes. ➤ When given as an anti-inflammatory therapy, salsalate reduced glycemic markers and improved the inflammatory markers in young, obese patients without diabetes. ➤ The effectiveness of salsalate as a treatment option for prediabetes is largely unrecognized by the medical community. ➤ Large clinical trials may help to establish the benefit of this inexpensive approach. ➤

within 10 years, without proper intervention.2,6 By 2030, the number of individuals with prediabetes is expected to be 472 million worldwide, leading to a large burden on society and on the healthcare system.7 Lifestyle modifications related to diet and exercise have been shown to delay or to possibly prevent the progression to diabetes in at-risk individuals.8 In addition, certain medications (eg, metformin and acarbose) have been shown to be effective in preventing or delaying the progression of prediabetes to diabetes.8-11

The History of Salsalate Salicylates, known as one of the oldest drugs used by clinicians, were first mentioned in the 5th century BC by Hippocrates when he described a bitter powder extract from willow bark that eased aches and pains and reduced fevers. The active extract salicin was first isolated by the German chemist Johann Andreas Buchner in 1828.12 Salicylates exist in 2 different forms—the prototypical acetylated form aspirin, and the nonacetylated form salsalate. Aspirin, which inhibits NF-κB, also inhibits cyclooxygenase enzymes, leading to alterations in bleeding time, platelet aggregation, and gastric irritation, which may cause side effects especially at increased dosages.13 Salsalate, which typically has been used to treat inflammatory conditions, such as rheumatoid arthritis, os-

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teoarthritis, and other rheumatologic conditions, only weakly inhibits the cyclooxygenase pathway secondary to the lack of an acetyl group, but it is a strong inhibitor of the NF-κB pathway.14 NF-κB is stored in an inactivated state in the cytoplasm of cells by the binding of IκB inhibitor proteins. These IκBs can be phosphorylated and deactivated by the IκB kinase.15,16 Salicylates have been shown to inhibit IκB kinase, thereby inhibiting the NF-κB cascade and decreasing the production of inflammatory cytokines (eg, IL-6, TNF-alpha, and CRP) and decreasing insulin resistance.14 Salsalate has been suggested as a possible treatment for diabetes as early as 1876 and as recently as in a 2013 study by Goldfine and colleagues.17 With the rising incidence of obesity and prediabetes, it has become prudent for more therapeutic options to be available. Short-term trials show that 3 g to 4.5 g of salicylate therapy daily has the ability to lower insulin resistance and to reduce the levels of glucose, triglycerides, and free fatty acid concentrations through the regulation of the IκB kinase beta/ NF-κB pathway, with few if any side effects.4,17-22 Nevertheless, the effectiveness of salsalate as a treatment option for prediabetes is largely unrecognized. This article summarizes the currently available data from 3 recent studies on the impact of salsalate therapy on the population of individuals with prediabetes.

Clinical Data from 3 Recent Clinical Trials Trial 1: Goldfine and Colleagues (2013) In a recent study by Goldfine and colleagues, 78 participants were enrolled in a 12-week, randomized, placebo-­ controlled study at the Phoenix and Boston VA Health Care systems.4 The purpose of the study was to evaluate whether using salsalate at its maximum safe dose in patients who are at risk for diabetes could improve their insulin resistance and other metabolic abnormalities.

Patients were eligible to be included in the study if they had an abnormal glucose tolerance test result or an abnormal fasting glucose level.4 This trial mostly involved men, with only 3 women in both arms of the study. Persons were excluded if they were less than 80% compliant with the 3-week placebo run-in, or if they were not able to attend the scheduled study visits. Throughout the duration of the study, the participants’ weight, blood pressure (BP), oral glucose tolerance test, fasting blood lipids, inflammatory markers, endothelial function, and insulin sensitivity using a hyperinsulinemic clamp were monitored to evaluate the effects of salsalate.4 The investigators found a 6% reduction in fasting glucose compared with placebo and declines in fasting C-peptide level, insulin clearance, and triacylglycerol levels in participants taking a mean dose of 3.7 g of sal-

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Table Salsalate versus Placebo in Obese Patients with Prediabetes Patients receiving placebo (N = 28) Baseline Postintervention P value Metabolic values

Patients receiving salsalate (N = 26) Baseline

Postintervention P value

Systolic blood pressure, mm Hg

122.7

124.6

.4

122.9

112.7

.01

Fasting plasma glucose, mg/dL

104.4

99.5a

.06

105.5

93.6a

.01

4.5

4.4a

.1

4.2

3.8a

.01

HOMA-B, μIU/mL/mmol/L

154.7

180.2

.2

139.8

189.4

.1

LDL cholesterol, mg/dL

102.5

94

.1

92

102.1

.01

HOMA-IR, mmol/L/μIU/mL

P <.05 between the 2 groups, which were compared at the end of the study.

