Trends in the Utilization of, Spending on, and Prices for Outpatient Antifungal Agents in US Medicaid Programs: 1991–2009

Clinical Therapeutics/Volume 34, Number 10, 2012

Trends in the Utilization of, Spending on, and Prices for Outpatient Antifungal Agents in US Medicaid Programs: 1991–2009 Vibha C. A. Desai, MS1; Teresa M. Cavanaugh, PharmD, MS1; Christina M. L. Kelton, PhD2; Jeff J. Guo, PhD1; and Pamela C. Heaton, PhD1 1

James L. Winkle College of Pharmacy, Academic Health Center, University of Cincinnati, Cincinnati, Ohio; and 2Carl H. Lindner College of Business, University of Cincinnati, Cincinnati, Ohio ABSTRACT Background: The incidence of invasive fungal infections (IFIs) has increased substantially in the recent past. Advances in medical technology, including broad-spectrum antibiotics, may increase the risk for fungal infections. Moreover, immunocompromised patients with cancer, HIV/AIDS, and/or transplants are susceptible to IFIs. Meanwhile, superficial fungal infections (SFIs) are common and can be difficult to cure. Objective: To provide a historical perspective on a dynamic market with expensive medications, this study describes trends in the utilization of, spending on, and average per-prescription spending on outpatient antifungal medications individually, in classes (for IFIs or SFIs), and overall, by the US Medicaid programs from 1991 to 2009. Methods: The publicly available Medicaid State Drug Utilization Data, maintained by the Centers for Medicare & Medicaid Services, were used. Annual prescription counts and reimbursement amounts were calculated for each of the antifungals reimbursed by Medicaid. Average per-prescription spending as a proxy for drug price was calculated by dividing reimbursement by the number of prescriptions. Results: Overall utilization for Medicaid beneficiaries remained steady, with 4.56 million prescriptions in 1991 and 4.51 million in 2009. Expenditures rose from $93.87 million to $143.76 million (in current-year US$) over the same time period. The drop in the utilization of first-generation azoles over the last 5 years of the study period can be explained in part by the movement of dual-eligibles from Medicaid to Medicare Part D and in part to a rise in fungal infections better treated with second-generation azoles or echinocandins. Whereas the average per-prescription price for generic (oral) fluconazole was $8 in 2009, the price per pre-

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scription of branded (intravenous) voriconazole was $2178. Conclusions: Overall spending by Medicaid on outpatient antifungal medications increased more slowly than did the growth of the Medicaid programs from 1991 to 2009. However, the utilization of antifungal agents for IFIs increased almost 10fold over this period, far outpacing the rise in the number of Medicaid beneficiaries. (Clin Ther. 2012; 34:2118–2131) © 2012 Elsevier HS Journals, Inc. All rights reserved. Key words: antifungal agents, antifungal drug utilization, invasive fungal infections, Medicaid, superficial fungal infections.

INTRODUCTION Fungi are microorganisms, ubiquitous in the environment, which, usually harmless, become opportunistic pathogens in certain individuals. Fungal infections can be classified broadly as life-threatening invasive fungal infections (IFIs) (eg, aspergillosis, candidiasis, histoplasmosis, cryptococcosis), which may affect the vital organs such as the heart, lungs, and brain, and superficial fungal infections (SFIs) (eg, tinea pedis, sporotrichosis, vulvovaginal candidiasis), which may affect the skin, hair, nails, genitalia, and mucosa. The incidence of IFIs has increased substantially over the recent past.1,2 Advances in medical technology, such as total parenteral nutrition, invasive moniThe data in this article were presented in poster format at the Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research, Baltimore, Maryland, May 2011. Accepted for publication September 6, 2012. http://dx.doi.org/10.1016/j.clinthera.2012.09.003 0149-2918/$ - see front matter © 2012 Elsevier HS Journals, Inc. All rights reserved.

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V.C.A. Desai et al. toring devices, and broad-spectrum antibiotics, may increase the risk for fungal infections.3 Adding to a growing population of susceptible hosts are immunocompromised individuals such as those with cancer, HIV/AIDS, and transplants, who, should they contract an IFI, have a mortality rate ranging from 40% to 85%.4 Amphotericin B deoxycholate was the first drug approved by the US Food and Drug Administration (FDA) for the treatment of IFIs, in the 1950s.5 It has a broad spectrum of activity and high efficacy and remained the mainstay of treatment for life-threatening IFIs for ⬎30 years; however, it has been associated with high rates of nephrotoxicity and infusion-related reactions (50%–90%).3 The introduction of the first azole antifungal agents, fluconazole in 1990 and itraconazole in 1992, substantially expanded the options for treatment.6 Later, between 1996 and 2000, new lipid preparations of amphotericin B, associated with fewer adverse reactions than amphotericin B deoxycholate, became available.7 In the last decade, echinocandins such as anidulafungin, caspofungin, and micafungin, as well as second-generation azoles such as posaconazole and voriconazole, with broad spectrums of activity and reduced adverse events, entered the antifungal market.8 –10 Flucytosine, first synthesized in 1957, is almost always used concurrently with another antifungal drug, usually amphotericin B deoxycholate, due to concerns over emerging resistance.11 It is used primarily to treat cryptococcosis but is also valuable for some cases of severe invasive aspergillosis.12 SFIs are the more common form of fungal infections. In most cases, SFIs are more easily treatable, although they can be difficult to cure. Tinea pedis, or athlete’s foot, affects ⬃70% of adults at least once in their lifetime.13 Uncomplicated vulvovaginal candidiasis, which affects 75% of women at least once in their lifetime, has cure rates ranging from 70% to 95% when treated with azole antifungals or nystatin.13 Complicated vulvovaginal candidiasis occurs in immunocompromised patients, and the cure rate in these patients ranges from 67% to 80%.14 Onychomycosis, an SFI of the nails, is the most difficult type of SFI to treat, having high treatment failure and recurrence rates, ranging from 20% to 50%.15,16 Oral terbinafine and itraconazole are the first-line agents for onychomycosis. Topical therapy includes ciclopirox nail lacquer.17,18 Oropharyngeal and esophageal candidiasis occurring among HIV/AIDS patients requires frequent courses of antifungal treatment, primarily with topical

