Economic Impact of Fidaxomicin on CDI Treatment in United States

PATHOGENESIS

Clostridium difficile infection (CDI) has progressively grown in incidence, and virulence, throughout North America and Europe.^1,2 The C difficile bacterium, a grampositive, anaerobic, spore-forming bacillus, can induce infections from a number of sources, including hospitalization, antibiotic use, and direct personal contact.^1,2 CDI presentation can range from mild asymptomatic diarrhea to severe toxic megacolon and fulminate colitis.^1,2 In the past decade a novel hypervirulent strain of C difficile, termed the North American Pulsed Field type 1 (NAP1), restriction endonuclease analysis type BI, or polymerase-chain-reaction ribotype 027 strain, has been identifi ed and studied.^3,4 The NAP1/BI/027 strain of C difficile is hallmarked by its ability to produce a binary toxin CDT, as well as its propensity to produce excessive amounts of enterotoxins A and B, relative to non- NAP1/BI/027 strains of C difficile.^3,4 The exact impact of this novel strain has not been clearly illuminated within the literature, with some researchers postulating that its presence may lead to a more severe infectious process, although more recent literature suggests that this may not be the case.^5,6

Current Guidelines in the Management of CDI

The 2010 consensus guidelines jointly published by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America provide guidance in the management of CDI in the adult patient.⁷ From these guidelines the management of CDI is separated into 2 broad categories, 1) mild to moderate and 2) severe, based on patient-specific characteristics. The current recommended treatment modality for either a first occurrence, or first recurrence, of mild to moderate CDI is oral metronidazole. Metronidazole has been a preferred agent in the management of mild to moderate CDI given its relative ease of administration, and cost, compared with oral vancomycin, combined with its high rate of clincal cure. The same high rates of clinical cure have not been consistently demonstrated when treating recurrent and/or severe CDI, and thus the use of oral vancomycin in these clinical situations is preferred. Furthermore, the potential for neurotoxicity with prolonged use of metronidazole further limits its use in these situations.

Fidaxomicin

The pharmacologic management of CDI had largely remained unchanged over the past 20 years, until May 2011 when fidaxomicin (Dificid) was approved for use by the FDA. Fidaxomicin is currently approved for the management of mild to moderate CDI in adult patients older than 18 years at a dose of 200 mg orally, twice daily for 10 days.⁸ However, this approval came after the most recent version of the practice guidelines for the management of CDI in adult patients was published.⁷ As such the exact role of fidaxomicin was not clarified within this publication.

In addition to fidaxomicin, the only other FDA-approved agent in the management of CDI is oral vancomycin (Vancocin).⁹ Despite not being FDA-approved, oral metronidazole (Flagyl) has long been recommended for use in mild to moderate CDI by consensus guidelines.⁷ Furthermore, in recent years a number of agents have been evaluated in the management of CDI, including tigecycline, intravenous immunoglobulin, and rifaximin, though none have gained FDA approval and all are often reserved for severe or refractory cases. With this, one can see that the pharmacologic options for the management of CDI are limited, thus placing providers and decision makers in a unique place regarding the use of fidaxomicin.

Fidaxomicin’s Spectrum of Activity

Fidaxomicin is a narrow spectrum macrocyclic antibiotic that is produced via the fermentation of Dactylosporangium aurantiacum, and is manufactured by Optimer Pharmaceuticals.^8,10 C difficile is primarily targeted by fidaxomicin within the GI tract. Fidaxomicin acts to disrupt bacterial synthesis by inhibiting DNA transcription.⁵ Current in vitro literature has demonstrated that the minimum inhibitory concentration required to kill 90% of C difficile bacteria (MIC90) for fidaxomicin is equal to 0.125 μg/mL. This MIC90 is 4 dilutions lower than that for metronidazole and vancomycin, each having a reported MIC90 of 0.5 μg/mL.¹¹ Thus, it has been suggested that fidaxomicin may be more effective at eradicating C difficile bacteria compared with metronidazole and vancomycin.¹¹ Additionally, fecal concentrations of fidaxomicin are high, with almost no appreciable drug reaching the systemic system.¹²

In spite of increased reports highlighting the progressive rates of resistance to macrolide antibiotics, there have been no reported cases of resistance with fidaxomicin to date. Furthermore, several known mechanisms of resistance such as macrolide efflux pumps and mutations have been studied and found not to confer resistance at this time.¹³ Moreover, the use of oral metronidazole and vancomycin have been associated with increased rates of vancomycinresistant enterococci (VRE).¹⁴ The development of VRE associated with fidaxomicin use have been reported to occur, but when compared with vancomycin these rates were statistically lower (7% [fidaxomicin] versus 33% [vancomycin]; P <.001).¹⁴ Thus, researchers have theorized that the use of fidaxomicin may result in lower rates of colonization against VRE, as well as reduced rates of recurrent CDI compared with oral metronidazole and vancomycin.