HOMA-B indicates homeostasis model assessment of beta-cell function; HOMA-IR, homeostasis model assessment of insulin resistance; LDL, low-density lipoprotein.

Source: Faghihimani E, Aminorroaya A, Rezvanian H, et al. Reduction of insulin resistance and plasma glucose level by salsalate treatment in persons with prediabetes. Endocr Pract. 2012;18:826-833.

a

salate daily. They also showed a decrease in adipose tissue NF-κB and an increase in adiponectin in the salsalate group. Many of these metabolic markers were not significantly different from the control group; however, the study was able to show a significant difference (P = .006) in the level of fasting glucose between the 2 arms of the study. Of note was the reduced insulin clearance that was seen during the use of the hyperinsulinemic clamp, which suggests that there was not a significant difference (P = .9) between the C-peptide level in either arm; this also points to the need for further investigation of salsalate’s mechanism of action on glucose.4

Trial 2: Faghihimani and Colleagues (2012) In the second recent trial, 66 prediabetic individuals were assigned to receive 3 g of salsalate or placebo for 12 weeks.21 The participants were instructed to consume an unrestricted diet consisting of at least 150 g of carbohydrates daily and to avoid heavy physical activity for at least 3 days before their laboratory tests. This study tested the hypothesis that giving salsalate to persons with prediabetes increases insulin sensitivity, stimulates basal insulin secretion, and thus improves glucose-insulin homeostasis.21 The measurement used to gauge insulin sensitivity is the homeostasis model assessment of insulin resistance (HOMA-IR). The HOMA-IR is calculated using the fasting plasma glucose (mmol/L) multiplied by insulin (μIU/mL) divided by 22.5. The HOMA-IR scores in the treatment group decreased from 4.2 to 3.8 (P = .01) after 12 weeks of intervention; the change in HOMA-IR score in the placebo group was insignificant, from 4.5 to 4.4 (Table).21 The study used the homeostasis model assessment of beta-cell function (HOMA-B) as an indirect estimate of beta-cell function. This is calculated using fasting insulin (μIU/mL) × 20/[fasting plasma glucose (mmol/L) – 3.5].

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By the end of the study, the HOMA-B score increased in the treatment group and much less so in the placebo group (Table).21 The secondary laboratory values that showed a significant difference with the intervention included systolic BP, fasting plasma glucose, and low-density lipoprotein (LDL) cholesterol. Systolic BP decreased in the treatment group from 122.9 mm Hg to 112.7 mm Hg but increased slightly, from 122.7 mm Hg to 124.6 mm Hg (P = .4), in the placebo group. The fasting plasma glucose decreased significantly (P = .01) in the group receiving salsalate and insignificantly (P = .06) in the placebo group. Surprisingly, the LDL cholesterol levels showed a negative trend in the salsalate group but a positive trend in the placebo group (Table).

The secondary laboratory values that showed a significant difference with the intervention included systolic BP, fasting plasma glucose, and low-density lipoprotein cholesterol.

Other variables that were investigated but did not show a significant difference between the 2 groups included age, waist size, body mass index (BMI), diastolic BP, 2-hour plasma glucose, insulin level, hemoglobin A1c, triglycerides, total cholesterol, and high-density lipoprotein cholesterol.21

Trial 3: Fleishman and Colleagues (2008) In the third study comparing salsalate and placebo, by Fleishman and colleagues, salsalate reduced glycemia and improved inflammatory cardiovascular risk indexes in overweight individuals.22 This study investigated salsalate as an anti-inflammatory modulator and its effects on glycemic, inflammatory, and lipid markers.

