Anthony Palmieri, RPh, PharmD

Gout is a rheumatic disease affecting nearly 3.9% (8.3 million) of adults in the United States, with men almost 40% more likely to beafflicted than women.

 Hyperuricemia, or elevated uric acid levels greater than 6.8 mg/dL, which result in the formation of monosodium urate crystals in joint tissues, is the primary cause of gout.

 Gout initially presents as an acute episode of arthritis, most commonly beginning in the metatarsalphalangeal joint at the base of the big toe.

 Risk factors for gout include lifestyle-related behaviors such as alcohol use and consumption of purine-rich foods, in particular organ meats and oily fishes.

Medical conditions including obesity, diabetes, and renal insufficiency contribute to the risk of gout, as do medications such as diuretics and chemotherapeutic agents.

 The treatment goals for acute and chronic gout differ, as do the medications used in each setting (

The goal of treatment for an acute episode of gout is pain relief through reduction of inflammation.

 This is often achieved by the use of over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs), prescription corticosteroids, or colchicine. For patients with chronic gout, the goal of treatment is to reduce the frequency of painful episodes by reducing and maintaining uric acid concentrations of less than 6 mg/dL using a combination of nonpharmacological interventions (ie, dietary and lifestyle changes) and pharmacological agents.

The American College of Rheumatology (ACR) has recommended first-line pharmacologic prophylaxis with a xanthine oxidase inhibitor (XOI), such as allopurinol or febuxostat, along with low-dose colchicine or an NSAID in treatment of chronic gout.

 Probenecid, a uricosuric, is recommended as an alternative first-line agent when either allopurinol or febuxostat is contraindicated or when a patient has demonstrated intolerance to at least 1 of the first-line agents.

 The ACR further designated the combination of an XOI and a uricosuric as a second-line treatment in refractory disease. A newer therapeutic option, pegloticase, is a recombinant uricase reserved as a third-line agent in cases of refractory disease where a patient has failed or was not able to tolerate an appropriately dosed oral urate-lowering therapy. Pegloticase is administered biweekly by infusion in a healthcare setting.

Until recently the cost of medication for the treatment of chronic gout was relatively low, with the monthly cost for a single medication ranging from $18 to $100, depending on disease severity and duration.

 However, treatment of chronic gout may require multiple medications, and the combined economic burden has been estimated by some investigators to be over $200 per month.

 The cost associated with gout therapies is poised to increase dramatically due to federal policy decisions and pipeline developments. In June 2006, the US Food and Drug Administration (FDA) initiated a new drug safety proposal to remove medications, such as colchicine, from the market that previously had not been required to demonstrate safety or efficacy.12 In order to incentivize evaluation of medications impacted by this initiative, the FDA offered marketplace exclusivity to companies that conducted the necessary safety and efficacy studies.

 In 2007, URL Pharma, a maker of generic medications (since acquired by Takeda Pharmaceutical Company Limited), conducted clinical trials to examine the efficacy of colchicine and identify the smallest efficacious dose for the treatment of gout.

 A lower-dose regimen with an incidence of adverse events similar to placebo was identified and in 2009 the manufacturer was granted 3 years of marketplace exclusivity for their colchicine formulation, Colcrys.

Following this approval, the FDA mandated the removal of all unapproved single-ingredient oral colchicine products from the market resulting in an unintended increase in the cost of treatment from pennies per day to nearly $5 per day.

This report will examine the prevalence of prescription medications utilized in the treatment of gout. In addition, the influence of Colcrys on utilization and cost of treatment for gout will be analyzed. Finally, the current status and economic consequence of recently launched and pipeline medications used for the treatment of gout will be discussed.

This descriptive analysis was conducted using de-identified CVS Caremark pharmacy claims data. Adult members who had a pharmacy claim in calendar years from 2009 to 2012 for at least 1 of the medications primarily used for the treatment of gout were selected for analysis. The medications considered were: colchicine, febuxostat, pegloticase, colchicine with probenecid, and allopurinol. Age and gender were based upon that reported for the last claim for each member. The generic dispensing rate (GDR) and cost per utilizer per day were also calculated. For this analysis, “cost” is defi ned as the total paid charges for the medication (the payer and member portions combined). The descriptive analyses were conducted using SAS 9.1 (SAS Institute, Cary, North Carolina).  

 A total of 955,356 unique members were identified with a pharmacy claim for at least 1 gout medication. This reflects a prevalence of 1.5% among adult members, which remained stable over the observation period (2009-2012). The average age of members with gout was 62.8 years (standard deviation ±14.2) and 75.9% of members utilizing prescription gout medications were male. The prevalence of gout varied by payer type (Figure 1), and as would be expected due to their older age, gout was more common among members in Medicare plans than members in other plans. Members in Medicaid plans had the lowest prevalence of gout. This is likely an artifact of coverage policies for prescription medications for treatment of gout in these plans and the high prevalence of young women and children among Medicaid beneficiaries.

The prevalence of use of prescription gout medications is illustrated in Table 2. Allopurinol had the highest utilization, with nearly 80% of members taking this medication, while colchicine was taken over by 30% of members. Since the introduction of branded colchicine (Colcrys), as well as the removal of generic versions, the use of colchicine has declined over 5 points. A steady year to year increase in market share for febuxostat is seen since its introduction in February 2009. There were very few claims paid for pegloticase over the 4-year period. Given the route of administration for this medication, claims for pegloticase would most likely be paid under the member’s medical benefit rather than the pharmacy benefit, and as a consequence would not be included in the data set.

