Association Between FDA Black Box Warnings and Medicare Formulary Coverage Changes

ABSTRACT

Objectives: To assess whether Medicare formularies restrict access to drugs receiving new FDA black box warnings for which safer drug alternatives are available.

Study Design: A retrospective analysis using Medicare Prescription Drug Plan Formulary files to determine formulary changes for drugs receiving FDA black box warnings between 2007 and 2013.

Methods: We identified all FDA-approved medications available in tablet or capsule formulation that received a black box warning between 2007 and 2013 related to death and/or cardiovascular risk. We then determined formulary coverage of these drugs pre-black box warning, 1 year after, and 2 years after. For each formulary, we identified formulary restrictiveness, defined as: unrestrictive coverage (no prior authorization or step therapy), restrictive coverage (prior authorization or step therapy required), or no coverage.

Results: Nine drugs with at least 1 FDA-approved safer drug alternative received 10 new black box warnings for death and/or cardiovascular risk between 2007 and 2013. In response to FDA black box warnings, overall formulary restrictiveness increased for 40% (n = 4) of drugs at 1 year, and for 50% (n = 5) at 2 years. However, for the majority of drugs (n = 7), most formularies remained unrestrictive 2 years after a new black box warning.

Conclusions: Medicare formularies became more restrictive for half of the drugs that recently received new FDA black box warnings for death and/or cardiovascular risk and for which safer drug alternatives are available. However, a substantial proportion of formularies remained unrestrictive, suggesting inconsistent responses to new safety information to curtail the use of these medications.

Am J Manag Care. 2017;23(9):e310-e315

Takeaway Points

The impact of FDA black box warnings on formulary restrictiveness is not well known. This study investigated whether Medicare formulary coverage changed after oral drugs with safe available drug alternatives received new FDA black box warnings related to death and/or cardiovascular risk.

• Some formularies either dropped coverage or began requiring prior authorization to restrict the prescribing of unsafe drugs.
• A substantial proportion of formularies made no changes to restrict coverage.
• There are opportunities to improve consistency in formulary responses to FDA black box warnings to curtail utilization of drugs with known safety risks and for which safer drug alternatives are available.

The FDA requires that drugs with serious or life-threatening risks have a boxed warning (commonly referred to as a “black box warning” [BBW]) on their label. The BBW is one of the FDA’s strongest actions short of drug recall or withdrawal, and is intended to inform patients and prescribers about serious safety concerns that must be considered in assessing the risks and benefits of a drug or that the FDA allows use of the drug only with restrictions to ensure safe use. However, BBWs have not been consistently associated with reduced prescribing^1-3 for several possible reasons. First, prescribers may be unaware that the FDA had issued the warnings.^1,4,5 Second, prescribers may think that, despite BBWs, the drugs have a superior benefit/risk ratio to alternative therapies or that the safety concern is not as severe as suggested, and opt to continue prescribing while using strategies to mitigate risk, such as closer patient monitoring.^1,4,6-8 Third, BBWs may apply only to limited patient populations, and prescribers may not believe the risk applies more generally.

Another possibility is that BBWs are not taken into account within insurance plan drug formularies. Formularies limit prescribing of unsafe drugs through 2 strategies: formulary exclusion (ie, no coverage) or utilization management (eg, prior authorization or step therapy). One study found no change to state Medicaid plans’ prior authorization requirements following the 2005 BBW for atypical antipsychotic use among the elderly,⁹ and another found that only 2 state Medicaid programs restricted use after the 2007 BBW for rosiglitazone.¹⁰ To better understand the potential role that insurance plan drug formularies may play in restricting the use of potentially unsafe drugs that have safer available alternatives, we characterized changes to Medicare formularies for oral drugs that received new BBWs between 2007 and 2013 for death and/or cardiovascular risk. As these are among the most severe adverse events, we hypothesized that they would have the greatest likelihood of resulting in formulary changes to restrict use. Because each BBW is specific to the drug’s indications and risk, we focused on a limited sample to provide an illustrative summary of formulary changes.

METHODSData Source

We conducted a retrospective analysis of Medicare formularies using data from the CMS Prescription Drug Plan Formulary Files. We obtained data on both standalone prescription drug plans and Medicare Advantage prescription drug plan formularies for Medicare Part D, as of each June and December from 2006 through 2015.