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The study population consisted of nondiabetic obese individuals aged <30 years with a BMI ≥30 kg/m2. Participants in the salsalate group received a high dose, 4 g daily, of the active drug. Salicylate levels were therapeutic throughout the study in the salsalate group but were undetectable in the placebo group.22 The results showed that fasting glucose had decreased 8% in the salsalate group compared with a 5% increase in the placebo group (P <.002), with significant decreases in other glycemic markers, including 75-g oral glucose tolerance test area under the curve (–20%; P <.003) and glycated albumin (–16%; P <.003). Fasting and oral glucose tolerance test insulin levels remained unchanged in both groups, with the exception of the decrease in C-peptide of 24% in the salsalate group and an increase of 55 in the placebo group (P <.01). Insulin sensitivity was also addressed in this study using the calculation of HOMA-IR, which decreased 39%. By contrast, insulin levels increased 21% in the salsalate group compared with the placebo group (P <.05).22 Regarding the inflammatory parameters in the salsalate and the placebo groups, adiponectin increased by 56% with salsalate and decreased 1% in the placebo group, whereas free fatty acid and CRP markers showed no significant change. Salsalate independently predicted change in fasting blood glucose, response to an oral glucose tolerance test, and glycated albumin, with adjustment for adiponectin, free fatty acids, and CRP after multiple regression analysis.22 The side effects reported in this study included tinnitus, headache, rash, and transient elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). A total of 3 patients reported side effects, with 2 patients from the salsalate group. Dose reductions in the 2 patients resolved the side effects. The AST and ALT elevations resolved spontaneously.22 Overall, the administration of salsalate as an anti-inflammatory therapy was shown to reduce glycemic markers in this study, as well as to improve inflammatory markers in young, obese patients without diabetes. This study had a short duration and a small sample size, but it was consistent with the hypothesis of improved dysglycemia secondary to the treatment of inflammation.

The mechanism by which salsalate reduced glycemic markers was theorized by the authors to be the inhibition of the I-κB/NF-κB pathway, although this effect was not evaluated during the study.22

Conclusion Diabetes is a growing epidemic, but prediabetes is increasing at an even higher rate. Lifestyle changes are effective tools to prevent the progression of prediabetes to diabetes. However, this method is difficult to sustain

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lifelong; therefore, medications are sometimes needed to aid patients in their fight against glucose dysregulation.

One unrecognized therapeutic intervention is salsalate.

As demonstrated in the 3 recent trials discussed here, the use of salsalate therapy, at doses of 3 g to 4.5 g daily, has the ability to lower insulin resistance and reduce the levels of glucose, triglycerides, and free fatty acid concentrations through the regulation of the I-κB/NF-κB pathway, with minimal side effects. This medication, which costs pennies a day, could be a useful and cost-efficient option in the treatment of individuals with prediabetes and the prevention of progression to diabetes.

Larger clinical trials are needed to convince the medical community of the benefits of this medication for the prevention of diabetes in high-risk individuals. The data presented here are encouraging and should lay the foundation for further investigation and grant funding. n Author Disclosure Statement Dr Anderson, Dr Wherle, Dr Park, Dr Nelson, and Dr Nguyen have no conflicts of interest to report.

References

1. National Diabetes Information Clearinghouse (NDIC). Insulin resistance and prediabetes. http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/#relate2014.

Accessed June 1, 2014.

2. American Diabetes Association. Standards of medical care in diabetes—2014.

Diabetes Care. 2014;37(suppl 1):S14-S80.

3. Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IκK-beta and NF-kappaB. Nat Med. 2005;11:183-190.

4. Goldfine AB, Conlin PR, Halperin F, et al. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia. 2013;56:714-723.

5. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).

Circulation. 2007;116:151-157.

6. Centers for Disease Control and Prevention. Diabetes public health resource: prediabetes. Updated August 13, 2012. www.cdc.gov/diabetes/consumer/prediabetes. htm. Accessed March 16, 2014.

7. Tabák AG, Herder C, Rathmann W, et al. Prediabetes: a high-risk state for diabetes development. Lancet. 2012;379:2279-2290.

8. Knowler WC, Barrett-Connor E, Fowler SE, et al; for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

9. Diabetes Prevention Program (DPP) Research Group. The Diabetes Prevention Program (DPP): description of lifestyle intervention. Diabetes Care. 2002;25:2165-2171.

10. Chiasson JL, Josse RG, Gomis R, et al; for the STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077.

11. Yang WY, Lixiang L, Jinwu Q, et al. The preventive effect of acarbose and metformin on the progression to diabetes mellitus in the IGT population: a 3-year multicentre prospective study. Chin J Endocrinol Metab. 2001;17:131-136.

12. Jack DB. One hundred years of aspirin. Lancet. 1997;350:437-439.

13. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110:255-258.

14. Hayden MS, Ghosh S. NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 2012;26:203-234.

15. Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006;25:6680-6684.

16. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998;396:77-80.

17. Goldfine AB, Fonseca V, Jablonski KA, et al; for the Targeting Inflammation Using Salsalate in Type 2 Diabetes Study Team. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2013;159:1-12.