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or oral azoles.19 –21 Nystatin, a widely used antifungal medication for SFIs and of bacterial origin, was isolated from Streptomyces noursei in 1950 and was patented in 1957.22 Cutaneous, vaginal, mucosal, and esophageal Candida are sensitive to nystatin23; however, due to the toxicity of nystatin, no intravenous formulations of nystatin have been approved for use in the United States.13 Ketoconazole, approved by the FDA in the 1980s as the first oral treatment of non–life-threatening systemic fungal infections, is now little used for systemic infections but is often used to treat dermatophytosis (ringworm) and is used as well for histoplasmosis, chromoblastomycosis, and paracoccidioidomycosis.24 Limited pharmacoeconomic analysis exists in the antifungal therapeutic area.25 One study reported that, in 2004, US $2 billion in annual hospital costs in the United States could be attributable to IFIs.26 In terms of the total cost of treatment, more expensive antifungal agents may be more cost-effective than lower-cost agents that are less effective and/or more toxic.27 Medicare and Medicaid are the 2 largest public payers for antifungal medications in the United States. Because Medicare Part D is relatively new (implemented in January 2006), a long-term trend in public spending on antifungals can be captured best by studying spending by Medicaid. Based on a literature search, no studies have reported the trends in the utilization and spending on antifungal agents. Accordingly, the aims of the present study were to assess the trends in utilization of, spending on, and prices for antifungal agents indicated for IFIs and SFIs in Medicaid beneficiaries. The results should be informative to health care providers and payers who must balance the efficacy, safety, and costs of antifungal medications on a daily basis.

METHODS A descriptive, retrospective data analysis was conducted using the publicly available National Summary Files from the Medicaid State Drug Utilization Data maintained by the Centers for Medicare & Medicaid Services (CMS), as part of the Medicaid Rebate Program, for the years 1991 to 2009.28 The database includes Medicaid beneficiaries from 49 states (all but Arizona), together with the District of Columbia. Each record in the database contains an 11-digit National Drug Code (NDC), drug name, year and quarter of Medicaid expenditure, number of pharmacy claims,

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Clinical Therapeutics number of units (eg, individual capsules, tablets), and total (prerebate) pharmacy reimbursement amount, including drug cost and dispensation fee. The first 5 digits of the NDC identify the drug manufacturer, and the remaining digits identify specific drug product by strength, dose formulation, and packaging. The database includes only outpatient prescriptions separately reimbursed by Medicaid as opposed to antifungal agents dispensed during patient hospitalizations. Antifungal agents, both branded and generic, were identified by name from an initial list obtained from eFacts.29 Adding up across all NDCs for a particular agent, subclass, and class (IFI or SFI), including oral, topical, and intravenous formulations, 19-year trends in the number of Medicaid prescriptions (utilization) and spending were determined. Although most of the individual drugs could be assigned easily to either the IFI or SFI class, some could not. Both oral and intravenous formulations of fluconazole and itraconazole were included in the IFI class, although these drugs may also be used for SFIs. Intravenous amphotericin B was included among the IFI antifungal agents, while topical amphotericin B was included with the SFI agents. Antifungal subclasses for the IFI agents included amphotericin B deoxycholate, lipid preparations of amphotericin B, first-generation azoles (fluconazole and itraconazole), second-generation azoles (posaconazole and voriconazole), and echinocandins (anidulafungin, caspofungin, and micafungin). Antifungal subclasses for the SFI agents included the azoles (butonazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, terconazole, and tioconazole), allyamines (butenafine, naftifine, and terbinafine), hydroxypyridines (ciclopirox), nonpolyenes (griseofulvin), and polyenes (amphotericin B topical and nystatin). The prices of antifungal agents were estimated as reimbursement divided by number of prescriptions for the NDC with the highest number of prescriptions reimbursed by Medicaid over the 19-year time period. For the SFI agents, prices per prescription of the mostprescribed oral and topical antifungal products were obtained. The specific NDCs for which prices were calculated are given in the Supplemental Appendix in the online version at http://dx.doi.org/10.1016/ j.clinthera.2012.09.003. Because reimbursement is for both drug cost and administration, reimbursement per prescription may vary substantially over time, especially for IV drugs, due to varying costs of

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administration. Because of the different types of antifungal products, the authors were reluctant to estimate an “average price” simply by dividing total reimbursement by the number of prescriptions. If they had, then a “price change” for a particular drug could represent either a true change in price (which the authors wanted to capture) or simply a different distribution of, for example, topical and oral prescriptions.