Sample

We used the FDA’s MedWatch website to identify all FDA-approved tablet or capsule formulation medications used in an outpatient setting that received BBWs between 2007 and 2013 related to death and/or cardiovascular risk. MedWatch is the agency’s safety information and adverse event reporting program. We examined all BBWs and first excluded those for drugs used in-hospital only or not relevant to Medicare beneficiaries. We also excluded BBWs for combination drugs, since the primary drug would already be included in our sample. Next, we excluded BBWs for cancer, HIV, or immunosuppressants as these are protected classes treating diseases that require specialized pathways of care. We also excluded warnings for a narrow subset of patients and warnings related to drug-drug interactions. Lastly, we limited our study to drugs with at least 1 drug alternative without a BBW approved for use for the same primary condition, based on the US Pharmacopeial Convention Category & Class versions 5.0 and 6.0. When a drug had multiple BBWs, each warning was considered a unique event.

Formulary Restrictiveness

Our main outcome was formulary restrictiveness based on formulary exclusion, step therapy, or prior authorization. For each drug’s lowest available dose, we classified all Medicare formularies as unrestrictive, restrictive, or no coverage at 3 time points: immediately preceding, at least 1 year after, and at least 2 years after the BBW. An unrestrictive formulary covered the drug without prior authorization or step therapy requirements. A restrictive formulary covered the drug but required either prior authorization and/or step therapy. A formulary that did not explicitly provide coverage did not include the drug on its formulary, which means patients are responsible for the entire drug cost except in very rare circumstances.

Statistical Analyses

We used descriptive statistics to characterize the proportion of formularies that were unrestrictive, restrictive, and did not provide coverage for each drug at all 3 time points. We used χ² or Fischer’s Exact tests to examine differences in formulary restrictiveness for each drug, comparing restrictiveness pre-BBW to restrictiveness at both 1 year and 2 years afterward. All statistical tests were 2-tailed with a type 1 error rate of 0.025 to account for multiple comparisons for each drug.

RESULTS

Nine medications in a tablet or capsule formulation received a total of 10 new BBWs related to death and/or cardiovascular risk between 2007 and 2013 and had at least 1 drug alternative without a BBW. Four of the 9 drugs (44%) had existing BBWs before the FDA issued BBWs between 2007 and 2013. Seven (70%) of the 10 BBWs were related to death and 5 (50%) to cardiovascular risk (2 related to both cardiovascular risk and death). Two BBWs, those for propylthiouracil and ketoconazole, specifically advised against use of the given medication except in very unique circumstances.

Two years after each of the 10 new BBWs, for 5 (50%) drugs, Medicare formularies became more restrictive, on average, by removing coverage or adding prior authorization requirements. There was no overall increase in step therapy requirements. For 1 (10%) drug, formularies became less restrictive on average and for 4 (40%) drugs there was no overall change in average formulary restrictiveness. When restricting to the 4 drugs with prior BBWs, results were overall similar: Medicare formularies became more restrictive for 2 (50%) drugs at both 1 and 2 years.

Rosiglitazone

Rosiglitazone is approved to improve glycemic control for type 2 diabetes. In August 2007, thiazolidinediones, a medication class that includes rosiglitazone and pioglitazone, received a BBW for congestive heart failure. Prior to this BBW, 78% (n = 255) of formularies provided unrestrictive coverage, 19% (n = 62) provided restrictive coverage, and 3% (n = 10) provided no coverage. There was no significant change in formulary restrictiveness at 1 or 2 years (Figure).

Prior to its strengthened February 2011 BBW for a significantly increased risk of myocardial infarction, 57% (n = 148) of formularies provided unrestrictive coverage, 36% (n = 94) provided restrictive coverage, and 7% (n = 18) provided no coverage. At 1 year, rates were 32%, 36%, and 32%, respectively (P <.001) (Figure), suggesting that formularies had become significantly more restrictive. Changes in restrictiveness were due to fewer formularies providing coverage and covering formularies requiring prior authorization (Table).

Pioglitazone

Pioglitazone is approved to improve glycemic control for type 2 diabetes. Prior to its August 2007 BBW for congestive heart failure, 67% (n = 220) of formularies provided unrestrictive coverage, 19% (n = 62) provided restrictive coverage, and 14% (n = 45) provided no coverage. At 1 year, rates were 73%, 27%, and 0%, respectively (P <.001) (Figure), suggesting that formularies had become significantly less restrictive. Changes in restrictiveness were predominantly due to more formularies providing coverage.