18. Kim JK, Kim YJ, Fillmore JJ, et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest. 2001;108:437-446.

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19. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Iκkbeta. Science.

2001;293:1673-1677. Erratum in: Science. 2002;295:277.

20. Hundal RS, Petersen KF, Mayerson AB, et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002;109:1321-1326.

21. Faghihimani E, Aminorroaya A, Rezvanian H, et al. Reduction of insulin resistance and plasma glucose level by salsalate treatment in persons with prediabetes.

Endocr Pract. 2012;18:826-833.

22. Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care. 2008;31:289-294.

Stakeholder Perspective Considering Salsalate Use in Patients at Risk for Diabetes

By Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology, and Adjunct Associate Professor of Endocrinology, Touro University Nevada

PAYERS: Newly released 2012 data from the Centers for Disease Control and Prevention estimated that nearly 30 million Americans (9.3% of the US population) currently have diabetes.1 Approximately 8 million of these people do not know that they have diabetes.

Another 86 million people (37% of US adults) are estimated to have prediabetes, a condition in which blood glucose levels are higher than normal but are not high enough to be classified as diabetes. The rates of prediabetes are similar for non-Hispanic whites (35%), non-Hispanic blacks (39%), and Hispanics (38%).1 Individuals with prediabetes are at an increased risk for type 2 diabetes, heart disease, and stroke.2 Without intervention (ie, lifestyle, drugs), 9% to 50% of them will progress to diabetes within 5 years.3 In 2012, diabetes cost the United States an estimated $245 billion—$176 billion in direct medical costs and $69 billion in indirect costs (ie, disability, work loss, premature death)—a 40% increase from 2007.1 Many studies have shown that early intervention can decrease the rate of progression from prediabetes to diabetes.4-7 The American Diabetes Association recommends lifestyle modification as the primary intervention in patients with prediabetes,8 a cheap and effective option with relatively no adverse effects. For those not responding to or unable to follow lifestyle modifications, pharmacologic options include metformin, acarbose, thiazolidinediones, and orlistat.

Anderson and colleagues review 3 recent studies regarding salsalate, an anti-inflammatory medication, as another treatment option for patients with prediabetes.

These short-term trials showed that 3 g to 4.5 g of salsalate daily can lower insulin resistance and reduce glucose, triglycerides, and free fatty acid concentrations with minimal side effects. Their data demonstrate that salsalate is also effective in patients with diabetes9,10;

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however, its effectiveness is relatively weak compared with current medications approved for diabetes.

The most effective use of this drug, therefore, would be in individuals with prediabetes, where glucose dysregulation is not as severe as in diabetes. Long-term studies are needed to evaluate the sustainability of this treatment option.

PATIENTS: Patients with prediabetes have an increased risk for diabetes, but not everyone will progress to diabetes. Evidence has shown that the glucose dysregulation at this stage is reversible with weight loss, changes in diet, and exercise.4,5 Modest weight loss (5%-10% of body weight), moderate-intensity exercise (30 minutes daily), and the use of pharmaceutical agents are proved interventions that can prevent the progression to diabetes.4-7 Salsalate may possibly be another option in the treatment repertoire for patients with prediabetes. n 1. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. www.cdc.gov/diabetes/ pubs/statsreport14/national-diabetes-report-web.pdf. Accessed June 12, 2014.

2. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).

Circulation. 2007;116:151-157.

3. Zhang X, Gregg EW, Williamson DF, et al. A1c level and future risk of diabetes: a systemic review. Diabetes Care. 2010;33:1665-1673.

4. Knowler WC, Barrett-Connor E, Fowler SE, et al, for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

5. Tuomilehto J, Lindström J, Eriksson JG, et al, for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.

6. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes. 2002;51:2796-2803.

7. Chiasson JL, Josse RG, Gomis R, et al, for the STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet. 2002;359:2072-2077.

8. American Diabetes Association. Standards of medical care in diabetes—2014.

Diabetes Care. 2014;37(suppl 1):S14-S80.

9. Goldfine AB, Fonseca V, Jablonski KA, et al. Salicylate (salsalate) in patients with type 2 diabetes: a randomized trial. Ann Intern Med. 2013;159:1-12.

10. Faghihimani E, Aminorroaya A, Rezvanian H, et al. Salsalate improves glycemic control in patients with newly diagnosed type 2 diabetes. Acta Diabetol. 2013;50:537-543.