RESULTS The total number of Medicaid-reimbursed prescriptions for (branded and generic) antifungal agents for IFIs increased by 1377% (from 105,922 to 1.56 million prescriptions) from 1991 to 2004, after which it dropped back to 1.01 million prescriptions in 2009 (Table I). Total reimbursement for IFI antifungal agents similarly increased by 629% from 1991 to 2004 (from $17.44 million to $127.07 million), dropping back to $38.15 million at the end of the time period. Table I shows that, after rising during the early 1990s, the utilization of amphotericin B deoxycholate started to decline after the introduction of lipid preparations. The first-generation azoles commanded the highest market share in terms of both utilization and reimbursement over the study period. Starting in 2001, utilization of and spending on secondgeneration azoles and echinocandins began to rise. The most striking trend in Figure 1 is the rising utilization of branded fluconazole among Medicaid beneficiaries. In 2003, ⬃1.5 million prescriptions for branded fluconazole were reimbursed by Medicaid. Even in 2009, after the introduction of newer antifungal medications, there were still ⬃1 million prescriptions for generic fluconazole reimbursed by Medicaid. The rapid rise of branded voriconazole, a second-generation azole, beginning in 2002, is also evident in Figure 1, although the 9000⫹ prescriptions of this newer antifungal medication in 2005 (plotted along the righthand axis) still represent a small market share compared with branded and generic fluconazole. The branded echinocandin caspofungin had a similar steep growth path until 2005, with a steep dropoff over the last 4 years of the study period. At the end of the period, growth in the utilization of branded micafungin can also be detected. Similar to utilization, the Medicaid spending trend for IFI antifungals was dominated by branded fluconazole (Figure 2). In 2003, Medicaid spent $90 million on this drug alone. Following the

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October 2012 Table I. Utilization of and spending on antifungal drugs for invasive fungal infections by US Medicaid Programs: 1991–2009.28 Utilization, No. of Prescriptions

Year 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007储 2008 2009

Total

Amphotericin B Deoxycholate

105,922 197,046 302,370 352,033 514,868 717,080 770,289 834,331 872,817 1,041,302 1,293,770 1,393,909 1,540,374 1,564,832 1,307,342 1,007,332 1,006,416 1,005,499 1,011,700

2297 3995 4354 4664 6046 6076 4504 3389 3104 2584 2293 3124 1792 1653 1510 894 809 723 703

Spending, Current-Year US$ (in millions)

Flucytosine

FirstGeneration Azoles*

Lipid Amphotericin B†

SecondGeneration Azoles‡

328 490 552 574 799 806 778 562 498 376 387 374 358 263 206 105 112 119 77

103,297 192,561 297,464 346,795 508,023 709,520 763,685 828,077 866,667 1,035,863 1,287,902 1,384,966 1,526,483 1,548,019 1,289,188 992,455 991,252 990,048 996,887

— — — — — 678 1322 2303 2548 2479 2634 2765 2664 2431 2239 2035 1679 1323 1022

— — — — — — — — — — — 1165 6221 8266 9166 7689 8786 9882 8529

Echinocandins — — — — — — — — — — 554 1515 2856 4200 5033 4154 3779 3404 4482

§,储

Total

Amphotericin B Deoxycholate

17.44 34.39 53.33 59.42 70.70 88.65 86.44 91.85 94.94 96.76 105.75 109.82 124.58 127.07 70.12 44.23 43.93 43.63 38.15

0.16 0.67 0.83 0.85 0.52 0.64 2.22 2.05 1.43 1.27 0.37 0.19 0.18 0.23 0.29 0.14 0.20 0.25 0.08

Flucytosine

FirstGeneration Azoles*

Lipid Amphotericin B†

SecondGeneration Azoles‡

Echinocandins§,储

0.07 0.11 0.12 0.15 0.20 0.18 0.20 0.28 0.36 0.35 0.34 0.32 0.33 0.29 0.23 0.14 0.24 0.34 0.25

17.21 33.61 52.38 58.41 69.98 87.16 81.82 85.23 87.83 90.39 98.24 99.50 107.66 102.93 43.17 22.36 20.93 19.50 16.65

— — — — — 0.67 2.19 4.29 5.31 4.74 5.91 6.21 5.01 4.87 5.39 4.71 3.95 3.19 2.47

— — — — — — — — — — — 1.29 6.95 10.84 12.34 10.61 13.90 17.19 15.90

— — — — — — — — — — 0.89 2.30 4.46 7.91 8.71 6.27 4.72 3.17 2.81

*Includes fluconazole and itraconazole. Although classified as treatments of invasive fungal infections, both fluconazole and itraconazole are also used to treat superficial fungal infections. † Includes injectable formulations. ‡ Includes posaconazole and voriconazole. § Includes anidulafungin, caspofungin, and micafungin. 储 All 2007 values were estimated as the average of 2006 and 2008 values.