Zyban (buproprion)

Zyban is approved for smoking cessation. Prior to its July 2009 BBW for serious neuropsychiatric events, including suicide, 24% (n = 75) of formularies provided unrestrictive coverage, 5% (n = 11) provided restrictive coverage, and 73% (n = 232) provided no coverage. There was no significant change in formulary restrictiveness at 1 year (Figure). At 2 years, rates were 19%, 0%, and 80%, respectively (P = .006), suggesting that formularies had become significantly more restrictive. Changes in restrictiveness were predominantly due to fewer formularies providing coverage.

Varenicline

Varenicline is approved for smoking cessation. Prior to its July 2009 BBW for serious neuropsychiatric events including suicide, 60% (n = 191) of formularies provided unrestrictive coverage, 21% (n = 68) provided restrictive coverage, and 19% (n = 59) provided no coverage. At 1 year, rates were 51%, 49%, and 0%, respectively (P <.001) (Figure). Changes in restrictiveness were predominantly due to more formularies requiring prior authorization (Table).

Quinine

Quinine is approved for malaria treatment, although it was widely used for nocturnal leg cramps. Prior to its November 2009 BBW explaining that use for nocturnal leg cramps could result in life-threatening hematological reactions, 60% (n = 159) of formularies provided unrestrictive coverage, 18% (n = 56) provided restrictive coverage, and 32% (n = 103) provided no coverage. There was no significant change in formulary restrictiveness at 1 year (Figure). At 2 years, rates were 41%, 27%, and 31%, respectively (P = .012), suggesting that formularies had become significantly more restrictive. Changes in restrictiveness were predominantly due to more formularies requiring prior authorization (Table).

Propylthiouracil

Propylthiouracil is approved for treatment of hyperthyroidism. Prior to its April 2010 BBW for potentially fatal liver failure, stating propylthiouracil was only indicated in patients intolerant of methimazole, 100% (n = 292) of formularies provided unrestrictive coverage. There was no significant change in formulary restrictiveness at 1 or 2 years (Figure).

Dronederone

Dronedarone is approved for treatment of paroxysmal or persistent atrial fibrillation or atrial flutter but included a BBW contraindicating its use in patients with advanced heart failure. Prior to its additional December 2011 BBW contraindicating its use in patients with permanent atrial fibrillation because of cardiovascular risk, 82% (n = 199) of formularies provided unrestrictive coverage, 9% (n = 22) provided restrictive coverage, and 9% (n = 23) provided no coverage. At 1 year, rates were 72%, 10%, and 18%, respectively (P <.001) (Figure), suggesting that formularies had become significantly more restrictive. Changes in restrictiveness were predominantly due to fewer formularies providing coverage. At 2 years, rates were 80%, 8%, and 12%, respectively (P = .63), suggesting that changes in formulary restrictiveness had reversed, as more formularies began covering the drug again.

Dantrolene

Dantrolene is approved for treatment of chronic spasticity. In July 2012, its prior BBW on fatal and nonfatal hepatotoxicity was updated to note that a higher proportion of hepatic events had fatal outcomes in elderly patients, although the majority of these cases were complicated by confounding factors. Prior to the addition to this BBW, 88% (n = 242) of formularies provided unrestrictive coverage, 0% (n = 11) provided restrictive coverage, and 12% (n = 34) provided no coverage. There was no significant change in formulary restrictiveness at 1 or 2 years (Figure).

Ketoconazole

Ketoconazole is approved as an antifungal therapy. Previous BBWs had been issued for QT prolongation and hepatotoxicity. Prior to the July 2013 BBW stating that the drug should only be used when other effective antifungal therapy was not available or tolerated, 100% (n = 314) of formularies provided unrestrictive coverage. At 1 year, 84% of formularies provided unrestrictive coverage, 16% provided restrictive coverage, and 1% provided no coverage (P <.001) (Figure), suggesting that formularies had become significantly more restrictive. Changes in restrictiveness were predominantly due to more formularies requiring prior authorization (Table).

DISCUSSION

After 10 new BBWs were issued by FDA between 2007 and 2013 for death and/or cardiovascular risk among 9 tablet or capsule drugs with safer available drug alternatives, we observed that Medicare formularies became somewhat, but not universally, more restrictive at 1 and 2 years afterward. Formularies sometimes removed coverage and/or implemented prior authorization requirements to deter the use of drugs with new safety warnings. However, a substantial number of formularies continued to provide unrestrictive coverage for these drugs after the FDA’s strong safety warning. Providing unrestrictive coverage when other effective but safer drug alternatives are available suggests that formularies are not taking advantage of existing utilization management strategies to promote the use of safer available alternative medications, thus unnecessarily exposing some Medicare beneficiaries to risky medications. There were no consistent patterns in the drugs for which BBWs were not associated with increased formulary restrictiveness.