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Please mark the categories that apply to your expertise: Administration/management Benefit design Disease management/state (eg, asthma, diabetes, heart disease, infectious diseases, pain management, etc) Drug therapy (including biologics, generics) Drug utilization Employers/health plans Finance/health economics Health information technology Health policy/reform Patient education/initiatives/quality-of-life issues Payer perspectives Pharmacoeconomics analyses Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits Reimbursement: Medicare/Medicaid, health insurance, prior authorization Research: methods, study design, data collection/analysis

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Pharmacy Management and Health Economics Outcomes

By Kate O’Rourke, Medical Writer

The following summaries highlight some of the key posters presented at the 26th Annual Meeting of the Academy of Managed Care Pharmacy (AMCP),

April 1-4, 2014, in Tampa, FL, focusing on areas of interest for payers, employers, drug manufacturers, providers, and other healthcare stakeholders.

Pharmacist-Provider Collaborative Care Model Improves Diabetes Outcomes A pharmacist-run medication therapy management (MTM) program in association with the provider can improve outcomes for patients with high-risk diabetes, according to a study by Nicole Hancy, PharmD, Director of Clinical Services, WellDyneRx, and colleagues. The investigators set out to evaluate the impact of a collaborative MTM program between a large managed Medicaid group and WellDyneRx, a full-service prescription benefit manager in Englewood, CO. WellDyneRx provides services to health plan members through a retail network of more than 65,000 pharmacies nationwide. The use of a targeted letter-writing campaign to physicians led to improved medication adherence in approximately 50% of the patients with diabetes who were identified as nonadherent to their diabetes medications.

“Pharmacists involved in a team-based care model can have positive contributions to patient care and safe medication use,” said Dr Hancy. “Our program promoted partnerships between the pharmacist and healthcare provider to enhance communication, improve collaboration among all parties involved, and, ultimately, optimize diabetes therapeutic outcomes.”

The study population included 244 patients with diabetes, defined as hemoglobin (Hb) A1c ≥9%, who were involved in an MTM program. In this program, a clinical pharmacist was linked to a primary care physician to perform a comprehensive medication review of patients with diabetes every 3 to 4 months. Pharmacists identified patients who were not adherent to their medication, had gaps in care, and/or lacked appropriate follow-up for HbA1c testing.

Nonadherence was measured by medication possession ratio (MPR); gaps in care, defined as a necessary change in therapy; and lacking statin, angiotensin-converting enzyme (ACE) inhibitor, or angiotensin receptor blocker

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therapy. Physicians with nonadherent patients received intervention letters from their respective pharmacist identifying medication nonadherence in the patient.

Three months after the intervention letters were sent to the providers of 101 patients with diabetes, the noncompliant patients had an average reduction in HbA1c of 0.8 mg/dL. In another cohort of 74 noncompliant patients, HbA1c was reduced by an average of 1.1 mg/dL 3 months after letters were sent out.

In the cohort of 101 targeted patients, 42 had a reduction in HbA1c, with the average reduction of 1.7 mg/dL. In the cohort of 74 targeted patients, 23 had a reduction in HbA1c, with an average reduction of 2.2 mg/dL. A total of 86 recommendations were made to address medication adherence in the 101-patient cohort, with 57% seeing an improvement in adherence, with an MPR of ≥80%. In the 74-patient cohort, 51 recommendations were made, and 43% of patients had an improvement in medication adherence, with an MPR of ≥80%. Approximately 56% of patients had their HbA1c rechecked when they were alerted to do so by the letters.

Approximately 15% of patients in the 2 cohorts identified as having gaps in care in their drug history were started on corresponding therapy such as ACE inhibitors or statins. However, because clinical information (ie, serum creatinine and comorbid conditions) were not available to the pharmacists, it is unclear whether this low percentage was caused by patients not actually being candidates for the recommendations. The study is ongoing, and the researchers plan to send out provider feedback forms with future intervention letters so that response to the recommendations can be better assessed. n [Poster: Hancy NE, Henderson MA, Taddei-Allen P, Page RN. Impact on pharmacist run medication therapy management program on diabetic patients.]

Continued

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Copay Waiver Incentive Used to Increase Mail-Order Medicines and Medication Adherence Copay incentives can be used to encourage the use of mail order for prescription refills, spurring an increase in medication adherence is the conclusion from a study led

by Nirmal K. Ghuman, PharmD, MPH, Senior Consultant, Analytic Consulting Services, CVS Caremark.

Copay incentives can be used to encourage the use of mail order for prescription refills, spurring an increase in medication adherence.

