Association of a Risk Evaluation and Mitigation Strategy Program With Transmucosal Fentanyl Prescribing

William Fleischman,Doris Auth,Joseph S Ross,Nilay D Shah,Shantanu Agrawal

doi:10.1001/jamanetworkopen.2019.1340

Abstract

Transmucosal immediate-release fentanyl (TIRF) drugs are potent, rapid-acting opioids approved to treat breakthrough pain in patients with cancer who are tolerant to other around-the-clock opioid analgesics. In March 2012, a US Food and Drug Administration-approved Risk Evaluation and Mitigation Strategy (REMS) was implemented, mandating prescribers, distributors, pharmacies, and patients to enroll in the REMS to prescribe, dispense, or receive TIRF drugs. To evaluate the association of the TIRF-REMS Access Program with TIRF prescribing. Cohort study using an interrupted time series analysis of TIRF prescriptions to Medicare Part D beneficiaries nationwide from 2010 to 2014. Data were analyzed from August 2017 through July 2018. Prescribing of TIRF per 100 000 Medicare Part D beneficiaries, overall and stratified by cancer status; percentage of TIRF prescriptions for patients without cancer, overall and by brand; and percentage of TIRF prescriptions for patients without known opioid tolerance, defined as patients prescribed at least 60 morphine milligram equivalents per day, overall and by brand. There were 99 601 TIRF prescriptions written by 8619 clinicians to 10 472 patients. Most of the patients (79%) were younger than 65 years (mean [SD] age, 56 [13] years), and most (67%) did not have cancer. Implementation of TIRF-REMS was associated with a 26.7% relative level decrease in TIRF prescribing (95% CI, -33.3% to -19.4%; P < .001) but was followed by 2.0% monthly increases in prescribing (95% CI, 1.3% to 2.7%; P < .001). Sensitivity analyses that accounted for overall opioid prescribing trends were consistent with these findings. Furthermore, there were no significant changes associated with REMS implementation in the level (0.47%; 95% CI, -5.36% to 4.69%; P = .85) or trend (0.16%; 95% CI, -0.06% to 0.37%; P = .15) of the percentage of prescriptions for patients without cancer. However, a sensitivity analysis that used a broader cancer definition found implementation was associated with a 7.2% (95% CI, -13.5% to -0.48%; P = .04) level decrease in the percentage of TIRF prescriptions for patients without cancer. Lastly, the TIRF-REMS was associated with a 22.5% level decline in the percentage of TIRF prescriptions for patients without known opioid tolerance (95% CI, -36.1% to -5.95%; P = .01) followed by 1.98% monthly decreases (95% CI, -3.19% to -0.80%; P = .001). Implementation of the TIRF-REMS Access Program, a restrictive drug distribution program, was associated with a temporary reduction in the rate of TIRF prescribing to Medicare Part D beneficiaries, and with a sustained decrease in the percentage of TIRF prescriptions for patients without known opioid tolerance. Implementation may have also been associated with a temporary decrease in the percentage of TIRF prescriptions for patients without cancer.

Highlights

Drug overdoses were the leading cause of accidental death in the United States in 2016.1 The opioid overdose epidemic has been attributed, in part, to a rapid increase in opioid analgesic prescribing in the period between 1990 and 2010.2 After peaking in 2012, US opioid analgesic prescribing rates have decreased slightly,[3] the amount prescribed in 2015 was still approximately 3 times as high as in 1999.4Transmucosal immediate-release fentanyl (TIRF) products are potent, rapid-acting opioid analgesics only approved for use for breakthrough pain in patients with cancer who are already receiving and who are known to be tolerant to around-the-clock opioid analgesics
Implementation of TIRF-Risk Evaluation and Mitigation Strategy (REMS) was associated with a 26.7% relative level decrease in TIRF prescribing but was followed by 2.0% monthly increases in prescribing
Implementation of the TIRF-REMS Access Program, a restrictive drug distribution program, was associated with a temporary reduction in the rate of TIRF prescribing to Medicare Part D beneficiaries, and with a sustained decrease in the percentage of TIRF prescriptions for patients without known opioid tolerance

Summary

Introduction

Transmucosal immediate-release fentanyl (TIRF) products are potent, rapid-acting opioid analgesics only approved for use for breakthrough pain in patients with cancer who are already receiving and who are known to be tolerant to around-the-clock opioid analgesics. Reports have suggested there is substantial off-label prescribing of TIRF products.[5,6] To address their growing use and potential harms, the US Food and Drug Administration (FDA) has required TIRF manufacturers to institute programs to restrict prescribing and promote appropriate opioid prescribing and safe use of opioid analgesics, including Risk Evaluation and Mitigation Strategies (REMS). Under the TIRF-REMS, prescribers and pharmacists are required to complete an educational program, patients must be enrolled and are required to sign an agreement attesting to their understanding of the risks and safe use of TIRFs, and distributors are required to agree to ship TIRF products only to enrolled pharmacies. The association of TIRF-REMS with TIRF prescribing has, to our knowledge, not been previously described

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