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1.6

10

No. of Prescriptions (in millions)

8 1.2 7 1.0

6 5

0.8

4

0.6

3 0.4 2 0.2 0

No. of Prescriptions (in thousands)

9

1.4

1 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007† 2008 2009 Fluconazole (branded) Itraconazole (generic) Micafungin*

Fluconazole (generic) Anidulafungin* Posaconazole*

0

Itraconazole (branded) Caspofungin* Voriconazole*

Figure 1. Utilization of specific antifungal agents for invasive fungal infections by US Medicaid programs, 1991– 2009.28 *Right-hand axis; †All 2007 values were estimated as the average of 2006 and 2008 values.

entry of generic fluconazole in 2004, spending on the branded formulation plummeted. In 2005, as seen in Figure 2, Medicaid spent ⬃$30 million on generic fluconazole and very little on the branded formulation. Meanwhile, however, spending on branded voriconazole reached $14 million in 2008. In Table II are estimated drug prices of the IFI antifungal drugs, calculated by dividing Medicaid reimbursement dollars by the number of prescriptions for the most highly utilized NDCs. In some years for some NDCs, there were very few prescriptions, leading to unreliable estimates. In addition, prices can vary substantially across drugs, depending on whether the formulation most prescribed over the study period was oral or intravenous. The price per prescription of (oral) branded fluconazole increased from $22 in 1994 to $33 in 2009 (a 50% increase), whereas that of (oral) generic fluconazole fell from $12 to a range of $8 to $10. The prices of both branded intravenous caspofungin and branded intravenous micafungin have decreased over time, whereas the price of branded intravenous itraconazole steadily increased from $174 to $838 from 1993 to 2009, with generic entry in 2005. The price per prescription of intravenous amphotericin

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B deoxycholate decreased gradually from $147 in 1991 to $47 in 2008, with an outlier price of $387 in 2001. Meanwhile, the lipid formulations of amphotericin B showed price stability (with an exception in 2006) around a price point of ⬃$1500. Compared with the numbers of prescriptions for IFI treatments, the numbers of prescriptions for SFIs were at least 4-fold during each of the 19 years from 1991 to 2009. Total utilization ranged from 4.45 million prescriptions in 1991 to 6.59 million prescriptions in 2004 (Table III). There were 3.50 million prescriptions reimbursed by Medicaid in 2009. The highest market share was held by the azoles; followed by the polyenes, primarily nystatin. In 1991, Medicaid spent $76.43 million on SFI antifungals. In 2009, it spent $105.61 million. Its peak spending was $277.92 million in 2004, over twice its spending on IFI antifungals for that same year. The highest share of spending was on the azoles throughout the period. Although the polyenes had the second highest spending in 2009, other subclasses were second highest at other times during the 2 decades. In 2008 and 2009, Medicaid spending figures on outpatient antifungal medications for IFIs and SFIs combined were $185.25 million and

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100

14

90 Spending (Current-Year US$ in millions)

12 80 10

70 60

8

50 6

40 30

4

20 2 10 $0

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007† 2008 2009 Fluconazole (branded) Itraconazole (generic) Micafungin*

Fluconazole (generic) Anidulafungin* Posaconazole*

$0

Itraconazole (branded) Caspofungin* Voriconazole*

Figure 2. Spending on specific antifungal agents for invasive fungal infections by US Medicaid programs, 1991–2009.28 *Right-hand axis; †All 2007 values were estimated as the average of 2006 and 2008 values.

$143.76 million, respectively. Compared with the ⬎$20 billion in Medicaid spending on outpatient drugs, spending on antifungals represents ⬃1.5% of its overall budget.30 For individual SFI agents, generic and branded prescriptions and spending were combined; in some cases, generic agents had several different brands. Among the antifungal agents for SFIs, nystatin was by far the most-utilized drug, with number of prescriptions ranging from 1.41 million to 2.55 million from 1991 to 2009 (Figure 3). In 2009, Medicaid beneficiaries utilized ⬃500,000 prescriptions each for branded and generic ketoconazole and clotrimazole—about one third of the utilization of nystatin that year. In 2009, Medicaid spent ⬃$20 million on nystatin and a similar amount on branded and generic griseofulvin (Figure 4). A large increase in spending on terbinafine by Medicaid can be seen in Figure 4. Whereas in 1992, Medicaid spent $3.11 million on terbinafine, it spent $75.24 million on this drug in 2004 —at least $30 million more than it spent on nystatin. By 2009, however,

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after generic entry, spending on terbinafine was less than what it was in 1993. Table IV shows per-prescription prices for the mostutilized oral and topical formulations of SFI antifungal agents. The branded oral formulations all exhibited rising prices over the study period. The price of branded griseofulvin rose 463% from 1991 to 2009, from $27 to $152. In 2005, generic entry occurred around the $90 price point. Meanwhile, the price of branded oral terbinafine rose from $155 in 1996 to $249 in 2009. Generic formulations of terbinafine, at less than one-tenth the price, were available from 2007 to 2009. All Medicaid spending values in the tables and figures are given in current dollars. Over the time period 1991 to 2009, the overall consumer price index (CPI) increased 57.52%, while the CPI–pharmaceuticals index increased 95.82%.31 Although many of the prices given in Tables II and IV do not show such high increases over the 2 decades, there are a few significant exceptions, including the 76.36% rise in the price of branded voriconazole, from $1235 in 2002 to $2178