Previous studies have demonstrated that patients who receive prescription refills through the mail have better medication adherence compared with individuals who refill their medications at local pharmacies. For example, in a 2010 study involving 13,922 patients with diabetes, those who received their medications by mail were more likely to take the drugs as prescribed than those who received their drugs from a pharmacy—84.7% versus 76.9%, respectively (P <.001).1 As a result, healthcare groups have been testing various approaches to incentivize individuals to use mail order for their medications.

In 2008, a large group health plan implemented a unique incentive that allowed households of members using mail-order service in the last 4 months of the plan year to be eligible for a $50 waiver. The waiver could be used for household copays at local pharmacies during the next plan year. Individuals could qualify for the incentive annually if they continued to use mail order for their medications.

In the new study, Dr Ghuman and colleagues evaluated the impact of the retail copay waiver on long-term

medication adherence and mail-dispensing rate. The team reviewed the annual average medication possession ratio (MPR) from 2007 to 2012 for medications used for several chronic conditions, including hypertension, hyperlipidemia, diabetes, asthma/chronic obstructive pulmonary disease (COPD), and heart failure.

The plan had an average of 30,000 members throughout the study period. The average member age was 80.2 years, and approximately 30% were male. On average, 14.9% of the plan’s population participated in the retail waiver program from 2008 to 2012.

The researchers found that the mail-dispensing rate increased over the study period, and the medication adherence improved for each of the 5 chronic conditions examined. Compared with 2007, the MPR in 2012 was increased by approximately 1% for medications for hypertension, hyperlipidemia, heart failure, and diabetes.

For asthma/COPD medications, the MPR rose from approximately 59% in 2007 to almost 64% in 2012.

The researchers concluded that other clients may want to consider providing similar retail copay waivers to promote mail utilization and to improve medication adherence. Future research will attempt to determine whether there are certain member characteristics or demographics that make patients more likely to participate in the retail copay waiver program. n 1. Duru OK, Schmittdiel JA, Dyer WT, et al. Mail-order pharmacy use and adherence to diabetes-related medications. Am J Manag Care. 2010;16:33-40.

[Poster: Ghuman NK, Shuey R, McGowan J. Impact on long-term adherence and mail dispensing rate of incentivizing utilization of mail through participation in a retail waiver program.]

Coverage Decisions for Genetic Testing and Personalized Medicine Genetic testing and personalized medicine are seen as the waves of the future for many diseases, especially for cancer. Little is known about the current coverage, payers’ attitudes about future expansion of coverage, and the determinants of that coverage.

According to a recent online survey, the majority of payers currently cover at least some genetic testing and personalized medicine, and plan to evaluate the need for expanded coverage of these services, according to the survey.

One of the most important findings from this study is that payers are seeking more pharmacoeconomic data

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that show the value of genetic testing as it relates to the selection of therapy and patient outcomes to make coverage decisions.

“Many of the new medications are specialty pharmaceuticals, and many have genetic tests to go along with them. We wanted to see if payers are onboard with advances in pharmacogenomics. The majority of payers are interested in expanding coverage for these services, but need more pharmacoeconomic data to demonstrate cost-effectiveness,” said lead investigator Nisreen Shamseddine, MS, of Xcenda, Palm Harbor, FL. “Of the 100s of genetic tests listed in the National Com-

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prehensive Cancer Network Biomarker Compendium, decision makers do not know which ones have value. The take-home message of our study is that, overall, genetic testing is important to decision makers, but they are currently operating without full information,” noted coinvestigator Melissa S. Denno, PharmD, MS, Manager, Global Health Economics and Outcomes Research, Xcenda.

The study was based on a double-blind online survey conducted between July 18, 2013, and August 4, 2013. The survey consisted of 28 questions about current and future coverage decisions regarding genetic testing and personalized medicine, including health economic questions.

The 60 respondents included pharmacy and medical directors representing coverage of 107 million lives. Regional plans (60%) and national plans (38%; 2% unspecified) representing commercial, Medicare, and/or Medicaid plans were included. The types of plans included managed care organizations, integrated health delivery systems, preferred provider organizations, and pharmacy benefit managers.

Of the respondents, 90% said that they currently covered some form of genetic testing, with approximately 40% of plans covering between 76% and 100% of the cost. Slightly more than 83% of the respondents noted that requests for genetic testing from physicians and patients have increased over the past 5 years. In all, 68% of respondents plan to increase coverage for genetic testing over the next 5 years compared with 5% who want to decrease coverage, approximately 17% who want to maintain the same coverage, and 10% who are unsure.