Clinical Data

Two large, prospective, multicenter, randomized, non-inferiority trials enrolling over 1000 adult subjects have evaluated the use of fidaxomicin compared with vancomycin in the management of mild to moderate CDI.^15,16 In each study fidaxomicin was dosed at 200 mg twice daily and compared with oral vancomycin 125 mg 4 times daily, each for a total of 10 days. Fidaxomicin was found to be non-inferior to oral vancomycin in producing a clinical cure of CDI in both studies, 88.2% (fidaxomicin) versus 85.8% (vancomycin), and 87.8% (fidaxomicin) versus 86.8% (vancomycin), respectively.^15,16 P values were not reported as part of either study for this outcome. Additionally, the rate of recurrence for fidaxomicin was found to be statistically lower when compared with vancomycin, 12.7% versus 26.9% (97.5% confidence interval [CI], —21.4 to –6.8; P <.001).¹⁵ Furthermore, in a composite study of all subjects from each phase III trial, fidaxomicin produced a higher rate of a clinical cure compared with vancomycin in patients requiring concomitant antibiotics, 90.0% versus 79.4%, respectively [95% CI, 0.23%-20.3%; P = .04].¹⁷ Lastly, it has been reported that fi daxomicin has been well tolerated and its adverse effect profi le is similar to that of vancomycin.¹⁵

From these data one can see that the use of fidaxomicin provides no worse of a treatment option compared with oral vancomycin, and in certain instances as outlined above, provides a more favorable option. The current literature does not contain any comparison against metronidazole, nor does it assess the effectiveness of fidaxomicin in severe CDI. The lack of reported literature within each of these areas limits the generalizability of fidaxomicin use in a wider patient population than those described above.

Pharmacoeconomic Considerations

To date there have been no published pharmacoeconomic evaluations of fidaxomicin. The current average wholesale price for fidaxomicin is $135 per 200 mg tablet, compared with $31.81 per 125 mg capsule of vancomycin, and $0.72 per 500 mg tablet of metronidazole.¹⁸ Also, many institutions compound oral vancomycin solution extemporaneously using intravenous vancomycin, further confounding this pricing difference. However, despite these differences in price, fidaxomicin has made significant inroads within the US market over the past 6 months. In a press release provided by Optimer Pharmaceuticals in January 2012, the manufacturer stated that over the last 3 months of 2011, a total of 4675 dosage units of fidaxomicin were shipped to hospital, retail, and long-term care pharmacies, compared with 2505 dosage units shipping from July to September 2011.¹⁹

Additionally, the manufacturer stated that fi daxomicin had been added to the formulary of at least 450 US-based hospitals by the end of 2011, with an increase of 30% in acceptance over the last 6 weeks of 2011.¹⁹ Optimer Pharmaceuticals also reported that fidaxomicin is currently available as a covered option by the top 5 commercial pharmacy benefit managers (PBMs) and 4 of the 5 top Medicare PBMs, as well as stating that the pricing structure for fidaxomicin is similar to that of oral vancomycin on these plans.¹⁹ The Table details the current PBM coverage of fidaxomicin within the United States at the time of writing. It should be noted that the coverage for fidaxomicin is subject to change at any time, and this table may not reflect state-specific coverage. However, from this information one can see that the potential for use of fidaxomicin is expanding in a number of arenas, both inpatient and outpatient.

Place in Therapy

Since its recent approval, fidaxomicin has been gaining use in the management of CDI, despite a lack of comparator data against metronidazole and having a limited indication. Ho wever, its use in recurrent CDI is one of the more promising areas for consideration, particularly based on the favorable results demonstrated within the published clinical trials. Another area of fidaxomicin use, which is actively being pursued by the manufacturer, is as a prophylactic agent against the development of CDI, particularly in immunosuppressed patients.

While the actual impact on PBMs cannot be fully known, one may anticipate minimal impact given the current lack of superiority data between the currently available agents, and the favorable cure rates associated with mild to moderate CDI with metronidazole treatment. Additionally, as fidaxomicin requires prior authorization and/or clinical review prior to approval with many of the surveyed plans, further layers of review may limit its use to only a small subset of potential candidates in the outpatient setting. However, as there are currently no recommendations for prophylactic agents against the development of CDI, should fidaxomicin receive FDA approval for this indication, this would represent a potentially large area of increased cost to payers and institutions.

One potential area where fidaxomicin may have its largest financial impact is on hospital budgets. Fidaxomicin has the potential to be utilized with increasing frequency for patients who have failed oral vancomycin therapy in the management of relapsing or recurrent CDI. These patients, given the nature of their disease, may require hospitalization, even for a short period of time. Thus, many institutions may bear the majority of the cost for fidaxomicin usage.

While the development of novel antibiotic classes is welcomed, their role in management of disease states with long-standing treatment options may not initially be clear. The current place for fidaxomicin remains largely in question. Further comparative evaluation for superiority, not only with oral vancomycin, but also with metronidazole, would help to elucidate this matter. In the absence of these data, the use of fidaxomicin may remain restricted to those patients who have not had success in the management of CDI using the currently recommended agents of metronidazole and vancomycin.