CMS instructs its contracting Part D sponsor formularies to consider drug safety and efficacy when making decisions about which drugs to include on formularies.¹¹ Further, although changes are generally constrained once the coverage year begins, CMS specifically allows formularies to add utilization management tools at any time after a new FDA BBW and allows these unsafe drugs to be removed without meeting advance notice requirements.¹¹

Limitations

First, our conclusions are limited to BBWs related to death and/or cardiovascular risk. Second, our analysis excluded drugs in a non-tablet or capsule formulation and those without safer available drug alternatives. Third, we did not examine changes in Medicare formulary tier, which is a strategy most likely to be used to impose cost-sharing requirements and limit the use of expensive, as opposed to unsafe, therapies. Fourth, our data may not be generalizable to formularies of insurers other than Medicare. Nevertheless, our findings provide important insights into the role of formulary policy because Medicare beneficiaries represent the largest proportion of insured patients using prescription medications. Finally, we did not examine the impact of formulary changes at the plan level or on prescriptions dispensed. Ultimately, linking formulary restrictiveness after BBWs to patient outcomes would help inform future formulary management decisions.¹²

CONCLUSIONS

Medicare formularies increased restrictions to some drugs with new FDA BBWs for death and/or cardiovascular risk. Although this indicates important action, a substantial portion of formularies provided unrestrictive drug coverage 1 and 2 years afterward. Increasing the use of formulary exclusion or restrictiveness for drugs that receive BBWs could help curtail prescriptions of unsafe medications when safer drug alternatives exist.

Acknowledgments

The authors are grateful to Patrick Gleason, PharmD, for his thoughtful suggestions on an earlier version of this manuscript. Dr Gleason did not receive any compensation for his assistance.Author Affiliations: Robert Wood Johnson Foundation Clinical Scholars Program (SSD, JSR), and Section of General Internal Medicine, Department of Internal Medicine (JSR), Yale School of Medicine (DLS), New Haven, CT; Cardiology, VA Connecticut Healthcare System (SSD), West Haven, CT; Carlson School of Management, University of Minnesota (PK-M), Minneapolis, MN; Division of Health Care Policy & Research, Mayo Clinic (NDS), Rochester, MN; Center for Outcomes Research and Evaluation, Yale-New Haven Hospital (JSR), New Haven, CT; Department of Health Policy and Management, Yale University School of Public Health (JSR), New Haven, CT.

Source of Funding: This project was supported in part by the Robert E. Leet and Clara Guthrie Patterson Trust Awards Program in Clinical Research, Bank of America, N.A., Trustee. Dr Dhruva is supported by the Robert Wood Johnson Foundation Clinical Scholars Program and the Department of Veterans Affairs.

Author Disclosures: Drs. Shah and Ross receive support through Yale University and the Mayo Clinic, respectively, from the Food and Drug Administration (FDA) as part of the Centers for Excellence in Regulatory Science and Innovation (CERSI) program. Dr Ross receives support through Yale University from the Centers of Medicare and Medicaid Services (CMS) to develop and maintain performance measures that are used for public reporting, from Johnson and Johnson to develop methods of clinical trial data sharing, from Medtronic, Inc, and the Food and Drug Administration (FDA) to develop methods for postmarket surveillance of medical devices, from the Blue Cross Blue Shield Association to better understand medical technology evaluation, and from the Laura and John Arnold Foundation. Dr Karaca-Mandic provides consulting services to Tactile Medical and Precision Health Economics. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. The sponsor played no role in the design of the study, analysis or interpretation of findings, or drafting the manuscript and did not review or approve the manuscript prior to submission. The authors assume full responsibility for the accuracy and completeness of the ideas presented.

Authorship Information: Concept and design (SSD, PK-M, NDS, DLS, JSR); acquisition of data (SSD, DLS, JSR); analysis and interpretation of data (SSD, PK-M, NDS, DLS, JSR); drafting of the manuscript (SSD, PK-M); critical revision of the manuscript for important intellectual content (SSD, PK-M, NDS, DLS, JSR); statistical analysis (SSD); obtaining funding (JSR); and supervision (JSR).

Address Correspondence to: Sanket S. Dhruva, MD, MHS, 333 Cedar St, SHM I-456, Box 208088, New Haven, CT 06520-8088. E-mail: sanket.dhruva@yale.edu. REFERENCES

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