Responding to the question of in which diseases is genetic testing expected to have significant impact on clinical outcomes, 98.3% of respondents identified cancer, 41.7% also identified cystic fibrosis, 26.7% noted HIV/AIDS, 25% indicated cardiovascular disease, and 16.7% added Alzheimer’s disease.

When asked which available biomarkers were currently covered by plans, the 2 most frequently covered were

HER2 for breast cancer (95% of plans) and KRAS mutation testing for metastatic colorectal cancer (91.7%).

Respondents said that literature was scarce about the cost-effectiveness of genetic testing and personalized medicine; 45.7% believe that personalized medicine would increase the cost of care for their plans.

Overall, 38.3% of respondents expressed interest in partnering with pharmaceutical companies in ways such as risk-based contracting or biomarker awareness programs to understand the value of genetic testing in the future.

A large majority (83.4%) of plans believe that genetic testing would dictate decisions about treatment selection. When asked what factors were clinically important for personalized medicine, the 3 most frequently named factors were predicting response to an agent, getting the most effective therapy the first time, and more efficient management of cost.

Respondents were fairly evenly split regarding the requirement for US Food and Drug Administration (FDA) support of genetic tests; 35% would require FDA regulation to cover a pharmacogenomic test, 30% would require at least an FDA recommendation, and 35% said that they would not need the FDA to weigh in on the issue if the scientific evidence were sufficient in support of such testing.

Overall, 38.3% of respondents expressed interest in partnering with pharmaceutical companies in ways such as risk-based contracting or biomarker awareness programs to understand the value of genetic testing in the future. n [Source: Shamseddine N, Denno M, Jackson J. Payers’ perspective on the future of genetic testing and personalized medicine.]

Intravenous Cancer Treatment Pricier in Hospital Outpatient than in Office-Based Setting A new study has demonstrated that intravenous (IV) cancer therapies are more costly, by approximately 10%, when patients receive them in a hospital outpatient setting rather than in a community-based physician office.

The study was presented at the 2014 Academy of Managed Care Pharmacy annual meeting.

Coinvestigator Barbara L. McAneny, MD, Chief Executive Officer and Managing Partner, New Mexico Cancer Center, Albuquerque, said that this research adds

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to the growing evidence that care is more costly in the hospital setting. “As we switch to more high-deductible health plans, out-of-pocket costs per patient go up considerably, which makes cancer care increasingly difficult for patients to afford,” Dr McAneny said. “The current trend of acquisition of practices by hospitals is exactly the wrong direction for the country to be going in at a time when healthcare costs are spiraling out of control.”

This new retrospective analysis was based on pharma-

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cy and medical claims compiled from the HealthCore Integrated Research Database, a database containing information from approximately 32 million members of 14 commercial health plans in the United States. The researchers gathered data from adults aged 18 to 65 years who received IV cancer treatment with a chemotherapy or a biologic agent between January 1, 2006, and August 31, 2012. Patients were included if they had 2 or more medical claims at least 30 days apart for a cancer, no secondary cancer, and at least 6 months of preindex and postindex health plan eligibility.

During a 12-month period, the average total healthcare costs were significantly higher for patients who received treatment in the outpatient setting than in the community setting—$122,473 versus $82,773.

Patients were assigned to a community physician office cohort or a hospital outpatient cohort, depending on where they received at least 95% of their IV treatment.

The researchers focused on 5 different cancer types in 18,740 patients: early breast cancer (47.5%), metastatic

breast cancer (22.1%), non-Hodgkin lymphoma/chronic lymphocytic leukemia (11.9%), metastatic lung cancer (10.1%), and colorectal cancer (8.4%).

During a 12-month period, the average total healthcare costs were significantly higher for patients who received treatment in the outpatient setting than in the community setting—$122,473 versus $82,773 (P <.001).

Patients seen in the outpatient setting also had longer treatment durations—415 days versus 300 days, respectively (P <.001); higher 6-month treatment costs— $103,460 versus $68,792, respectively (P <.001); and higher 12-month treatment costs—$143,206 versus $98,071, respectively (P <.001).

The difference was more acute in the “other outpatient services” category, and the researchers speculate that this could be caused by high reimbursement for facility fees and services in the hospital outpatient setting. After adjusting for baseline characteristics, the average annual costs for patients seen in community offices were 8% lower than for patients seen in a hospital outpatient setting. n [Poster: Fisher MD, Yim YM, Luthra R, et al. Effect of treatment setting on healthcare costs in five major cancer types from a large commercially insured population.]