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2124 Table II. Average spending per prescription for specific antifungal agents for invasive fungal infections by US Medicaid Programs, 1991–2009.*28 Values are in current-year US$. Fluconazole Year 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007† 2008 2009

Itraconazole

Amphotericin B Deoxycholate

Lipid Amphotericin B

Anidulafungin

Caspofungin

Flucytosine

Branded

Generic

Branded

Generic

Micafungin

Posaconazole

Voriconazole

147 147 143 148 85 90 78 59 59 80 387 84 79 78 30 28 38 47 —

— — — — — 994 1616 1739 1871 1728 1917 1695 1377 1544 1873 4176 2792 1408 1646

– — — — — — — — — — — — — — — — — 1028 766

– — — — — — — — — — 1797 1461 1583 1852 1735 1663 1591 1518 1373

246 254 248 287 279 258 287 497 780 950 927 211 2682 3158 105 — — — —

— — — 22 20 20 21 22 22 22 21 22 22 24 31 31 32 32 33

— — — — — — — — — — — — — 12 10 8 9 10 8

— — 174 193 224 228 226 249 284 313 344 378 416 455 513 553 620 686 838

— — — — — — — — — — — — — — 411 412 430 448 462

— — — — — — — — — — — — — — 1195 946 920 894 519

— — — — — — — — — — — — — — — 2211 2190 2168 2442

— — — — — — — — — — — 1235 1271 1447 1557 1661 1857 2053 2178

*Calculated for the most-utilized drug formulation (National Drug Code) for each of the antifungal drugs in Table II. † All 2007 values were estimated as the average of 2006 and 2008 values.

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October 2012 Table III. Utilization of and spending on antifungal drugs for superficial fungal infections by US Medicaid Programs: 1991–2009.28 Utilization, No. of Prescriptions (in thousands)

Spending, Current-Year US$ (in millions)

Year

Total

Azoles*

Allyamines†

Hydroxypyridines‡

Nonpolyenes§

Polyenes㛳

Total

Azoles*

Allyamines†

Hydroxypyridines‡

Nonpolyenes§

Polyenes㛳

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007¶ 2008 2009

4450 5549 6180 5999 5584 5605 5217 5071 4773 4799 5651 5963 6153 6592 5981 4144 5744 7343 3500

2640 3373 3736 3598 3330 3216 2875 2767 2633 2567 2690 2795 2690 2836 2502 1878 3604 5330 1548

12 21 127 218 219 282 348 405 366 278 356 392 415 468 418 237 202 167 155

168 179 170 139 112 96 79 66 64 140 289 388 474 438 402 188 147 107 102

197 262 306 320 307 298 258 229 216 224 238 243 271 295 266 227 208 190 183

1434 1714 1841 1725 1616 1713 1657 1604 1493 1589 2079 2145 2304 2555 2393 1614 1582 1549 1512

76.43 101.94 121.57 122.83 119.02 125.10 128.44 136.54 139.61 149.37 182.29 207.97 242.82 277.92 255.49 168.26 154.94 141.62 105.61

55.80 75.41 87.63 85.33 81.15 79.20 72.44 72.04 73.32 77.48 84.66 83.00 85.24 86.02 71.60 56.50 66.69 76.89 53.17

0.25 0.48 3.92 7.43 8.22 15.41 27.46 36.49 37.97 36.95 43.09 55.61 66.51 83.97 75.57 45.26 30.22 15.17 8.10

2.68 3.18 3.25 2.80 2.44 2.19 1.91 1.70 1.77 6.01 18.01 26.51 36.23 40.20 41.04 20.36 14.30 8.24 6.40

5.68 8.08 10.05 11.17 11.58 11.78 10.90 10.43 11.04 12.16 13.62 16.52 20.97 25.61 24.07 21.53 20.09 18.65 17.34

12.03 14.79 16.72 16.10 15.63 16.52 15.73 15.88 15.51 16.77 22.91 26.32 33.86 42.11 43.20 24.61 23.64 22.67 20.59

*Includes butonazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, terconazole, and tioconazole. Although classified as treatments of invasive fungal infections, fluconazole and itraconazole are also used to treat superficial fungal infections. Utilization of and spending on those agents are given in Table I. † Includes butenafine, naftifine, and terbinafine. ‡ Includes ciclopirox. § Includes griseofulvin. 㛳 Includes amphotericin B topical and nystatin. ¶ All 2007 values were estimated as the average of 2006 and 2008 values.

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2.75 2.50 No. of Prescriptions (in millions)

2.25 2.00 1.75 1.50 1.25 1.00 0.75 0.50 0.25 0

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007† 2008 2009 Clotrimazole Nystatin

Econazole Terbinafine

Griseofulvin Terconazole

Ketoconazole Other*

Miconazole

Figure 3. Utilization of specific antifungal agents for superficial fungal infections by US Medicaid programs, 1991–2009.28 Values represent combined branded-drug and generic prescriptions. *Includes branded and generic amphotericin B, butenafine, butoconazole, ciclopirox, naftifine, oxiconazole, sertoconazole, sulconazole, and tioconazole; †All 2007 values were estimated as the average of 2006 and 2008 values.

in 2009, and the 103.23% rise in the price of branded terbinafine, from $155 in 1996 to $315 in 2006, before generic entry.