In 2009, the combined GDR for prescription gout medications was nearly 99%. With the withdrawal of generic colchicine from the market and the introduction of febuxostat, the combined GDR declined to 78% by 2012. The impact on the combined GDR of the FDA’s decision  to grant marketplace exclusivity to Colcrys is illustrated in 

. The GDR fell in 2010 and 2011 as pharmacy inventories of generic colchicine were depleted and by 2012 it had fallen to 0.3%. During this period, the cost per unit increased from $0.17 to $4.53. This was accompanied by an increase in the annual cost of treatment with colchicine on a per user per year basis from $27 to $560.

The average cost per unit of medications prescribed for the treatment of gout is summarized in 

. In addition to the dramatic increase in the cost of colchicine there was an increase in the cost of febuxostat, while the cost of the other gout medications remained constant. The extremely high cost for pegloticase is based upon a limited number of claims, but is consistent with the stated cost of the medication and dosing schedule.

 Nonetheless, the magnitude of the estimate for pegloticase provides evidence of the potential impact specialty medications may have on the cost of treatment for gout in the future.

Summary of Findings and Impact of Pipeline Medications

Gout is a relatively common rheumatic disease affecting over 8 million adults in the United States.

 Based upon the prevalence of medication utilization in this analysis we estimate that approximately 3.6 million adults in the United States are taking prescription medications for gout. Until recently, these prescription medications for the treatment of gout were relatively inexpensive. However, this has been reversed because of 2 factors: 1) the unintended consequence of policy decisions; and 2) the recent launch of additional gout therapies.

The intended result of the FDA Unapproved Drug Initiative was to provide FDA oversight, as well as guidance on indications, dosing, and drug interactions for medications that previously had not demonstrated evidence of safety and efficacy.

 However, in the case of colchicine the Initiative has had the unintended consequence of a 21-fold increase in the cost of medication (Table 3). According to the results, 28.5% of members receiving prescription medications for the treatment of gout were on colchicine in 2012 (Table 2). Extrapolating this to the national health budget would indicate that the annual burden to the US healthcare system of treatment with colchicine in 2012 is more than $540 million larger than it was in 2009. The higher cost of colchicine may have also put access to the medication beyond the reach of some members, indicated by a reduction in its use from 33.9% in 2009 to 28.5% in 2012. This would indicate that in 2012 approximately 194,000 people with gout who would otherwise have been taking colchicine either switched to an alternative gout medication or fell off of therapy—each of which represents a shift in the treatment burden to the member that should be recognized.

These data allows estimation of the increased cost for pharmacy benefit plans that has resulted from the policy change in colchicine and the introduction of febuxostat. There has been an estimated increase of $0.26 per member per month (PMPM) to cover prescription treatment of gout since 2009 (from $0.06 to $0.32 PMPM). Of this increase, $0.18 per member per month PMPM (71%) is due to the increased cost of colchicine, and $0.08 PMPM (28%) is due to the introduction of febuxostat. The cost associated with other gout treatments was relatively fl at or declined

Due to a lack of data, the role of pegloticase or forthcoming specialty medications in infl uencing the cost of care of members with gout could not be evaluated. Claims for pegloticase, similar to other infused products, are rarely part of the pharmacy benefi t. However, it is estimated that 3% of patients with gout do not respond to existing therapies and thus would benefi t from pegloticase.

 Therefore, while the impact of pegloticase was not captured in this study, its impact could be substantial.

 suggests, there continues to be a strong interest in the development of new medications for the treatment of gout. The pending medication approvals include both oral medications with existing mechanisms of action, and new mechanisms of action and an injectable medication. The oral medications lesinurad, ulodesine, and arhalofenate are being studied in patients who are unable to achieve target serum urate levels on allopurinol or febuxostat alone. Since the utilization of other medications such as diuretics can contribute to hyperuricemia, lesinurad is being studied in a population that takes these medications concurrently. Arhalofenate may offer additional benefi ts such as decreased triglycerides and blood glucose along with its urate-lowering effects. The injectable medication in the pipeline is an interleukin-1 (IL-1) inhibitor, canakinumab, which is currently approved for the treatment of children with autoinflammatory cryopyrin-associated periodic syndromes and seeking a supplemental indication for the symptomatic relief of gout fl ares refractory to other treatments.25 While the pipeline refl ects possible therapies for those with comorbidities and for refractory members, the introduction of additional branded and specialty therapies may result in a continued increase in the cost of care.

This study has demonstrated that both the decisions of policy makers and innovations in treatment will impact the cost of treatment for diseases such as gout that have traditionally been low in cost. Decisions concerning a single medication, colchicine, have resulted in a 5-fold increase in the PMPM cost for treatment of gout with prescription medications. At this point there are not enough data to quantify the impact of current or upcoming specialty medications on the cost to pharmacy or medical plans for the treatment of gout, but these medications promise to present a continuing challenge for plan administrators. Therefore, it will be more important thanever to continue to look for ways to manage the rising cost of care. Utilization management tools such as prior authorization, step therapy, or medical carve outs will help to ensure that the use of these expensive therapies is appropriate and cost-effective.

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With new drugs in the pipeline and the impact of updated FDA drug safety policies on colchicine, gout may no longer be inexpensive to treat.