Costs Increase in Last 6 Months of Life for Patients with Metastatic Breast Cancer Patients with HER2-positive metastatic breast cancer consume 2.5 times more financial resources when they are within 6 months of death, according to a retrospective, observational review based on data from the IMS LifeLink Health Plan Claims Database between January 1, 2002, and June 30, 2012.

The study highlights real-world healthcare resource utilization and costs of patients with HER2-positive metastatic breast cancer who received trastuzumab near the end of life. Patients were excluded if they received lapatinib for first- or second-line therapy. IMS LifeLink is a comprehensive database of integrated medical and pharmacy claims from more than 79 US health plans, for approximately 87 million deidentified lives. The researchers divided the patients into 2 cohorts: 670 patients who were alive at the end of the 6 months of follow-up, and 196 patients who were dead by the end of the 6-month follow-up period.

The investigators calculated costs from the allowed amount on the claims, which were adjusted for inflation to 2012 US dollars. The mean 6-month total healthcare cost was almost 3 times higher in patients who died

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during the predefined period than in patients who were still alive—$69,426 versus $26,857 (95% confidence interval, 3.133; P <.001).

The mean costs were significantly higher for each healthcare component cost measured for those who were dead at the end of the 6-month period and those who were alive: • Inpatient hospital care: $18,883 vs $2706 • Hospice: $2214 vs $2 • Emergency department: $1667 vs $212 • Physician office: $22,816 vs $10,579 • Other outpatient: $18,569 vs $11,056 • Home health/durable medical equipment: $670 vs $210 • Pharmacy: $4659 vs $2092.

In the cohort of patients who died, there was a 20fold increase in inpatient costs and a 14-fold increase in hospice costs between the sixth month and the first month before the end of life. Emergency department cost and home healthcare cost also increased in the last 2 months of life. “The main driver of higher costs during those 2 last months is hospitalization,” said the lead investigator of the study, Thomas J. Bramley, RPh, PhD,

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Senior Vice President, Scientific Consulting, Xcenda.

In the cohort of patients who were still alive at 6 months, the monthly costs were similar throughout the study. The researchers cautioned that results cannot be generalized to patients who were not commercially insured or who had HER2-negative breast cancer.

Amy P. Abernethy, MD, PhD, Palliative Medical Specialist, Director, Duke Cancer Care Research Program, said that the finding that healthcare, especially inpatient care and hospice costs, is more expensive in the last 6 months of life is consistent with other studies. As people get sicker, they need more healthcare, including treatments for cancer and hospitalizations, suggests Dr Abernethy.

Hospice care, which helps keep people out of hospitals, increased in the last 6 months, potentially lowering some of the inpatient costs. The researchers did not provide information on whether the treatments that were provided made “good sense.”

“Part of the problem is that it is really hard to figure out who is going to die and who needs a shift to a hospice

focus and when. We can’t say whether or not there is any signal [in this study] that these women should not have

“The number one take-home message is that we have to get better at figuring out where people are on the curve of prognosis, so that we can help them make good decisions.” been getting therapy, because we don’t actually have a sense of how sick they were at the time of treatment,” Dr Abernethy pointed out. “The number one take-home message is that we have to get better at figuring out where people are on the curve of prognosis, so that we can help them make good decisions.” n [Poster: Bramley T, Cheng Q, Lunacsek O. The economic burden of end-of-life care in metastatic breast cancer.]

VISIT OUR ENHANCED USER-FRIENDLY WEBSITE American Health & Drug Benefits is an independent, peer-reviewed journal founded in 2008 Examines drug and other healthcare intervention value for payers, purchasers, providers, patients, manufacturers, regulators, distributors, and evaluators Provides up-to-date information on new drugs approved by the FDA

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

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

Areas of High Interest: • Health Information Exchange • Health Plan Initiatives • Innovations in Healthcare • Literature Reviews • Managed Care • Medicare/Medicaid • Patient Outcomes/Advocacy • Pharmacoeconomics

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

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

Clinical Topics of High Interest: Aging—With the aging of the US population, there is a growing need for early implementation of outcomes-based preventive and therapeutic strategies for older people.

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

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

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

Cancer care—The growing focus on high-cost biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management.

Cardiovascular disease—Outcomes-based research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

Diabetes, Obesity—The growing epidemics of these twin metabolic conditions mandate a thorough examination of best therapies, adherence issues, access, and prevention strategies.

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

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

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

neurologic disorders—The central nervous system is associated with many complicated medical disorders and an enormous economic burden.

Articles must follow the Manuscript Instructions for Authors at www.AHDBonline.com Submit articles to editorial@engagehc.com or online 242

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Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2014 All rights reserved.

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