DISCUSSION Utilization of antifungal agents for IFIs increased almost 10-fold over the 2 decades of the study period, from 0.11 million antifungal prescriptions in 1991 to 1.01 million prescriptions in 2009. Similar to the trends in Medicaid spending, utilization, and prices for other drug classes—such as antipsychotics,32 antiasthma medications,33 antidepressants,34 and antiHIV/AIDs drugs35—rising demand for antifungals is a key factor. The rise in available intravenous formulations for outpatients is unique to the antifungals, however. As described in the Introduction, advances in medical technology as well as the longer life spans of immunocompromised individuals translate to an increasing need for antifungal drugs. Another contributor to the increase in spending (and utilization) was the rise in the number of Medicaid beneficiaries. The average monthly enrollment in Medicaid in the year 1990

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was 22.9 million. In 2010, that figure reached 53.6 million (over one sixth of the US population), following the worst economic recession (December 2007 to June 2009) in a quarter century,36 representing a 134.1% increase in the number of beneficiaries. One event that caused an overall decrease in utilization and spending was the movement of the low-income elderly population, who were dually eligible for Medicaid and Medicare, from Medicaid to Medicare Part D following the implementation of Part D in 2006. Because elderly patients are at least as vulnerable as are younger patients to fungal infections due to compromised immune systems and multiple medical problems,37 the drop in utilization after 2006 may not be surprising. In 2004, with the entry of generic fluconazole, it would have been expected that fluconazole utilization would have continued on its upward path. However, fluconazole utilization decreased, while that of the echinocandins and second-generation azoles increased, suggesting that new antifungals may have offered meaningful improvements over earlier drugs. Although the most commonly encountered fungal infections

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Spending (Current-Year US$ in millions)

80 70 60 50 40 30 20 10 0

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007† 2008 2009 Clotrimazole Nystatin

Econazole Terbinafine

Griseofulvin Terconazole

Ketoconazole Other*

Miconazole

Figure 4. Spending on specific antifungal agents for superficial fungal infections by US Medicaid programs, 1991–2009.28 Values represent combined branded-drug and generic prescriptions. *Includes branded and generic amphotericin B, butenafine, butoconazole, ciclopirox, naftifine, oxiconazole, sertoconazole, sulconazole, and tioconazole; †All 2007 values were estimated as the average of 2006 and 2008 values.

have been and remain candidiasis, aspergillosis, and cryptococcosis,38 an emergence of strains and species with intrinsic and acquired resistance has been seen (eg, emergence of the azole-resistant non-albicans Candida, especially C krusei and C glabrata, and the emergence of the non-Aspergillus molds, eg, mucormycosis, zygomycosis, fusariosis).39 Moreover, the azoles inhibit the cytochrome P450 enzymes and cause drug– drug interactions with agents metabolized by these same enzymes. Hence, they must be used with caution in patients with HIV/AIDS who are on antiretrovirals as well as in patients with cancer who are on chemotherapeutic agents for malignancies.40 Hence, as the number of immunocompromised patients rises over time, more reliance on the nonazole agents is expected. As noted, antifungal resistance is a serious problem in clinical practice. In general, fungi can be intrinsically resistant to antifungal drugs (primary resistance) or can develop resistance in response to exposure to the drug during treatment (secondary resistance).41 It has been reported that C glabrata can be resistant to flu-

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conazole and that C krusei is intrinsically resistant to fluconazole. With respect to C albicans, the development of secondary resistance to fluconazole treatment has been most commonly encountered in HIV-infected patients with oropharyngeal candidiasis who are receiving prolonged treatment with fluconazole. Resistance to itraconazole has also been reported among these patients. The Aspergillus spp are intrinsically resistant to fluconazole as well.41 The lipid preparations of amphotericin B have a significantly reduced rate of nephrotoxicity relative to amphotericin B,42,43 and, at the end of the study period, were utilized more than was amphotericin B deoxycholate despite their much higher price. Voriconazole and posaconazole are available for oral administration for the treatment of IFIs and are used prophylactically in patients with neutropenic fever.44 Hence, despite their high price, their use increased significantly compared with that of other agents. Against invasive aspergillosis, initial therapy with voriconazole was found in a large clinical trial to have been associated with improved survival, with fewer severe adverse

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Oral Formulations Clotrimazole Year

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1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007† 2008 2009

Griseofulvin

Topical Formulations Nystatin

Terbinafine

Clotrimazole

Nystatin

Terbinafine

Branded Generic Branded Generic Branded Generic Branded Generic Branded Generic Branded Generic Branded Generic 41 44 47 48 49 49 51 58 60 63 63 64 59 88 61

87 77 78 76 75 67

27 29 32 34 38 41 45 50 57 61 66 74 84 95 105 121 128 140 152

9 10 12 14 16 30 22 17 16 14

94 93 92 91 86

6 6 6 9 10 12 12 21 27 31 32 31 28 26

155 166 180 197 207 210 233 245 265 285 315 374 433 249

21 42 18

13 14 14 15 17 20 20 20 21 22 24 20 21 20 17 28 14

16 16 16 16 16 16 16 20 21 16 18 19 18 21 20 20 19

*Values calculated for the most-utilized drug formulation (National Drug Code) for each of the antifungal drugs in this table. † All 2007 values were estimated as the average of 2006 and 2008 values.

21 23 24 25 26 27 27 29 33 36 37 36 38 39 41 32 27 23 20

6 6 6 6 6 6 6 6 7 7 7 7 7 7 7 7 7 8 7

20 22 23 24 25 25 26 28 29 31 33 35 38 42 44 46 47

17 18 17 17 16 17 17 16 16 15 15

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2128 Table IV. Average spending per prescription for selected specific antifungal agents for superficial fungal infections by US Medicaid Programs: 1991–2009.*28 Values are in current-year US$.

V.C.A. Desai et al. events than with initial therapy with amphotericin B.8 Moreover, posaconazole is the only drug that acts against the fungi that cause mucormycosis (zygomycosis).45 Echinocandins have efficacy comparable to that of amphotericin B deoxycholate and have a favorable adverse-events profile, with minimal drug– drug interactions. Moreover, they act against both the Candida and Aspergillus spp.10,46 These may be the reasons for the rapid increase in the utilization of the echinocandins. Antifungal agents for SFIs are available in various formulations, such as creams, lotions, ointment, suspension, powder, lozenges, and tablets. Many products for SFIs are available over the counter (which Medicaid generally reimburses47), and many are used prophylactically. Oral drugs are prescribed when the milder fungal infections are refractory to treatment with topical drugs. Although fluconazole and itraconazole are classified as treatments of IFIs, these agents are also used for SFIs, such as mucocutaneous candidiasis, oropharyngeal candidiasis, dermatophytoses, and onychomychosis.13 Topical and oral azoles are used for the treatment of mucocutaneous, oropharyngeal, and esophageal candidiasis,13 while terbinafine and itraconazole are the first-line options for onychomychosis.15,48 Clotrimazole, fluconazole, nystatin, and itraconazole are the drugs most often used for vulvovaginal candidiasis.13 Because of concerns over hepatotoxicity, ketoconazole is less preferred for mucosal fungal infections.49 How drug prices are determined is a topic beyond the scope of this study, although a healthy literature exists.50,51 That extremely high prices characterize newer branded drugs, whereas generically manufactured drugs are much less expensive, is not unique to the antifungal therapeutic class. Cost relief is generally obtained only after the patents on branded drugs expire.32–35 Although, in principle, cost- and comparative-effectiveness studies could advise patients, physicians, and payers as to the value of, for example, a second-generation azole or echinocandin over an older antifungal drug, the pharmacoeconomic literature related to antifungal agents remains sparse.25 Because of the high cost of some of the newer drugs, it is hoped that the results presented here will provide some impetus for future pharmacoeconomic analysis. This study had a number of limitations. First, patient-specific information was not available from the

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database; thus, it was not possible to determine indication for medication use. Adherence to medication therapy could not be assessed. One interesting question is whether the utilization of antifungal agents among Medicaid beneficiaries has been appropriate, excessive, or insufficient. Unfortunately, the data cannot answer this question either. Second, as with all database studies, misclassification bias may be present if the CMS data contain reporting errors. For 2007, many of the spending and utilization values had coding errors. To ensure data reliability, all 2007 values in this study were imputed. Third, all data are prerebate and so they may overestimate to some degree (that we cannot measure) the actual acquisition cost to US Medicaid programs. Fourth, the authors did not use the quarterly data available from Medicaid; because of relatively large quarterly fluctuations in the utilization of and spending on antifungal drugs, the authors chose to present the smoother annual trends. Finally, results are specific to the Medicaid population. Low-income Medicaid beneficiaries comprise ⬃20% of the US population. However, their age and sex distributions differ substantially from those of the general US population, with higher proportions of women and children. In Medicaid in 2007, females accounted for 58% of recipients, and children accounted for 48%.52 Hence, to the extent that fungal infections are distributed differently between the sexes and across age groups, this study does not reflect general national trends.

CONCLUSIONS Overall spending by Medicaid on outpatient antifungal medications increased from $93.9 million in 1991 to $143.76 million in 2009, a relatively modest increase compared with the growth of the Medicaid program over the same period of time. Utilization of antifungal agents for IFIs increased almost 10-fold over the 2 decades of the study period, far outpacing the rise in the number of Medicaid beneficiaries.

ACKNOWLEDGMENTS The authors are very appreciative of the comments and suggestions provided by their colleague Kelly E. Caudle and by 2 anonymous referees for this journal. Ms. Desai, Dr. Kelton, and Dr. Guo designed the study. Ms. Desai assembled the data, performed the literature review, conducted the statistical analysis, and wrote the first version of the manuscript. Dr.

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Clinical Therapeutics Kelton provided guidance on methods and statistics and edited the manuscript. Dr. Cavanaugh provided valuable comments on antifungal classification and resistance. Dr. Heaton edited the manuscript.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article.

SUPPLEMENTAL MATERIAL A supplemental appendix accompanying this article can be found in the online version at doi: http://dx. doi.org/10.1016/j.clinthera.2012.09.003.

REFERENCES 1. Hobson R. The global epidemiology of invasive Candida infections—is the tide turning? J Hosp Infect. 2003;55:159 – 168. 2. Garbino J, Kolarova L, Rohner P, et al. Secular trends of candidemia over 12 years in adult patients at a tertiary care hospital. Medicine. 2002;81:425– 433. 3. Enoch D, Ludlam H, Brown N. Invasive fungal infections: a review of epidemiology and management options. J Med Microbiol. 2006;55:809 – 818. 4. Pfaller MA, Pappas PG, Wingard JR. Invasive fungal pathogens: current epidemiological trends. Clin Infect Dis. 2006; 43(Suppl 1):S3–S14. 5. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Clin Infect Dis. 1990;12:308 – 329. 6. Maertens J. History of the development of azole derivatives. Clin Microbiol Infect. 2004;10:1–10. 7. Lister J. Amphotericin B lipid complex (Abelcet) in the treatment of invasive mycoses: the North American experience. Eur J Haematol. 1996;56(Suppl 57):18 –23. 8. Herbrecht R, Denning D, Patterson T, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408 – 415. 9. Perfect J, Marr K, Walsh T, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis. 2003;36:1122–1131. 10. Denning D. Echinocandin antifungal drugs. Lancet. 2003; 362:1142–1151. 11. Papon N, Noël T, Florent M, et al. Molecular mechanism of flucytosine resistance in Candida lusitaniae: Contribution of the FCY2, FCY1, and FUR1 genes to 5-fluorouraciland fluconazole cross-resistance. Antimicrob Agents Chemother. 2007;51:369 –371. 12. Vermes A, Guchelaar H-J, Dankert J. Flucytosine: A review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000;46:171–179.

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V.C.A. Desai et al. 29. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; March 2005. 30. Centers for Medicare & Medicaid Services. National Health Expenditures by Type of Service and Source of Funds, CY 1960-2009. https:// www.cms.gov/NationalHealthExpend Data/02_NationalHealthAccounts Historical.asp#TopOfPage. Accessed June 25, 2012. 31. Bureau of Labor Statistics. Consumer Price Index. All Urban Consumers (CPI-U). US City Average. ftp://ftp.bls.gov/pub/special.requests/ cpi/cpiai.txt. Accessed June 25, 2012. 32. Jing Y, Kelton CML, Guo JJ, et al. Price, utilization, and spending for antipsychotic medications in the Medicaid program. Drug Benefit Trends. 2007;19:27– 41. 33. Chiu S-F, Kelton CML, Guo JJ, et al. Utilization, spending, and price trends for long-acting beta agonists and inhaled corticosteroids in the U.S. Medicaid program from 1991 to 2010. Am Health Drug Benefits. 2011;4:140 –149. 34. Chen Y, Kelton CML, Jing Y, et al. Utilization, price, and spending trends for antidepressants in the US Medicaid program. Res Social Administrative Pharm. 2008;4:244 –257. 35. Jing Y, Klein P, Kelton CML, Li X, Guo JJ. Utilization and spending trends for antiretroviral medications in the U.S. Medicaid program from 1991 to 2005. http:// www.aidsrestherapy.com/content/ 4/1/22. Accessed June 25, 2012. 36. Centers for Medicare & Medicaid Services. Data Compendium, 2010. http://www.cms.gov/Data Compendium/14_2010_Data_ Compendium.asp#TopOfPage. Accessed June 25, 2012. 37. Kauffman CA, Yoshikawa TT. Fungal infections in older adults. Clin Infect Dis. 2001;33:550 –555. 38. Azie N, Neofytos D, Pfaller M, et al. The PATH (Prospective Antifungal

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Address correspondence to: Christina M. L. Kelton, PhD, University of Cincinnati, Carl H. Lindner College of Business, 414 Lindner Hall, 2925 Campus Green Drive, PO Box 210195, Cincinnati, OH 45221– 0195. E-mail: [email protected]

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Supplemental Appendix. Top-prescribed antifungal products by National Drug Code. Drug Invasive fungal infections Amphotericin B (IV) Amphotericin B deoxycholate Lipid amphotericin B Anidulafungin (IV) Caspofungin (IV) Fluconazole (oral) Branded Generic Itraconazole (IV) Branded Generic Micafungin (IV) Posaconazole (IV) Voriconazole (IV) Superficial fungal infections Clotrimazole Oral Branded Generic Topical Branded Generic Griseofulvin (oral) Branded Generic Nystatin Oral Branded Generic Topical Branded Generic Terbinafine Oral Branded Generic Topical Branded Generic

Code

00469233090 61799010141 00049011528 00006382210 00049350079 00172541211 50458029004 00185055030 00469325010 00085132801 00049318030

00026309555 00054414622 00085061302 51672127502 00062020604 10147081004

00003045735 00677061301 00003059320 00603148149

00078017046 00067399885 00078017915 00067399885

IV ⫽ intravenous.

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